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Cited by 28Metabolism and Genetic DisordersAdrenal Hormones and DisordersLysosomal Storage Disorders Research

X-linked adrenoleukodystrophy and primary adrenal insufficiency

Open access
Cappa, Marco, Todisco, Tommaso, Bizzarri, Carla·2023·Frontiers in Endocrinology
DOI 10.3389/fendo.2023.1309053PMC PMC10687143
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Abstract

X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene (ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.

AI snapshot

Written from the paper’s full text.

TL;DR

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurodegenerative disorder in which primary adrenal insufficiency (PAI) is a major endocrine complication, occurring in about 70% of ALD/AMN patients and 5% of female carriers. This narrative review summarizes the shared pathophysiology, diagnosis, and management of X-ALD–related PAI, emphasizing early VLCFA screening in boys with PAI and age-specific hormone replacement.

Key findings

  • X-ALD has an estimated birth prevalence of 1 in 17,000; PAI prevalence is reported as 70% in ALD/AMN patients and 5% in female carriers, while adrenal function is abnormal in 90% of neurologically symptomatic ALD boys and 70% of men with AMN.
  • Among 49 affected boys without neurological symptoms (ages 5 months to 13 years), 80% already had biochemical evidence of PAI at ALD diagnosis without clinical symptoms; cumulative PAI probability peaked by age 10 years (46.8%), rose by an additional 28.6% up to age 40, and by 5.6% thereafter.
  • Mineralocorticoid function remains intact in approximately 50% of X-ALD–related PAI cases, consistent with VLCFA accumulation mainly in the zona fasciculata and reticularis; in the authors’ cohort of 49 female carriers, only 2 had PAI.
  • Treatment recommendations include hydrocortisone 10 mg/m²/day in children, hydrocortisone 15–25 mg/day or cortisone acetate 20–35 mg/day in adults, and fludrocortisone 100 mcg in children or 50–100 mcg in adults when mineralocorticoid replacement is needed; HCT and gene therapy have not been shown to reverse PAI.

Methods

  • Narrative review exploring the relationship between PAI and X-ALD, including shared pathophysiology, clinical manifestations, diagnosis, and therapeutic interventions.
  • Evidence base includes population studies, an international retrospective review of medical records, published cohorts, and the authors’ own cohort of 49 female carriers.
  • No systematic search strategy, inclusion criteria, quality appraisal, or meta-analysis is described; the paper synthesizes literature and clinical experience narratively.

Limitations

  • Stated in the paper: the pathogenesis of X-ALD–related PAI remains unclear; why PAI develops only in a proportion of ALD/AMN patients is incompletely understood; the extent of PAI development is uncertain due to lack of comprehensive prospective natural history studies.
  • Stated in the paper: no long-term observational studies after HCT, no evidence that HCT changes the course of PAI, and no published data on the effect of a newer nutritional approach on adrenal function.
  • Evident from the text: this is a narrative review without a described systematic search or formal quality assessment, and several cited findings come from small, retrospective, or observational studies; the authors’ own cohort of 49 female carriers is mentioned without full methods.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fendo.2023.1309053

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

28 of 72 cited sources checked · 13 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    AMN is characterized by spinal cord involvement, leading to progressive motor dysfunction and sensory deficits.

    “It is characterized by spinal cord involvement, leading to progressive motor dysfunction and sensory deficits.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source
    • cites [22] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J Rare Dis source
  • Premisecitation

    In approximately 85% of individuals with clinical symptoms, brain 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.

    “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.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source

      Section 1.2 (page unavailable) describes cerebral ALD lesions as hyperintense on T2 and FLAIR MRI and says they usually begin in the corpus callosum before extending into parieto-occipital or, alternatively, frontal white matter. It does not give an 85% figure for symptomatic individuals or describe the lesions as necessarily symmetric and confluent; it explicitly says they can be asymmetric. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [22] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J Rare Dis source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
  • Premisecitation

    AMN is the most common form of adult-onset X-ALD.

    “AMN is the most common form of adult-onset X-ALD.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source
    • cites [22] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J Rare Dis source
  • Premisecitation

    Adrenal cell function is disrupted by altered microviscosity of the cell membrane when exposed to C26:0, leading to impaired response to ACTH stimulation.

    “Furthermore, function of adrenal cells has been witnessed to be disrupted by altered microviscosity of the cell-membrane when exposed to C26:0, leading to an impaired response to adrenocorticotropin (ACTH) stimulation (20).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Whitcomb, 1988, Effects of long-chain, saturated fatty acids on membrane microviscosity and adrenocorticotropin responsiveness of human adrenocortical cells in vitro, J Clin Invest source

      The Discussion reports that human adrenocortical cells incubated with long-chain fatty acids had increased membrane microviscosity and an impaired response to ACTH; the reported experiments include hexacosanoic acid (C26:0). It proposes, rather than establishes, that the microviscosity change causes the impaired response. The supplied Discussion passages do not specify a page. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Lorenzo's oil fails to halt the progression of pre-existing neurological symptoms.

    “However, the effectiveness of this therapeutic approach has been met with skepticism, as Lorenzo’s oil fails to halt the progression of pre-existing neurological symptoms, so that hitherto it is not routinely recommended by X-ALD guidelines (37).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [37] Engelen, 2022, International recommendations for the diagnosis and management of patients with adrenoleukodystrophy: A consensus-based approach, Neurology source

      The Results > Dietary Therapy recommendation says evidence for Lorenzo’s oil as a disease-modifying treatment is insufficient and that controlled trials showing improved outcomes are lacking. This supports skepticism about its efficacy, but does not establish that it fails to halt progression of pre-existing neurological symptoms. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 21

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In children, glucocorticoid replacement therapy should be started with hydrocortisone at a total daily dose of 10 mg/m2, with dose titration according to individual needs.

    “In children, glucocorticoid replacement therapy (GCCrt) should be started with hydrocortisone (HC) at a total daily dose of 10 mg/m2, with dose titration according to individual needs (35).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Bornstein, 2016, Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline, J Clin Endocrinol Metab source

      The “Treatment and monitoring during childhood” recommendation specifies a starting hydrocortisone dose of 8 mg/m² per day for children with primary adrenal insufficiency, not 10 mg/m². It does support adjusting doses according to individual need. (LLM, conf=0.92)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    AMN primarily affects hemizygous males, although heterozygous females can also be affected to a lesser extent, with similar but later progression usually after the 4th or 5th decade of life.

    “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).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source
    • cites [22] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J Rare Dis source

  • May combine two claims.

    Premisecitation

    Progression of these lesions is unpredictable; it can be severe and rapid in the childhood cerebral form and milder and slower in adult-onset forms.

    “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).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source
    • cites [22] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J Rare Dis source

      The “Cerebral ALD (childhood, adolescent and adult)” section describes childhood cerebral ALD as rapidly progressive and says that adult cerebral ALD usually has slower *initial* symptom progression. It does not establish that adult-onset cerebral disease is generally milder or remains slower: the phenotype table lists adult cerebral ALD as rapid, while the Prognosis section says adults who develop cerebral demyelination have the same poor prognosis as boys with inflammatory cerebral ALD. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CerALD is the most severe form of X-ALD, typically affecting young boys between 4 and 8 years of age, and is characterized by progressive inflammatory demyelination in the cerebral white matter.

    “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.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source

      Section 1.2 calls cerebral ALD the most severe X-ALD phenotype and describes demyelination of cerebral white matter that can become rapidly progressive and inflammatory. It gives ages 5–12 years, not 4–8, and notes that lesions are initially noninflammatory. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [22] Engelen, 2012, X-linked adrenoleukodystrophy (X-ALD): clinical presentation and guidelines for diagnosis, follow-up and management, Orphanet J Rare Dis source

      The “Cerebral ALD (childhood, adolescent and adult)” section describes cerebral ALD as among the most rapidly progressive and devastating X-ALD phenotypes and attributes the rapid decline of childhood cerebral ALD to inflammatory demyelination affecting cerebral white matter. It says these phenotypes most frequently present in childhood, but does not give 4–8 years as the typical age range; the clinical-management section instead recommends screening boys aged 3–12. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    X-ALD is primarily caused by mutations in the ABCD1 gene located on the X chromosome (Xq28), which spans 19.9 kb and 10 exons.

    “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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Kemp, 2012, X-linked adrenoleukodystrophy: clinical, metabolic, genetic and pathophysiological aspects, Biochim Biophys Acta source

      Section 3, “Genetic aspects of X-ALD” (page not available), identifies ABCD1 mutations as the genetic cause of X-ALD, describes X-linked inheritance, and states that the gene covers 19.9 kb and contains 10 exons. Our copy does not specify the Xq28 location, so that part of the claim is not supported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    A lentiviral vector has been used to introduce a wild-type copy of the ABCD1 gene into patients' hematopoietic stem cells ex vivo, and the genetically modified cells have been reintroduced into the patients.

    “A lentiviral vector has been used to introduce a wild-type copy of the ABCD1 gene into the patients’ hematopoietic stem cells ex vivo. Subsequently, the genetically modified cells have been reintroduced into the patients (48).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Cartier, 2009, Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy, Science source

  • May combine two claims.

    Premisecitation

    The granulated HC formulation offers small dosages of 0.5, 1, 2, and 5 mg, which can prove useful in children taking small quantities of HC.

    “This formulation offers small dosages of 0.5, 1, 2, and 5 mg, which can prove useful in children taking small quantities of HC (41).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [41] Neumann, 2018, Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency, Clin Endocrinol (Oxf) source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Gene therapy has shown potential in various genetic disorders, including X-ALD.

    “Gene therapy is a cutting-edge approach that has shown potential in various genetic disorders, including X-ALD.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Cartier, 2009, Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy, Science source

      The paper reports clinical benefit from gene therapy in two patients with X-ALD. Its discussion proposes possible applications in other genetic CNS diseases, but does not report that gene therapy has shown potential across various genetic disorders. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A new oil mixture allows erucic acid to cross the blood brain barrier and reduce VLCFA levels in spinal fluid.

    “Recently, a new nutritional approach has been proposed with a new oil mixture allowing erucic acid to cross the blood brain barrier and reduce VLCFA levels in spinal fluid (45).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Cappa, 2012, A mixture of oleic, erucic and conjugated linoleic acids modulates cerebrospinal fluid inflammatory markers and improve somatosensorial evoked potential in X-linked adrenoleukodystrophy female carriers, J Inherit Metab Dis source

      The Results (Lipid metabolism findings) report that the LO + CLA mixture lowered VLCFA measures in plasma, but VLCFAs and erucic acid were below detectable levels in cerebrospinal fluid, so a reduction there was not shown. The Introduction says erucic acid likely crosses the blood–brain barrier, but the paper does not show that the new mixture enables it to do so; it reports that CLA crosses instead. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The early detection of the characteristic biochemical abnormalities associated with ALD and AMN has proven to be reliable to detect affected subjects but also poses new clinical ethical issues.

    “The early detection of the characteristic biochemical abnormalities associated with ALD and AMN has proven to be reliable to detect affected subjects but also poses new clinical ethical issues (52).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [52] Kemper, 2017, Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation, Genet Med source

      The Conclusions (page unavailable) say New York data suggest X-ALD can be reliably identified through newborn screening, and the Potential harms section describes concerns about unwanted carrier information, anxiety, false positives, and overdiagnosis. The paper does not say biochemical screening can identify who will develop AMN; it notes poor prediction of disease course. Thus the claim overstates both the certainty of detection and its specificity for AMN. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    No data on the effect of this nutritional approach on adrenal function has been published.

    “No data on the effect of this nutritional approach on adrenal function has been published.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Findingnone given

    There are no long-term observational studies after HCT and there is no evidence so far that HCT can change the course of PAI in ALD patients.

    “There are no long-term observational studies after HCT and there is no evidence so far that HCT can change the course of PAI in ALD patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    The potential benefit of Lorenzo's oil in regard to PAI has not been deeply investigated, and definitive evidence is still lacking.

    “The potential benefit of Lorenzo’s oil in regard to PAI has not been deeply investigated, and definitive evidence is still lacking.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cognitive impairment is generally absent at presentation in AMN, but secondary cerebral involvement may appear during progression.

    “Cognitive impairment is generally absent at presentation, but a secondary cerebral involvement may appear during the progression of the disease (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Schirinzi, 2019, Natural history of a cohort of ABCD1 variant female carriers, Eur J Neurol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is no evidence that X-ALD birth prevalence varies among regions or ethnic groups.

    “and there is no evidence that this prevalence varies among regions or ethnic groups (1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] X-linked adrenoleucoystrophy2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Identical ABCD1 variants can result in highly diverse clinical phenotypes, suggesting additional factors influence disease expression.

    “Nonetheless, identical variants can result in highly diverse clinical phenotypes, suggesting the presence of additional factors that influence the expression of the disease (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Engelen, 2014, Poll-The BT. X-linked adrenoleukodystrophy: pathogenesis and treatment, Curr Neurol Neurosci Rep source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    X-ALD has an estimated birth prevalence of 1 in 17,000 subjects, considering both hemizygous males and heterozygous females.

    “According to population studies X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] X-linked adrenoleucoystrophy2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    The cumulative probability of experiencing PAI reached its peak by age 10 years (46.8%), remained notably elevated up to 40 years of age (an additional 28.6%), and subsequently declined significantly beyond that point (an additional 5.6%).

    “the cumulative probability of experiencing PAI reached its peak by the age of 10 years (46.8%), remained notably elevated up to 40 years of age (an additional 28.6%), and subsequently declined significantly beyond that point (an additional 5.6%) (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Huffnagel, 2019, The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration, J Clin Endocrinol Metab source

  • May combine two claims.

    Premisecitation

    Due to the absence of comprehensive prospective investigations into the natural progression of the disease, the extent to which PAI develops in individuals with X-ALD remains uncertain, with different studies indicating a penetrance of 50-100%.

    “Due to the absence of comprehensive prospective investigations into the natural progression of the disease, the extent to which PAI develops in individuals with X-ALD remains uncertain, with different research studies indicating a penetrance of 50-100% (26).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Huffnagel, 2019, The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration, J Clin Endocrinol Metab source

  • Classified as probably not a substantial claim.

    Premisenone given

    Synthetic or long-acting glucocorticoids should not be used for glucocorticoid replacement therapy in children because of their negative impact on linear growth and puberty.

    “Synthetic or long-acting glucocorticoids should not be used for GCCrt in children, because of their negative impact on linear growth and puberty.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    During puberty, the daily requirement of hydrocortisone can vary as a consequence of endogenous sexual steroid production, so dose titration may be necessary.

    “It is worth noting that during puberty daily requirement of HC can vary as a consequence of endogenous sexual steroids production, so that dose titration may be necessary (38).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Kerrigan, 1993, Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis, J Clin Endocrinol Metab source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Treatment effectiveness in children with PAI must be carefully monitored by clinical evaluation of growth velocity, weight, blood pressure and energy status every 3 to 6 months.

    “Treatment effectiveness in children with PAI must be carefully monitored by clinical evaluation of growth velocity, weight, blood pressure and energy status every 3 to 6 months (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Johannsson, 2015, Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy, Clin Endocrinol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Capalbo et al. reported that 32.1% of patients were diagnosed with PAI by stimulation testing.

    “Notably, Capalbo et al. reported that 32.1% of the patients were diagnosed with PAI by stimulation testing (8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Capalbo, 2021, Primary adrenal insufficiency in childhood: data from a large nationwide cohort, J Clin Endocrinol Metab source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In adults with PAI and X-ALD, standard glucocorticoid replacement regimens consist of oral hydrocortisone (15-25 mg/day) or cortisone acetate (20-35 mg/day) in two or three divided doses.

    “Standard regimens consist of oral HC (15–25 mg/day) or cortisone acetate (20–35 mg/day) in two or three divided doses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisereasoning

    Normalization of ACTH levels should not be pursued in X-ALD-related PAI because the relative resistance of the adrenal gland to ACTH would require a significant hydrocortisone overdose.

    “The normalization of ACTH levels should not be pursued, as for the relative resistance of the adrenal gland to ACTH, the normalization would be achieved only at the cost of a significant HC overdose.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The adrenal gland in X-ALD-related PAI has relative resistance to ACTH.

  • May combine two claims.

    Premisecitation

    PAI was identified in X-ALD patients as young as 7 months and 5 months old; these individuals showed biochemical irregularities associated with PAI but did not exhibit clinical symptoms.

    “PAI was identified in X-ALD patients as young as 7 months and 5 months old. These individuals showed biochemical irregularities associated with PAI but yet did not exhibit any clinical symptoms (25, 26).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Dubey, 2005, Adrenal insufficiency in asymptomatic adrenoleukodystrophy patients identified by very long-chain fatty acid screening, J Pedia source
    • cites [26] Huffnagel, 2019, The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration, J Clin Endocrinol Metab source

  • May combine two claims.

    Premisecitation

    After HCT or gene therapy, improvement in disease burden is usually not observed, and stop or minimization of progression represent the primary therapeutic goals.

    “Improvement in disease burden is usually not observed, and stop or minimization of progression represent the primary therapeutic goals (49).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Gupta, 2022, Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy, Expert Opin Biol Ther source

  • May combine two claims.

    Interpretationreasoning

    Patients that have undergone transplantation and fail to engraft with donor-derived cells experience progression of neuroinflammation and white matter damage, suggesting that the immune suppression associated with allogeneic HCT may decrease neuroinflammation.

    “Patients that have undergone transplantation and fail to engraft with donor-derived cells experience progression of neuroinflammation and white matter damage, suggesting that the immune suppression associated with allogeneic HCT may decrease neuroinflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Hormone replacement therapy remains the cornerstone of treatment for PAI in X-ALD.

    “Hormone replacement therapy remains the cornerstone of treatment for PAI in X-ALD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    The dosing and management of glucocorticoid and mineralocorticoid replacement therapies differ based on age groups and individual needs.

    “The dosing and management of glucocorticoid and mineralocorticoid replacement therapies differ based on age groups and individual needs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Early diagnosis would allow for surveillance of cerebral disease and reduce potential residue.

    “However, as neurological impairment does not improve after HCT, an early diagnosis would allow for surveillance of cerebral disease and reduce potential residue (46).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Shapiro, 2000, Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    While the neurological deterioration is a dominant clinical aspect of X-ALD, PAI and endocrine complications contribute significantly to the disease burden.

    “While the neurological deterioration is a dominant clinical aspect of X-ALD, PAI and endocrine complications contribute significantly to the disease burden.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The development of PAI in X-ALD can occur early, even in the absence of clinical symptoms.

    “The development of PAI in X-ALD can occur early, even in the absence of clinical symptoms, highlighting the importance of early screening and monitoring.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Emerging therapeutic approaches, such as modified-release formulations and gene therapy, hold promise for improving treatment outcomes and addressing the complexities of PAI in X-ALD.

    “Emerging therapeutic approaches, such as modified-release formulations and gene therapy, hold promise for improving treatment outcomes and addressing the complexities of PAI in X-ALD.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Diagnosis of X-ALD relies on the assessment of VLCFA levels, genetic testing, and clinical presentation.

    “Diagnosis of X-ALD relies on the assessment of VLCFA levels, genetic testing, and clinical presentation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    X-ALD is a complex progressive genetic disorder with a wide spectrum of clinical phenotypes.

    “X-ALD is a complex progressive genetic disorder with a wide spectrum of clinical phenotypes.”
    Quote in the paperNot a substantial claim
36 of 36

  • The paper relies on this without support.

    The association between PAI and X-ALD has been observed in clinical practice.

    “Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood.”

  • The paper relies on this without support.

    Hormone replacement therapy in X-ALD does not vary significantly from PAI caused by other conditions.

    “As hormone replacement therapy in X-ALD does not vary significantly from PAI caused by other conditions, it is mandatory to start hormone treatment even without an established diagnosis of X-ALD.”

  • The paper relies on this without support.

    The adrenal gland in X-ALD-related PAI has relative resistance to ACTH.

    “as for the relative resistance of the adrenal gland to ACTH, the normalization would be achieved only at the cost of a significant HC overdose.”

  • The paper relies on this without support.

    In children with CerALD, growth and general wellbeing can be hampered by the condition itself.

    “Notably, in children with CerALD growth and general wellbeing can be hampered by the condition itself”

  • The paper relies on this without support.

    ALDP is a constitutive part of the peroxisomal membrane and transports VLCFAs from the membrane to the matrix where they undergo β-oxidation.

    “ALDP is a constitutive part of the peroxisomal membrane. It transports VLCFAs from the membrane to the matrix where they eventually undergo β-oxidation.”

  • The paper relies on this without support.

    ALDP deficiency results in defective peroxisomal β-oxidation of very long chain fatty acids.

    “ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA).”

  • The paper relies on this without support.

    VLCFAs accumulate in the nervous system (brain white matter and spinal cord), testis and adrenal cortex.

    “VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex.”

  • The paper relies on this without support.

    In children with X-ALD, primary adrenal insufficiency can occur early in life.

    “As PAI in children with X-ALD can occur early in life, oral supplement of sodium chloride 1gr/day should be added in infants up to 1 year of age.”

  • The paper relies on this without support.

    The tablets commercially available in the market come with a minimum dosage of 5 mg in the USA and Europe.

    “The tablets commercially available in the market come with a minimum dosage of 5 mg in the USA and Europe.”

  • The paper relies on this without support.

    A granulated HC formulation has recently gained approval in Europe.

    “A granulated HC formulation has recently gained approval in Europe.”

  • The paper relies on this without support.

    The ABCD1 gene product (ALDP) is incorporated in the peroxisomal membrane and is not released into the environment with the ability to provide ‘cross correction’ of adjacent cells.

    “The ABCD1 gene product (ALD protein, ALDP) is incorporated in the peroxisomal membrane and is not released into the environment with the ability to provide ‘cross correction’ of adjacent cells.”

  • The paper relies on this without support.

    In December 2013, neonatal screening for ALD was started in the state of New York.

    “After refining the liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay of C26:0-LPC and several pilot studies, in December 2013, neonatal screening for ALD was started in the state of New York.”

  • The paper relies on this without support.

    There is neither clear evidence nor strong recommendation for the use of dehydroepiandrosterone (DHEA) in PAI.

    “As far as we are aware of, there is neither clear evidence nor strong recommendation for the use of dehydroepiandrosterone (DHEA) in PAI.”
13 of 13

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Cappa, 1990, Hormonal evaluation in adrenoleukodystrophy, 81
  2. Moser, 2001, X-linked Adrenoleukodystrophy
  3. Kanakis, 2018, Adrenal Insufficiency Due to X-Linked Adrenoleukodystrophy

Cited by

Sorted by citations

Related

Authors
Cappa, M., Todisco, T., & Bizzarri, C.
Affiliations
Bambino Gesù Children's Hospital (IT)
Corresponding author
Bizzarri, Carla
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2023-11-16
Volume
14
Pages
1309053-1309053
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2023.1309053
PMC
PMC10687143
OpenAlex
W4388723871
Semantic Scholar
63831613ebe11a44f30c270f188aa2587571ff60
Cited by
28
References
48
Citations by year
2026: 9 · 2025: 13 · 2024: 6
FWCI
4.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
X-linked adrenoleukodystrophy, Addison's disease, ABCD1 gene, very long chain fatty acids, peroxisomal beta-oxidation, adrenomyeloneuropathy, ACTH response, glucocorticoid replacement therapy, mineralocorticoid therapy
MeSH terms
Addison Disease, Adrenal Cortex, Adrenoleukodystrophy, Adult, Child, Fatty Acids, Female, Glucocorticoids, Humans, Male, 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.

Cited sources are checked by gpt-6-sol.

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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