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X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects
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X-linked adrenoleukodystrophy (X-ALD) is the most frequent peroxisomal disease. The two main clinical phenotypes of X-ALD are adrenomyeloneuropathy (AMN) and inflammatory cerebral ALD that manifests either in children or more rarely in adults. About 65% of heterozygote females develop symptoms by the age of 60years. Mutations in the ABCD1 gene affect the function of the encoded protein ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta-oxidation of very long-chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in accumulation of VLCFA in plasma and tissues. While all patients have mutations in the ABCD1 gene, there is no general genotype-phenotype correlation. Environmental factors and a multitude of modifying genes appear to determine the clinical manifestation in this monogenetic but multifactorial disease. This review focuses on the clinical, biochemical, genetic and pathophysiological aspects of X-ALD.
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“Interestingly, a SNP has been identified in the promoter region of the ELOVL1 (Kemp and Aubourg, unpublished observations).”
§ 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].
What the sources say
- Not checked yetcites Kemp and Aubourg, unpublished observations
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“the real incidence of AMN in heterozygous women is likely to be close to 65% by the age of 60 years (Engelen et al., manuscript in preparation).”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
What the sources say
- Not checked yetcites Engelen et al., manuscript in preparation
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In the paper
“About 10% of boys with cerebral ALD may not enter into the active inflammatory and devastating stage of the disease.”
§ 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).
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“The discovery by Moser and coworkers that VLCFA (in particular C26:0) are also elevated in readily accessible materials like blood cells and plasma of X-ALD patients has been of crucial importance for the diagnosis of X-ALD [24].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD
What the sources say
- Not checked yetcites [24] 24. H.W. Moser, A.B. Moser, K.K. Frayer, W. Chen, J.D. Schulman, B.P. O'Neill, Y. Kishimoto, Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids, Neurology 31 (1981) 1241-1249. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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.
In the paper
“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.”
§ 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).
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“Reinecke and coworkers combined histopathological and biochemical analyses of the brain and demonstrated that VLCFA accumulate in morphological normal brain indicating that the biochemical abnormality precedes histopathological changes [33].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD
What the sources say
- Not checked yetcites [33] 33. C.J. Reinecke, D.P. Knoll, P.J. Pretorius, H.S. Steyn, R.H. Simpson, The correlation between biochemical and histopathological findings in adrenoleukodystrophy, J. Neurol. Sci. 70 (1985) 21-38.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesThe 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.
In the paper
“the AMN phenotype is fully penetrant in adults after the age of 55 years.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.3. Other X-ALD phenotypes
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear? Based: unclearThe 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.
In the paper
“Approximately 65% of children or adults with cerebral ALD have adrenocortical insufficiency that can precede the onset of neurologic symptoms for years or decades.”
§ 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).
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“In 2005, Asheuer and coworkers demonstrated that brain VLCFA levels in normal appearing white matter correlate with the clinical phenotype [34].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.1. The biochemical defect in X-ALD
What the sources say
- Not checked yetcites [34] 34. M. Asheuer, I. Bieche, I. Laurendeau, A. Moser, B. Hainque, M. Vidaud, P. Aubourg, Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy, Hum. Mol. Genet. 14 (2005) 1293-1303. source
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In the paper
“there is no correlation between X-ALD phenotype and mutations in the ABCD1 gene”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > Abstract
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- It may state two separate claims as one. 14
- Probably not a substantial claim. 10
In the paper
“The first symptoms of AMN usually appear when male patients are between 20 and 30 years but usually before the fifth decade [3].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
What the sources say
- Not matchedcites [3] 3. B.M. van Geel, L. Bezman, D.J. Loes, H.W. Moser, G.V. Raymond, Evolution of phe- notypes in adult male patients with X-linked adrenoleukodystrophy, Ann. Neu- rol. 49 (2001) 186-194.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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In the paper
“However, 35% of patients with AMN have a marked progression of their myelopathy within the first 3-5 years of clinical symptom onset.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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.
In the paper
“AMN males develop progressive stiffness and weakness of the legs, impaired vibration sense in the lower limbs, sphincter disturbances and impotence.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
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In the paper
“Addison's disease is present in less than 1% of heterozygous women.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
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.
In the paper
“Cerebral ALD presents usually with a rapidly progressive inflammatory demyelination within the brain resulting in severe cognitive and neurologic disability, a vegetative state within two to five years of clinical symptom onset and death thereafter.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > Abstract
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In the paper
“Adrenocortical insufficiency (Addison's disease) is present in approximately two-thirds of males with AMN but is often latent without evident clinical manifestations, including melanoderma.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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.
In the paper
“In two-thirds of AMN patients, the neurologic disability progresses slowly.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 1.1. Adrenomyeloneuropathy (AMN) in males and heterozygous women
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“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].”
§ 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.
What the sources say
- Not checked yetcites [64] 64. S. Kemp, A. Pujol, H.R. Waterham, B.M. van Geel, C.D. Boehm, G.V. Raymond, G.R. Cutting, R.J. Wanders, H.W. Moser, ABCD1 mutations and the X-linked adreno- leukodystrophy mutation database: role in diagnosis and clinical correlations, Hum. Mutat. 18 (2001) 499-515. source
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In the paper
“All X-ALD patients have mutations within the ABCD1 gene, which confirmed that this is the genetic cause of X-ALD.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3. Genetic aspects of X-ALD
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.
In the paper
“Based on the results obtained the authors concluded that VLCFA cause cell death by a combination of a disturbance in calcium homeostasis and mitochondrial dysfunction, but not primarily via ROS-production.”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.2. Toxicity of VLCFA
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“ALDP deficiency in X-ALD has two major effects: 1) it impairs peroxisomal VLCFA beta-oxidation and 2) it raises cytosolic VLCFacyl-CoA levels [50].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.3. VLCFA metabolism
What the sources say
- Not checked yetcites [50] 50. R. Ofman, I.M. Dijkstra, C.W. van Roermund, N. Burger, M. Turkenburg, A. van Cruchten, C.E. van Engen, R.J. Wanders, S. Kemp, The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy, EMBO Mol. Med. 2 (2010) 90-97. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The affected members of this kindred carry a missense mutation p.Arg389His that results in stable ALDP correctly localized to peroxisomes.”
§ 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.
What the sources say
- Not checked yetcites [64] 64. S. Kemp, A. Pujol, H.R. Waterham, B.M. van Geel, C.D. Boehm, G.V. Raymond, G.R. Cutting, R.J. Wanders, H.W. Moser, ABCD1 mutations and the X-linked adreno- leukodystrophy mutation database: role in diagnosis and clinical correlations, Hum. Mutat. 18 (2001) 499-515. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts [50].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 2.4. Origin of VLCFA
What the sources say
- Not checked yetcites [50] 50. R. Ofman, I.M. Dijkstra, C.W. van Roermund, N. Burger, M. Turkenburg, A. van Cruchten, C.E. van Engen, R.J. Wanders, S. Kemp, The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy, EMBO Mol. Med. 2 (2010) 90-97. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Wang and coworkers reported that among 489 X-ALD families tested at the Kennedy Krieger Institute, 4.1% of the patients were affected by a de novo mutation in the index case, which indicates that the mutation occurred in the germ line [62].”
§ Review X-linked adrenoleukodystrophy: Clinical, metabolic, genetic and pathophysiological aspects ☆ > 3. Genetic aspects of X-ALD
What the sources say
- Not checked yetcites [62] 62. Y. Wang, R. Busin, C. Reeves, L. Bezman, G. Raymond, C.J. Toomer, P.A. Watkins, A. Snowden, A. Moser, S. Naidu, G. Bibat, S. Hewson, K. Tam, J.T. Clarke, L. Charnas, G. Stetten, B. Karczeski, G. Cutting, S. Steinberg, X-linked adrenoleuko- dystrophy: ABCD1 de novo mutations and mosaicism, Mol. Genet. Metab. 104 (2011) 160-166.
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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.
What the sources say
- Not checked yetcites [39] 39. S. Fourcade, J. Lopez-Erauskin, J. Galino, C. Duval, A. Naudi, M. Jove, S. Kemp, F. Villarroya, I. Ferrer, R. Pamplona, M. Portero-Otin, A. Pujol, Early oxidative dam- age underlying neurodegeneration in X-adrenoleukodystrophy, Hum. Mol. Genet. 17 (2008) 1762-1773. source
- Not checked yetcites [40] 40. A. Pujol, C. Hindelang, N. Callizot, U. Bartsch, M. Schachner, J.L. Mandel, Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy, Hum. Mol. Genet. 11 (2002) 499-505. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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.
In the paper
“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.”
§ 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].
Strength:plain· not yet calibratedn = 52Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].
What the sources say
- Not checked yetcites [81] 81. W. Bodmer, C. Bonilla, Common and rare variants in multifactorial susceptibility to common diseases, Nat. Genet. 40 (2008) 695-701. source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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.
In the paper
“It is therefore possible that the primary consequence of the loss of ALDP function in oligodendrocytes triggers progressive axonal damage without significant demyelination.”
§ 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.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“The Abcd1 knockout mouse develops a phenotype that resembles AMN at 18-20 months of age, but no cerebral demyelination [40].”
§ 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.
What the sources say
- Not checked yetcites [40] 40. A. Pujol, C. Hindelang, N. Callizot, U. Bartsch, M. Schachner, J.L. Mandel, Late onset neurological phenotype of the X-ALD gene inactivation in mice: a mouse model for adrenomyeloneuropathy, Hum. Mol. Genet. 11 (2002) 499-505. source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“A deficiency in ALDP impairs peroxisomal VLCFA beta-oxidation but also raises cytosolic levels of C24:0/C26:0-CoA which are substrate for further elongation by ELOVL1 (adapted from[51]).”
§ 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].
What the sources say
- Not checked yetcites [51] 51. S. Kemp, R. Wanders, Biochemical aspects of X-linked adrenoleukodystrophy, Brain Pathol. 20 (2010) 831-837. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].
What the sources say
- Not checked yetcites [96] 96. N.J. Munn, E. Arnio, D. Liu, R.A. Zoeller, L. Liscum, Deficiency in ethanolamine plas- malogen leads to altered cholesterol transport, J. Lipid Res. 44 (2003) 182-192.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].
What the sources say
- Not checked yetcites [97] 97. R. Maeba, N. Ueta, Ethanolamine plasmalogens prevent the oxidation of choles- terol by reducing the oxidizability of cholesterol in phospholipid bilayers, J. Lipid Res. 44 (2003) 164-171.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
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.
In the paper
“Polymorphisms in genes involved in the different pathways that promote or counteract this pro-inflammatory stage may also play an important role in advancing or preventing the transition from a proinflammatory to a full-blown neuroinflammatory stage.”
§ 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].
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.
“Not all X-ALD males develop cerebral demyelination with severe neuroinflammation.”
The paper relies on this without support.
There is an absence of general genotype-phenotype correlation in X-ALD.
“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.”
The paper relies on this without support.
There is no correlation between the levels of VLCFA in plasma or fibroblasts and the X-ALD phenotype.
“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].”
The paper relies on this without support.
A significant number of heterozygous women develop AMN in adulthood.
“A significant number of heterozygous women develop AMN in adulthood and prenatal diagnosis of a female fetus to establish whether the fetus has X-ALD may be offered on an individual basis.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“X-ALD is primarily caused by mutations in the ABCD1 gene located on the X chromosome (Xq28), which spans for 19.9 kb and 10 exons (11).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In approximately 85% of the individuals with clinical symptoms, brain magnetic resonance imaging (MRI) shows a characteristic pattern of symmetric confluent hyperintense lesions in T2 and FLAIR images, usually first appearing in the parieto-occipital region of both hemispheres.”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This is the most severe form of X-ALD, typically affecting young boys (typically between 4 and 8 years of age). It is characterized by progressive inflammatory demyelination in the cerebral white matter.”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“AMN is the most common form of adult-onset X-ALD.”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“It primarily affects hemizygous males, although heterozygous females can also be affected to a lesser extent, with a similar but later progression of symptoms (usually after the 4th-or 5th decade of life).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“It is characterized by spinal cord involvement, leading to progressive motor dysfunction and sensory deficits.”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“The progression of these lesions is unpredictable; it can be severe and rapid in the childhood cerebral form; milder and slower in forms with adult onset (11, 22).”
From X-linked adrenoleukodystrophy and primary adrenal insufficiency (2023) · cites this paper as [11]
In the citing paper
“Although X-ALD does not involve any developmental defect or delay, it is characterized by remarkable clinical heterogeneity. The main phenotypes are adrenomyeloneuropathy (AMN) and cerebral ALD (CALD), the devastating inflammatory and demyelinating form of X-ALD [120].”
From Peroxisomes in brain development and function (2016) · cites this paper as [120]
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SOD2 as a potential modifier of X-linked adrenoleukodystrophy clinical phenotypes
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CD1 Gene Polymorphisms and Phenotypic Variability in X-Linked Adrenoleukodystrophy
Barbier, M., Sabbagh, A., Kasper, E., Asheuer, M., Ahouansou, O., Pribill, I., Forss-Petter, S., Vidaud, M., Berger, J., & Aubourg, P. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029872 · Cited by 18
Self-citationAssociation of X-Linked Adrenoleukodystrophy with HLA DRB1 Alleles
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Self-citationEfferent and afferent evoked potentials in patients with adrenomyeloneuropathy
Matsumoto, H., Hanajima, R., Terao, Y., Hamada, M., Yugeta, A., Shirota, Y., Yuasa, K., Satō, F., Matsukawa, T., Takahashi, Y., et al. (2009) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2009.11.005 · Cited by 15
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Self-citationRole for peroxisome proliferator-activated receptor-gamma in Alzheimer's disease.
van Geel (2001) · Open Repository and Bibliography (University of Luxembourg) · doi:10.1002/1531-8249(20010201)49:2 · Cited by 7
Flagged first, then by citations
1 of the 108 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Smith, 1991, A genetic basis for the multiple phenotypes of X-linked adrenoleukodystrophy, Am. J. Hum. Genet., 49, 165
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Very long-chain fatty acids: elongation, physiology and related disorders
Kihara, A. (2012) · The Journal of Biochemistry · doi:10.1093/jb/mvs105 · Cited by 453
Human disorders of peroxisome metabolism and biogenesis
Waterham, H. R., Ferdinandusse, S., & Wanders, R. J. A. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.11.015 · Cited by 384
Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology
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Metadata
- Authors
- Kemp, S., Berger, J., & Aubourg, P.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Medical University of Vienna (AT)
- Inserm (FR)
- Corresponding author
- Kemp, Stephan
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 1822
- Issue
- 9
- Pages
- 1465-1474
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2073937441
- Cited by
- 283
- References
- 108
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 24 · 2023: 16 · 2022: 19 · 2021: 29 · 2020: 15 · 2019: 22 · 2018: 19 · 2017: 23 · 2016: 16 · 2015: 28 · 2014: 30 · 2013: 15 · 2012: 5
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Netherlands Organization for Scientific Research (91786328)
- Vienna Science and Technology Fund (LS154)
- INSERM
- European Union Framework Programme 7 (241622)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- X-linked adrenoleukodystrophy, ABCD1 gene, ALDP, peroxisomal disorders, very long chain fatty acids, peroxisomal beta-oxidation, ELOVL1, adrenomyeloneuropathy, genotype-phenotype correlation, peroxisomal membrane proteins, disease pathophysiology
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Animals, Brain, Fatty Acids, Female, Humans, Mutation, Phenotype, Pregnancy, Prenatal Diagnosis, ATP-Binding Cassette Transporters
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-11 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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