Expanding the ABCD1 mutation spectrum: a novel variant in X-linked adrenomyeloneuropathy

X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by pathogenic variants in the ABCD1 gene, leading to impaired peroxisomal β-oxidation of very-long-chain fatty acids (VLCFAs). Adrenomyeloneuropathy (AMN) is a frequent adult phenotype characterized by progressive spastic paraparesis and axonal neuropathy. We report the first case of AMN associated with a novel ABCD1 variant.

Clinical, neuroradiological, biochemical, neurophysiological, and genetic evaluations were performed in a 60-year-old male presenting with gait impairment and urinary dysfunction. Brain and spinal cord MRI, nerve conduction studies, plasma VLCFA analysis, and targeted next-generation sequencing for hereditary spastic paraplegia were carried out. Functional validation included Western blot analysis on cultured skin fibroblasts.

Neurological examination showed spastic paraparesis with gait impairment. Brain MRI demonstrated confluent white matter hyperintensities, while spinal MRI revealed spinal cord atrophy. Plasma VLCFA levels were markedly elevated. Genetic testing identified a previously undescribed hemizygous ABCD1 variant, c.1922G > T (p.Gly641Val), classified as likely pathogenic according to ACMG criteria. The variant was absent from public databases. Western blot analysis demonstrated absent ABCD1 protein expression in patient-derived fibroblasts, supporting the pathogenicity of the variant.

We describe the first reported case of AMN associated with the novel ABCD1 c.1922G > T (p.Gly641Val) variant, expanding the mutational spectrum of X-ALD. The combination of biochemical findings and absent ALDP expression in patient-derived fibroblasts provides strong support for the pathogenicity of this previously undescribed variant. Reports integrating clinical, biochemical, genetic, and functional data may facilitate interpretation and classification of novel ABCD1 variants in clinical practice.