X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.2. The cerebral demyelinating form of X-ALD Cerebral ALD is the most severe phenotype of X-ALD.A newborn male with an ABCD1 gene mutation has a 35-40% risk to develop cerebral ALD between the ages of 5 and 12 years.As mentioned above, 20% of adult AMN males are also at risk to develop cerebral ALD.Overall, for male X-ALD patients the lifetime risk to develop cerebral ALD, either in childhood or in adulthood, is around 60%.There is an age-related correlation with the onset of cerebral ALD and disease progression: the earlier the onset of cerebral demyelination, the more rapid the progression of the disease.Patients are neurologically unaffected until they develop cerebral demyelination visible on brain MRI (as abnormal hypersignal of white matter on T2 and FLAIR sequences, hyposignal of white matter on T1 sequences) [1,12,13].Usually the initial lesions involve either the splenium of the corpus callosum and then extend into the adjacent white matter of the parietooccipital lobes (Fig. 1A) or alternatively the genu of the corpus callosum and then extend into the white matter of the frontal lobes.Initial demyelinating lesions may also occur in the pyramidal tracts, within the brainstem or internal capsule (Fig. 1B) and then extend into the centrum semiovale (frontal white matter).The cerebral demyelinating lesions can be asymmetric, particularly when previous head trauma or even stroke seems to have initiated the onset of cerebral ALD.Initially, the demyelinating lesions are not inflammatory (based on absence of lesion enhancement on T1 sequences after peripheral injection of gadolinium) and progress slowly.The patients have virtually no neurologic symptoms, except sometimes mild cognitive dysfunctions.Suddenly, the disease becomes inflammatory (with evidence of demyelinating lesion enhancement after peripheral injection of gadolinium) and at this stage the disease starts to progress rapidly.The patients enter then into an active phase of devastating neurologic and cognitive deterioration that includes emotional lability, hyperactive behavior, school failure for boys, and either visuospatial impairment or frontal syndrome according to the sites of cerebral demyelinating lesions.This cognitive deterioration is rapidly associated with neurologic deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures.Eventually, a vegetative state ensues within two to five years leading to death at varying intervals thereafter.Approximately 65% of children or adults with cerebral ALD have adrenocortical insufficiency that can precede the onset of neurologic symptoms for years or decades. About 10% of boys with cerebral ALD may not enter into the active inflammatory and devastating stage of the disease.The same may occur in adult males with cerebral ALD.This phenotype is often referred to as "chronic or arrested cerebral X-ALD".With white matter lesions involving either the parieto-occipital or the frontal white matter, these patients end up developing marked visual-spatial or executive cognitive deficits, but without significant neurological or sensory (visual, auditive) symptoms.After an initial progression of the demyelinating lesions that often result in loss of myelin and ventricular dilatation and cortical atrophy, the patient can remain stable for a decade or even longer.But a full progression to the inflammatory stage remains possible, even after 10 to 15 years without progression of cerebral demyelination.Electrophysiological tests are useless for the early diagnosis of cerebral ALD as brainstem visual evoked responses become abnormal only in the advanced stage of the disease.The occurrence of childhood cerebral ALD in females is exceptional.It is hypothesized and partially supported by laboratory studies that the few girls who developed CCALD had skewed X-inactivation toward the X-chromosome carrying the mutated ABCD1 gene (Kemp, unpublished data).

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.2. The cerebral demyelinating form of X-ALD Cerebral ALD is the most severe phenotype of X-ALD.A newborn male with an ABCD1 gene mutation has a 35-40% risk to develop cerebral ALD between the ages of 5 and 12 years.As mentioned above, 20% of adult AMN males are also at risk to develop cerebral ALD.Overall, for male X-ALD patients the lifetime risk to develop cerebral ALD, either in childhood or in adulthood, is around 60%.There is an age-related correlation with the onset of cerebral ALD and disease progression: the earlier the onset of cerebral demyelination, the more rapid the progression of the disease.Patients are neurologically unaffected until they develop cerebral demyelination visible on brain MRI (as abnormal hypersignal of white matter on T2 and FLAIR sequences, hyposignal of white matter on T1 sequences) [1,12,13].Usually the initial lesions involve either the splenium of the corpus callosum and then extend into the adjacent white matter of the parietooccipital lobes (Fig. 1A) or alternatively the genu of the corpus callosum and then extend into the white matter of the frontal lobes.Initial demyelinating lesions may also occur in the pyramidal tracts, within the brainstem or internal capsule (Fig. 1B) and then extend into the centrum semiovale (frontal white matter).The cerebral demyelinating lesions can be asymmetric, particularly when previous head trauma or even stroke seems to have initiated the onset of cerebral ALD.Initially, the demyelinating lesions are not inflammatory (based on absence of lesion enhancement on T1 sequences after peripheral injection of gadolinium) and progress slowly.The patients have virtually no neurologic symptoms, except sometimes mild cognitive dysfunctions.Suddenly, the disease becomes inflammatory (with evidence of demyelinating lesion enhancement after peripheral injection of gadolinium) and at this stage the disease starts to progress rapidly.The patients enter then into an active phase of devastating neurologic and cognitive deterioration that includes emotional lability, hyperactive behavior, school failure for boys, and either visuospatial impairment or frontal syndrome according to the sites of cerebral demyelinating lesions.This cognitive deterioration is rapidly associated with neurologic deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures.Eventually, a vegetative state ensues within two to five years leading to death at varying intervals thereafter.Approximately 65% of children or adults with cerebral ALD have adrenocortical insufficiency that can precede the onset of neurologic symptoms for years or decades. About 10% of boys with cerebral ALD may not enter into the active inflammatory and devastating stage of the disease.The same may occur in adult males with cerebral ALD.This phenotype is often referred to as "chronic or arrested cerebral X-ALD".With white matter lesions involving either the parieto-occipital or the frontal white matter, these patients end up developing marked visual-spatial or executive cognitive deficits, but without significant neurological or sensory (visual, auditive) symptoms.After an initial progression of the demyelinating lesions that often result in loss of myelin and ventricular dilatation and cortical atrophy, the patient can remain stable for a decade or even longer.But a full progression to the inflammatory stage remains possible, even after 10 to 15 years without progression of cerebral demyelination.Electrophysiological tests are useless for the early diagnosis of cerebral ALD as brainstem visual evoked responses become abnormal only in the advanced stage of the disease.The occurrence of childhood cerebral ALD in females is exceptional.It is hypothesized and partially supported by laboratory studies that the few girls who developed CCALD had skewed X-inactivation toward the X-chromosome carrying the mutated ABCD1 gene (Kemp, unpublished data).

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.3. Other X-ALD phenotypes

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§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.2. The cerebral demyelinating form of X-ALD Cerebral ALD is the most severe phenotype of X-ALD.A newborn male with an ABCD1 gene mutation has a 35-40% risk to develop cerebral ALD between the ages of 5 and 12 years.As mentioned above, 20% of adult AMN males are also at risk to develop cerebral ALD.Overall, for male X-ALD patients the lifetime risk to develop cerebral ALD, either in childhood or in adulthood, is around 60%.There is an age-related correlation with the onset of cerebral ALD and disease progression: the earlier the onset of cerebral demyelination, the more rapid the progression of the disease.Patients are neurologically unaffected until they develop cerebral demyelination visible on brain MRI (as abnormal hypersignal of white matter on T2 and FLAIR sequences, hyposignal of white matter on T1 sequences) [1,12,13].Usually the initial lesions involve either the splenium of the corpus callosum and then extend into the adjacent white matter of the parietooccipital lobes (Fig. 1A) or alternatively the genu of the corpus callosum and then extend into the white matter of the frontal lobes.Initial demyelinating lesions may also occur in the pyramidal tracts, within the brainstem or internal capsule (Fig. 1B) and then extend into the centrum semiovale (frontal white matter).The cerebral demyelinating lesions can be asymmetric, particularly when previous head trauma or even stroke seems to have initiated the onset of cerebral ALD.Initially, the demyelinating lesions are not inflammatory (based on absence of lesion enhancement on T1 sequences after peripheral injection of gadolinium) and progress slowly.The patients have virtually no neurologic symptoms, except sometimes mild cognitive dysfunctions.Suddenly, the disease becomes inflammatory (with evidence of demyelinating lesion enhancement after peripheral injection of gadolinium) and at this stage the disease starts to progress rapidly.The patients enter then into an active phase of devastating neurologic and cognitive deterioration that includes emotional lability, hyperactive behavior, school failure for boys, and either visuospatial impairment or frontal syndrome according to the sites of cerebral demyelinating lesions.This cognitive deterioration is rapidly associated with neurologic deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures.Eventually, a vegetative state ensues within two to five years leading to death at varying intervals thereafter.Approximately 65% of children or adults with cerebral ALD have adrenocortical insufficiency that can precede the onset of neurologic symptoms for years or decades. About 10% of boys with cerebral ALD may not enter into the active inflammatory and devastating stage of the disease.The same may occur in adult males with cerebral ALD.This phenotype is often referred to as "chronic or arrested cerebral X-ALD".With white matter lesions involving either the parieto-occipital or the frontal white matter, these patients end up developing marked visual-spatial or executive cognitive deficits, but without significant neurological or sensory (visual, auditive) symptoms.After an initial progression of the demyelinating lesions that often result in loss of myelin and ventricular dilatation and cortical atrophy, the patient can remain stable for a decade or even longer.But a full progression to the inflammatory stage remains possible, even after 10 to 15 years without progression of cerebral demyelination.Electrophysiological tests are useless for the early diagnosis of cerebral ALD as brainstem visual evoked responses become abnormal only in the advanced stage of the disease.The occurrence of childhood cerebral ALD in females is exceptional.It is hypothesized and partially supported by laboratory studies that the few girls who developed CCALD had skewed X-inactivation toward the X-chromosome carrying the mutated ABCD1 gene (Kemp, unpublished data).

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > Abstract

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§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.2. The cerebral demyelinating form of X-ALD Cerebral ALD is the most severe phenotype of X-ALD.A newborn male with an ABCD1 gene mutation has a 35-40% risk to develop cerebral ALD between the ages of 5 and 12 years.As mentioned above, 20% of adult AMN males are also at risk to develop cerebral ALD.Overall, for male X-ALD patients the lifetime risk to develop cerebral ALD, either in childhood or in adulthood, is around 60%.There is an age-related correlation with the onset of cerebral ALD and disease progression: the earlier the onset of cerebral demyelination, the more rapid the progression of the disease.Patients are neurologically unaffected until they develop cerebral demyelination visible on brain MRI (as abnormal hypersignal of white matter on T2 and FLAIR sequences, hyposignal of white matter on T1 sequences) [1,12,13].Usually the initial lesions involve either the splenium of the corpus callosum and then extend into the adjacent white matter of the parietooccipital lobes (Fig. 1A) or alternatively the genu of the corpus callosum and then extend into the white matter of the frontal lobes.Initial demyelinating lesions may also occur in the pyramidal tracts, within the brainstem or internal capsule (Fig. 1B) and then extend into the centrum semiovale (frontal white matter).The cerebral demyelinating lesions can be asymmetric, particularly when previous head trauma or even stroke seems to have initiated the onset of cerebral ALD.Initially, the demyelinating lesions are not inflammatory (based on absence of lesion enhancement on T1 sequences after peripheral injection of gadolinium) and progress slowly.The patients have virtually no neurologic symptoms, except sometimes mild cognitive dysfunctions.Suddenly, the disease becomes inflammatory (with evidence of demyelinating lesion enhancement after peripheral injection of gadolinium) and at this stage the disease starts to progress rapidly.The patients enter then into an active phase of devastating neurologic and cognitive deterioration that includes emotional lability, hyperactive behavior, school failure for boys, and either visuospatial impairment or frontal syndrome according to the sites of cerebral demyelinating lesions.This cognitive deterioration is rapidly associated with neurologic deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures.Eventually, a vegetative state ensues within two to five years leading to death at varying intervals thereafter.Approximately 65% of children or adults with cerebral ALD have adrenocortical insufficiency that can precede the onset of neurologic symptoms for years or decades. About 10% of boys with cerebral ALD may not enter into the active inflammatory and devastating stage of the disease.The same may occur in adult males with cerebral ALD.This phenotype is often referred to as "chronic or arrested cerebral X-ALD".With white matter lesions involving either the parieto-occipital or the frontal white matter, these patients end up developing marked visual-spatial or executive cognitive deficits, but without significant neurological or sensory (visual, auditive) symptoms.After an initial progression of the demyelinating lesions that often result in loss of myelin and ventricular dilatation and cortical atrophy, the patient can remain stable for a decade or even longer.But a full progression to the inflammatory stage remains possible, even after 10 to 15 years without progression of cerebral demyelination.Electrophysiological tests are useless for the early diagnosis of cerebral ALD as brainstem visual evoked responses become abnormal only in the advanced stage of the disease.The occurrence of childhood cerebral ALD in females is exceptional.It is hypothesized and partially supported by laboratory studies that the few girls who developed CCALD had skewed X-inactivation toward the X-chromosome carrying the mutated ABCD1 gene (Kemp, unpublished data).

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.2. The cerebral demyelinating form of X-ALD Cerebral ALD is the most severe phenotype of X-ALD.A newborn male with an ABCD1 gene mutation has a 35-40% risk to develop cerebral ALD between the ages of 5 and 12 years.As mentioned above, 20% of adult AMN males are also at risk to develop cerebral ALD.Overall, for male X-ALD patients the lifetime risk to develop cerebral ALD, either in childhood or in adulthood, is around 60%.There is an age-related correlation with the onset of cerebral ALD and disease progression: the earlier the onset of cerebral demyelination, the more rapid the progression of the disease.Patients are neurologically unaffected until they develop cerebral demyelination visible on brain MRI (as abnormal hypersignal of white matter on T2 and FLAIR sequences, hyposignal of white matter on T1 sequences) [1,12,13].Usually the initial lesions involve either the splenium of the corpus callosum and then extend into the adjacent white matter of the parietooccipital lobes (Fig. 1A) or alternatively the genu of the corpus callosum and then extend into the white matter of the frontal lobes.Initial demyelinating lesions may also occur in the pyramidal tracts, within the brainstem or internal capsule (Fig. 1B) and then extend into the centrum semiovale (frontal white matter).The cerebral demyelinating lesions can be asymmetric, particularly when previous head trauma or even stroke seems to have initiated the onset of cerebral ALD.Initially, the demyelinating lesions are not inflammatory (based on absence of lesion enhancement on T1 sequences after peripheral injection of gadolinium) and progress slowly.The patients have virtually no neurologic symptoms, except sometimes mild cognitive dysfunctions.Suddenly, the disease becomes inflammatory (with evidence of demyelinating lesion enhancement after peripheral injection of gadolinium) and at this stage the disease starts to progress rapidly.The patients enter then into an active phase of devastating neurologic and cognitive deterioration that includes emotional lability, hyperactive behavior, school failure for boys, and either visuospatial impairment or frontal syndrome according to the sites of cerebral demyelinating lesions.This cognitive deterioration is rapidly associated with neurologic deficits such as hemiplegia or quadriparesis, cerebellar ataxia, impaired central auditory discrimination, visual field defects, cortical blindness and often seizures.Eventually, a vegetative state ensues within two to five years leading to death at varying intervals thereafter.Approximately 65% of children or adults with cerebral ALD have adrenocortical insufficiency that can precede the onset of neurologic symptoms for years or decades. About 10% of boys with cerebral ALD may not enter into the active inflammatory and devastating stage of the disease.The same may occur in adult males with cerebral ALD.This phenotype is often referred to as "chronic or arrested cerebral X-ALD".With white matter lesions involving either the parieto-occipital or the frontal white matter, these patients end up developing marked visual-spatial or executive cognitive deficits, but without significant neurological or sensory (visual, auditive) symptoms.After an initial progression of the demyelinating lesions that often result in loss of myelin and ventricular dilatation and cortical atrophy, the patient can remain stable for a decade or even longer.But a full progression to the inflammatory stage remains possible, even after 10 to 15 years without progression of cerebral demyelination.Electrophysiological tests are useless for the early diagnosis of cerebral ALD as brainstem visual evoked responses become abnormal only in the advanced stage of the disease.The occurrence of childhood cerebral ALD in females is exceptional.It is hypothesized and partially supported by laboratory studies that the few girls who developed CCALD had skewed X-inactivation toward the X-chromosome carrying the mutated ABCD1 gene (Kemp, unpublished data).

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > Abstract

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§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3. Genetic aspects of X-ALD

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.3. Genotype and phenotype in X-ALD In other, non-peroxisomal ABC-transporters, like for example ABCB1 (Pgp/MDR1) or ABCA4 (ABCR), individual mutations can lead to residual transporter capacity and, as in the case of ABCA4, be associated with a later onset form of Stargardt disease [66].There is no simple and general genotype-phenotype relation in X-ALD.Large deletions, nonsense mutations or frame shift mutations which result in the complete absence of a functional ALDP are found in patients covering the full spectrum of X-ALD phenotypes including very mild forms of late onset AMN.The best example for this is the most common ABCD1 mutation, a deletion of two base-pairs resulting in a frame shift (p.Gln472fsX83) leading to a truncated ALDP that lacks the ATP-binding domain and is thus nonfunctional.This micro-deletion has been identified in 81 out of 1234 analyzed ABCD1 genes and the affected patients presented with all different variants of X-ALD [67].Another striking demonstration of the lack of a simple genotype-phenotype correlation is the presence of five different phenotypes in six male patients of a family with a destabilizing missense mutation, p.Pro484Arg [68].These observations clearly demonstrate that the total lack of a functional ALDP transporter alone does not necessarily lead to the severe form of X-ALD.Thus, additional factors are required to initiate the inflammatory process.Head trauma has been described as one of several possible "environmental" risk factors able to trigger the rapidly progressive inflammatory demyelination in AMN patients [69].However, this does not exclude that some mutations with residual transporter activity might exclusively lead to AMN, irrespective of other factors.For example, a Dutch kindred has been described in which all heterozygous females are asymptomatic and all X-ALD males are either still asymptomatic at old age or show mild phenotypes including gonadal insufficiency and AMN without cerebral involvement [64].The affected members of this kindred carry a missense mutation p.Arg389His that results in stable ALDP correctly localized to peroxisomes.This mutation may thus represent such a rare variant of a genotype-phenotype relation.

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.4. Origin of VLCFA

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.3. Genotype and phenotype in X-ALD In other, non-peroxisomal ABC-transporters, like for example ABCB1 (Pgp/MDR1) or ABCA4 (ABCR), individual mutations can lead to residual transporter capacity and, as in the case of ABCA4, be associated with a later onset form of Stargardt disease [66].There is no simple and general genotype-phenotype relation in X-ALD.Large deletions, nonsense mutations or frame shift mutations which result in the complete absence of a functional ALDP are found in patients covering the full spectrum of X-ALD phenotypes including very mild forms of late onset AMN.The best example for this is the most common ABCD1 mutation, a deletion of two base-pairs resulting in a frame shift (p.Gln472fsX83) leading to a truncated ALDP that lacks the ATP-binding domain and is thus nonfunctional.This micro-deletion has been identified in 81 out of 1234 analyzed ABCD1 genes and the affected patients presented with all different variants of X-ALD [67].Another striking demonstration of the lack of a simple genotype-phenotype correlation is the presence of five different phenotypes in six male patients of a family with a destabilizing missense mutation, p.Pro484Arg [68].These observations clearly demonstrate that the total lack of a functional ALDP transporter alone does not necessarily lead to the severe form of X-ALD.Thus, additional factors are required to initiate the inflammatory process.Head trauma has been described as one of several possible "environmental" risk factors able to trigger the rapidly progressive inflammatory demyelination in AMN patients [69].However, this does not exclude that some mutations with residual transporter activity might exclusively lead to AMN, irrespective of other factors.For example, a Dutch kindred has been described in which all heterozygous females are asymptomatic and all X-ALD males are either still asymptomatic at old age or show mild phenotypes including gonadal insufficiency and AMN without cerebral involvement [64].The affected members of this kindred carry a missense mutation p.Arg389His that results in stable ALDP correctly localized to peroxisomes.This mutation may thus represent such a rare variant of a genotype-phenotype relation.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.3. VLCFA metabolism

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.4. Origin of VLCFA

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.2. The nature and frequency of ABCD1 mutations Based on mutational analysis of the ABCD1 gene in X-ALD patients, 587 different mutations have been described up to now [64] (http:// www.x-ald.nl).Of these mutations, 300 (51%) are missense mutations, 166 (28%) frame shift mutations, 68 (12%) nonsense mutations, 35 (6%) amino acid insertions/deletions and 18 (3%) larger deletions of one or more exons.It is described that 77% of all non-recurrent ABCD1 mutations result in the absence of ALDP (http://www.x-ald.nl).This is, on the one hand, due to the fact that 50% of ABCD1 mutations, such as nonsense and frame shift mutations as well as larger deletions lead to a truncated protein.On the other hand, many missense mutations result in unstable protein; here the absence of ALDP might be a question of sensitivity of detection.In most cases, the absence of detectable ALDP was judged by using anti-ALDP immunofluorescence microscopy in cultured fibroblasts from patients.However, fibroblasts express relatively low levels of ABCD1 and thus, in some cases a partial reduction may lead to the complete disappearance of anti-ALDP immunofluorescence, while still being detectable by using the more sensitive western blot method.Indeed, Zhang and coworkers developed a method for accurate quantification of low amounts of ALDP and reinvestigated ALDP expression in cell lines that had been scored previously ALDP negative based on immunofluorescence [22].This revealed that residual ALDP is detectable in all analyzed cell lines with a missense mutation, but the levels were often below the level of detection by immunofluorescence.Hence, ALDP could be detectable by immunohistochemistry when cell types with high ABCD1 expression level are used.Disease-associated missense mutations are not equally distributed over the protein.Analysis of the distribution of the 300 missense mutations reveals that there are two regions in which the majority of missense mutations are found.The first region is located in the transmembrane domain region between amino acids 83 and 344 and the second is located in the ATPbinding domain between amino acids 500 and 668.The N-terminal 73 amino acids and the C-terminal 50 amino acids are mostly spared from missense mutations.Thus, caution is warranted when interpreting missense mutations in this region.The mutation p.Asn13Thr, for example, has been shown to represent a polymorphism, as this mutation did not affect the ability to compensate for the lack of functional ALDP after transfection [65].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.2. The nature and frequency of ABCD1 mutations Based on mutational analysis of the ABCD1 gene in X-ALD patients, 587 different mutations have been described up to now [64] (http:// www.x-ald.nl).Of these mutations, 300 (51%) are missense mutations, 166 (28%) frame shift mutations, 68 (12%) nonsense mutations, 35 (6%) amino acid insertions/deletions and 18 (3%) larger deletions of one or more exons.It is described that 77% of all non-recurrent ABCD1 mutations result in the absence of ALDP (http://www.x-ald.nl).This is, on the one hand, due to the fact that 50% of ABCD1 mutations, such as nonsense and frame shift mutations as well as larger deletions lead to a truncated protein.On the other hand, many missense mutations result in unstable protein; here the absence of ALDP might be a question of sensitivity of detection.In most cases, the absence of detectable ALDP was judged by using anti-ALDP immunofluorescence microscopy in cultured fibroblasts from patients.However, fibroblasts express relatively low levels of ABCD1 and thus, in some cases a partial reduction may lead to the complete disappearance of anti-ALDP immunofluorescence, while still being detectable by using the more sensitive western blot method.Indeed, Zhang and coworkers developed a method for accurate quantification of low amounts of ALDP and reinvestigated ALDP expression in cell lines that had been scored previously ALDP negative based on immunofluorescence [22].This revealed that residual ALDP is detectable in all analyzed cell lines with a missense mutation, but the levels were often below the level of detection by immunofluorescence.Hence, ALDP could be detectable by immunohistochemistry when cell types with high ABCD1 expression level are used.Disease-associated missense mutations are not equally distributed over the protein.Analysis of the distribution of the 300 missense mutations reveals that there are two regions in which the majority of missense mutations are found.The first region is located in the transmembrane domain region between amino acids 83 and 344 and the second is located in the ATPbinding domain between amino acids 500 and 668.The N-terminal 73 amino acids and the C-terminal 50 amino acids are mostly spared from missense mutations.Thus, caution is warranted when interpreting missense mutations in this region.The mutation p.Asn13Thr, for example, has been shown to represent a polymorphism, as this mutation did not affect the ability to compensate for the lack of functional ALDP after transfection [65].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.2. Toxicity of VLCFA

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.4. Origin of VLCFA

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.3. Genotype and phenotype in X-ALD In other, non-peroxisomal ABC-transporters, like for example ABCB1 (Pgp/MDR1) or ABCA4 (ABCR), individual mutations can lead to residual transporter capacity and, as in the case of ABCA4, be associated with a later onset form of Stargardt disease [66].There is no simple and general genotype-phenotype relation in X-ALD.Large deletions, nonsense mutations or frame shift mutations which result in the complete absence of a functional ALDP are found in patients covering the full spectrum of X-ALD phenotypes including very mild forms of late onset AMN.The best example for this is the most common ABCD1 mutation, a deletion of two base-pairs resulting in a frame shift (p.Gln472fsX83) leading to a truncated ALDP that lacks the ATP-binding domain and is thus nonfunctional.This micro-deletion has been identified in 81 out of 1234 analyzed ABCD1 genes and the affected patients presented with all different variants of X-ALD [67].Another striking demonstration of the lack of a simple genotype-phenotype correlation is the presence of five different phenotypes in six male patients of a family with a destabilizing missense mutation, p.Pro484Arg [68].These observations clearly demonstrate that the total lack of a functional ALDP transporter alone does not necessarily lead to the severe form of X-ALD.Thus, additional factors are required to initiate the inflammatory process.Head trauma has been described as one of several possible "environmental" risk factors able to trigger the rapidly progressive inflammatory demyelination in AMN patients [69].However, this does not exclude that some mutations with residual transporter activity might exclusively lead to AMN, irrespective of other factors.For example, a Dutch kindred has been described in which all heterozygous females are asymptomatic and all X-ALD males are either still asymptomatic at old age or show mild phenotypes including gonadal insufficiency and AMN without cerebral involvement [64].The affected members of this kindred carry a missense mutation p.Arg389His that results in stable ALDP correctly localized to peroxisomes.This mutation may thus represent such a rare variant of a genotype-phenotype relation.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.3. Genotype and phenotype in X-ALD In other, non-peroxisomal ABC-transporters, like for example ABCB1 (Pgp/MDR1) or ABCA4 (ABCR), individual mutations can lead to residual transporter capacity and, as in the case of ABCA4, be associated with a later onset form of Stargardt disease [66].There is no simple and general genotype-phenotype relation in X-ALD.Large deletions, nonsense mutations or frame shift mutations which result in the complete absence of a functional ALDP are found in patients covering the full spectrum of X-ALD phenotypes including very mild forms of late onset AMN.The best example for this is the most common ABCD1 mutation, a deletion of two base-pairs resulting in a frame shift (p.Gln472fsX83) leading to a truncated ALDP that lacks the ATP-binding domain and is thus nonfunctional.This micro-deletion has been identified in 81 out of 1234 analyzed ABCD1 genes and the affected patients presented with all different variants of X-ALD [67].Another striking demonstration of the lack of a simple genotype-phenotype correlation is the presence of five different phenotypes in six male patients of a family with a destabilizing missense mutation, p.Pro484Arg [68].These observations clearly demonstrate that the total lack of a functional ALDP transporter alone does not necessarily lead to the severe form of X-ALD.Thus, additional factors are required to initiate the inflammatory process.Head trauma has been described as one of several possible "environmental" risk factors able to trigger the rapidly progressive inflammatory demyelination in AMN patients [69].However, this does not exclude that some mutations with residual transporter activity might exclusively lead to AMN, irrespective of other factors.For example, a Dutch kindred has been described in which all heterozygous females are asymptomatic and all X-ALD males are either still asymptomatic at old age or show mild phenotypes including gonadal insufficiency and AMN without cerebral involvement [64].The affected members of this kindred carry a missense mutation p.Arg389His that results in stable ALDP correctly localized to peroxisomes.This mutation may thus represent such a rare variant of a genotype-phenotype relation.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3. Genetic aspects of X-ALD

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.3. VLCFA metabolism

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.2. Toxicity of VLCFA

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.3. VLCFA metabolism

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.1. AMN AMN, the most frequent phenotype of X-ALD, is nearly completely penetrant in adult males and affects 65% of heterozygous women by the age of 60 years (Engelen et al., manuscript in preparation).The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].The neuropathological hallmark of AMN is an axonopathy with microgliosis but without significant myelin changes [83].In the CNS, ALDP is mostly expressed in oligodendrocytes, microglia, astrocytes and endothelial cells [84], but not in most neurons with the exception of hypothalamus, basal nucleus of Meynert, periaqueductal gray matter and in the locus coeruleus [85].A direct role for oligodendrocytes to sustain axonal function is supported by the observation that mice lacking 2′,3′-cyclic nucleotide phosphodiesterase (CNPase) or proteolipid protein (PLP) display axonal dysfunction without demyelination in the spinal cord and brain [86,87].It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.Confirmation that this hypothesis is correct would require the targeted inactivation of the Abcd1 gene specifically in mouse oligodendrocytes and follow up to evaluate whether these mice indeed develop the AMN-like phenotype.In X-ALD patients, this degenerative process, however, is very slow and takes decades to finally result in clinical symptoms of AMN.Interestingly, Abcd1 knockout mice display oxidative damage to proteins in the spinal cord already at the age of 3 months [39], long before the first neuropathological lesions in the spinal cord at around 16 months of age and clinical signs at 20 months of age [40].Loss of function of ALDP and possibly the accumulation of VLCFA result in oxidative stress in oligodendrocytes.This oxidative stress and/or antioxidant defense impairment in oligodendrocytes could be the major factor that initiates axonal damage in X-ALD.This notion is supported by the observation that antioxidants reduce markers for oxidative stress and axonal degeneration in the spinal cord of Abcd1 knockout mice [88].Yet, recent transcriptomic analysis highlighted other pathways that are dysregulated in Abcd1 knockout mice, including oxidative phosphorylation, adipocytokine and insulin signaling pathways, protein synthesis and turnover, NFkappa B mediated pro-inflammatory response, inflammatory response related to TGF beta, and the Toll-like receptor pathway [89].Consistent with the microgliosis observed at the neuropathological level, these data suggest that a pro-inflammatory status is also present in AMN.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3.4. Genetic modifiers in X-ALD Segregation analysis suggests that in addition to the disease causing ABCD1 mutations and environmental factors, other genetic autosomal inherited factors are involved in the clinical manifestation of X-ALD [70,70,71].The demonstration that ALDP-related protein (ALDRP, ABCD2), the closest homolog of ALDP, has an overlapping function with ALDP [72] suggested the ABCD2 gene as a putative X-ALD modifier gene.However, sequence and segregation analyses of the ABCD2 gene in a large X-ALD family with different phenotypes, as well as two independent association studies of polymorphisms and clinical phenotypes excluded ABCD2 as a major modifier locus in X-ALD [73,74].Investigations of other candidate genes such as the HLA haplotype have shown conflicting results [75,76], but these analyses may have been performed in underpowered sample collectives making a final conclusion uncertain.However, positive association studies with variants in genes involved in methionine metabolism [77,78], and SOD2 [79], or altered gene expression of Bubblegum (a member of the VLCFacyl-CoA synthetase family) [34], and ABCD4 (PMP69/P70R, another half ABC-transporter with high homology to ALDP) [34], might indicate their involvement in the pathology of X-ALD.Also, detailed investigations of the CD1 gene cluster involving 23 carefully selected tag-SNPs within this gene region in 87 childhood cerebral ALD and 52 pure-AMN patients (defined as older than 45 years and without cerebral involvement) identified one SNP, rs973742, located 4 kb downstream from the CD1D gene.The minor allele was significantly more frequent in pure-AMN patients (χ 2 = 7.6; P = 0.006).However, this association was no longer statistically significant after Bonferroni correction for multiple testing [80].This is a general problem associated with rare diseases in which the sample size is relatively small, but nevertheless it likely provides evidence for a possible involvement in the molecular mechanism of X-ALD.ELOVL1 is another candidate modifier gene based on its important function in VLCFA synthesis [50].Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).The functional effect of this SNP is under investigation.In summary, it seems unlikely that there is a single modifier locus that allows the prediction of the future phenotypic outcome for a presymptomatic X-ALD patient.The data currently available point to the existence of many rare genetic variant interactions that affect the clinical manifestations in X-ALD patients.This is the experience that is observed in many multifactorial diseases [81].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

• AssumptionRests on an assumption: Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.
• AssumptionRests on an assumption: There is an absence of general genotype-phenotype correlation in X-ALD.

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

None of the sources cited for this claim have been checked yet.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].

§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 4.2. Cerebral demyelination Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.Because of the absence of general genotype-phenotype correlation in X-ALD, it is likely that a combination of genetic, epigenetic and environmental factors play an essential role as triggers for the development of cerebral ALD.This is supported by the development of different clinical phenotypes in monozygotic twins [90,91] and the observation that moderate head trauma can initiate cerebral demyelination in AMN patients [69].Even though there is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype, VLCFA are highly elevated in myelinspecific lipid species [18,[26][27][28][29].These VLCFA-enriched complex lipids could be a key factor that contributes to the initiation of myelin instability and then cerebral demyelination.Indeed, VLCFA levels are higher in the normal appearing white matter of patients with cerebral ALD than in the normal white matter of AMN patients [34].In line with this, oligodendrocytes derived from induced pluripotent stem cells from a patient with cerebral ALD accumulated more VLCFA than those derived from an AMN patient [92].The synthesis of VLCFA (C26:0) is enhanced in X-ALD [56] and it requires the elongases ELOVL6 and ELOVL1 [50,51].Genetic polymorphism in these elongases may affect the further elongation of C26:0 acyl-CoA esters into even longer fatty acids that would result in more sustained myelin sheath instability.It has been hypothesized that secondary peroxisomal dysfunction may contribute to cerebral demyelination and even neuroinflammation in X-ALD [93].This hypothesis is based on the observation that mice lacking functional peroxisomes in oligodendrocytes initially show normal myelination, but develop axonal swelling followed by cerebral demyelination and infiltration of inflammatory T cells [94]. Plasmalogens are reduced in the brain lesions of cerebral ALD patients [95].A decrease in plasmalogen levels could alter the transport of cholesterol which is an essential component of the myelin sheath [96], it could increase the oxidation of cholesterol in phospholipid bilayers [97] which in turn may result in cytotoxic, oxidative and inflammatory activities [98] and increased oxidative stress in glial cells [99].