ABCD1 – Hereditary Spastic Paraplegia

ABCD1 encodes the peroxisomal ATP-binding cassette half-transporter ALDP essential for very-long-chain fatty acid (VLCFA) β-oxidation. Loss-of-function variants in ABCD1 cause X-linked adrenoleukodystrophy (X-ALD), but a subset of patients present predominantly with progressive spastic paraparesis indistinguishable from hereditary spastic paraplegia (Hereditary Spastic Paraplegia).

X-linked recessive inheritance is observed, with affected males and variably symptomatic heterozygous females. To date, 27 unrelated male probands have been reported with an HSP phenotype: two siblings in a Chinese family (c.1661G>A (p.Arg554His)) (PMID:23664929); seven Greek kindred members (c.1174_1178del (p.Leu392SerfsTer7)) (PMID:26049658); seven Chinese ALD patients identified among 142 HSP referrals (PMID:31777199); and eleven Taiwanese HSP patients carrying ABCD1 mutations (PMID:34649108).

Segregation analyses in two families demonstrated co-segregation of ABCD1 variants with disease in seven affected relatives (one additional sibling pair and six kindred members) (PMID:23664929; PMID:26049658).

The variant spectrum includes both missense and truncating alleles. Notable examples are c.1661G>A (p.Arg554His) and c.1174_1178del (p.Leu392SerfsTer7), with additional unique frameshift, nonsense, and splice-site changes identified across cohorts. These variants uniformly lead to ALDP instability or loss of peroxisomal targeting.

In targeted HSP cohorts, ABCD1 mutations account for approximately 4.8–4.9% of cases, highlighting the importance of differential diagnosis in male patients with spastic paraplegia even in the absence of adrenal or cerebral white matter changes (PMID:31777199; PMID:34649108).

Functional studies in zebrafish abcd1 mutants reveal elevated VLCFA levels, hypomyelination, oligodendrocyte deficiency, and impaired motor function, while cellular assays confirm peroxisomal β-oxidation deficits and VLCFA accumulation consistent with HSP pathology (PMID:28911205).

Collectively, robust genetic evidence and concordant functional data support a Strong ClinGen gene–disease association between ABCD1 and hereditary spastic paraplegia. ABCD1 sequencing should be integrated into HSP diagnostic panels to enable accurate molecular diagnosis, guide management, and inform genetic counseling.

References

• European journal of medical genetics • 2013 • Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia. PMID:23664929
• Journal of the neurological sciences • 2015 • A novel ABCD1 mutation detected by next generation sequencing in presumed hereditary spastic paraplegia: A 30-year diagnostic delay caused by misleading biochemical findings. PMID:26049658
• Molecular Genetics & Genomic Medicine • 2020 • Spastic paraplegia as the predominant phenotype in a cohort of Chinese patients with adrenoleukodystrophy. PMID:31777199
• Parkinsonism & related disorders • 2021 • Investigating ABCD1 mutations in a Taiwanese cohort with hereditary spastic paraplegia phenotype. PMID:34649108
• 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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