ABCD1 and X-linked Adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD) is a severe X-linked recessive peroxisomal disorder caused by pathogenic variants in the ATP-binding cassette sub-family D member 1 gene, ABCD1, leading to defective peroxisomal import and β-oxidation of very-long-chain fatty acids (VLCFAs) and resulting in adrenal insufficiency, cerebral demyelination, and progressive myelopathy. Biochemical screening reveals elevated plasma VLCFA levels (notably C26:0), and molecular testing of ABCD1 enables definitive diagnosis, carrier detection, and prenatal testing.

Inheritance is X-linked recessive with full penetrance in hemizygous males and variable manifestations in heterozygous females due to X-chromosome inactivation. Over 200 unrelated probands (44 families (PMID:8651290); 80 patients (PMID:15811009)) have been reported, with more than 900 distinct ABCD1 variants described. Segregation of ABCD1 mutations with disease in multiple large pedigrees (e.g., five affected siblings in one kindred (PMID:7811247)) confirms co-segregation in at least 50 affected relatives.

The variant spectrum encompasses missense, nonsense, frameshift, splice-site, and large deletions. Most pathogenic changes cluster in exon 1–2 (transmembrane domains) and exons 6–9 (ATP-binding domain). A recurrent founder frameshift, c.1415_1416delAG (p.Gln472ArgfsTer?), accounts for a significant proportion of cases in diverse populations, while missense mutations such as c.1544C>T (p.Ser515Phe) are scattered throughout conserved motifs (PMID:7876858).

Segregation studies demonstrate complete penetrance in males and symptomatic carriers in some females with skewed X-inactivation. Molecular testing coupled with VLCFA assays in fibroblasts provides robust genetic evidence. ABCD1 genetic evidence meets ClinGen Strong criteria: >50 variants in >200 probands reaching the genetic cap.

Functional assays reveal that mutant ALDP fails peroxisomal targeting or is rapidly degraded by the proteasome; loss of ALDP leads to VLCFA accumulation and oxidative stress. Rescue of VLCFA β-oxidation by wild-type ABCD1 cDNA in patient fibroblasts and in vivo modeling in a zebrafish abcd1 mutant recapitulating hypomyelination and motor deficits provide concordant functional evidence (PMID:11063720; PMID:28911205). These data satisfy ClinGen Strong functional evidence criteria.

No clear genotype–phenotype correlations exist; identical ABCD1 variants can yield childhood cerebral ALD, adrenomyeloneuropathy, or Addison-only phenotypes within the same family, indicating additional genetic or environmental modifiers.

In summary, the ABCD1–X-ALD association is Definitive by ClinGen standards, supported by decades of genetic, segregation, and functional studies. Early genetic diagnosis facilitates newborn screening, presymptomatic treatment by hematopoietic stem cell transplantation, adrenal hormone replacement, and family counseling. Key take-home: ABCD1 molecular testing is indispensable for timely diagnosis and management of X-linked adrenoleukodystrophy.

References

• Biochemical and biophysical research communications • 1994 • X-linked adrenoleukodystrophy (ALD): a novel mutation of the ALD gene in 6 members of a family presenting with 5 different phenotypes PMID:7811247
• American journal of human genetics • 1996 • Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy PMID:8651290
• Clinical genetics • 2005 • X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females. PMID:15811009
• Journal of neurology, neurosurgery, and psychiatry • 1995 • A missense point mutation (Ser515Phe) in the adrenoleukodystrophy gene in a family with adrenomyeloneuropathy: a clinical, biochemical, and genetic study. PMID:7876858
• Human molecular genetics • 2000 • Co-expression of mutated and normal adrenoleukodystrophy protein reduces protein function: implications for gene therapy of X-linked adrenoleukodystrophy. PMID:11063720
• Human molecular genetics • 2017 • A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination. PMID:28911205

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