ABCD1 – Adrenomyeloneuropathy

Adrenomyeloneuropathy (AMN) is an X-linked recessive neurodegenerative disorder caused by pathogenic variants in ABCD1, manifesting as adult-onset progressive spastic paraparesis with adrenal insufficiency. Over 200 unrelated AMN cases across >10 pedigrees have been reported, with co-segregation of ABCD1 variants in affected males and obligate carrier females, and concordant functional deficits in peroxisomal very-long-chain fatty acid (VLCFA) metabolism, supporting a Definitive ClinGen classification for the gene–disease association (see Scores).

Inheritance is X-linked recessive with complete penetrance in hemizygous males and variable expressivity in heterozygous females. Co-segregation in >12 affected relatives across multiple families underscores strong genetic linkage, with each male proband presenting elevated VLCFA and confirmed ABCD1 variant status (PMID:7995738).

Genetic evidence includes >940 distinct ABCD1 variants: 769 missense, 132 nonsense, 120 frameshift, and 50 splice-site changes disrupting peroxisomal targeting or ATP-binding domains (PMID:35053399). The prototypical missense variant c.1544C>T (p.Ser515Phe) has been documented in multiple AMN pedigrees, segregating with disease and carrier status (PMID:7876858).

Clinically, AMN patients present in the second to fifth decade with spastic paraparesis (HP:0002313), adrenal insufficiency (HP:0000846), peripheral neuropathy (HP:0009830) and sensory ataxia. Female carriers may exhibit mild myelopathy or spasticity, highlighting the need for molecular testing in symptomatic females (PMID:20195870).

Functional studies demonstrate that loss-of-function ABCD1 mutants fail to import VLCFA into peroxisomes, resulting in β-oxidation deficits and neuroinflammation. An abcd1-null zebrafish model recapitulates hypomyelination, oligodendrocyte loss, and motor dysfunction, reversible by human ABCD1 expression, corroborating haploinsufficiency as the pathogenic mechanism (PMID:28911205).

No significant conflicting evidence has been reported; rare asymptomatic hemizygotes and late-onset cases reflect phenotypic heterogeneity rather than refuting the association.

Integration of robust genetic segregation and concordant functional assays establishes a haploinsufficiency mechanism for ABCD1 in AMN. Early molecular diagnosis facilitates genetic counseling, VLCFA monitoring, and timely interventions.

Key Take-home: ABCD1 sequencing is essential in adult-onset spastic paraparesis with adrenal dysfunction to confirm AMN and guide management.

References

• The Journal of the American Osteopathic Association • 1994 • A variant of adrenomyeloneuropathy in a family with adrenoleukodystrophy and adrenomyeloneuropathy. PMID:7995738
• 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
• Journal of neurology • 2010 • Female carriers of X-chromosomal adrenoleukodystrophy: a major differential diagnosis in progressive myelopathy. PMID:20195870
• 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
• Cells • 2022 • Structure and Function of the ABCD1 Variant Database: 20 Years, 940 Pathogenic Variants, and 3400 Cases of Adrenoleukodystrophy. PMID:35053399

Evidence Based Scoring (AI generated)