Work

Adrenoleukodystrophy in adults: phenotypic characterisation and natural history in a large cohort

Year: 2026

Type: article

Abstract: BACKGROUND: Adult adrenoleukodystrophy is a rare X linked disorder with heterogeneous phenotypes, complicating prognosis and trial design. We characterised phenotype and natural history in a large single-centre nationwide cohort and contextualised findings with prior reports. METHODS: variants evaluated at Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (January 2004-June 2023), with reassessments between July and December 2023. Clinical, genetic, biochemical, MRI and neurophysiological data were analysed. RESULTS: variants, including 11 novel mutations. Adrenomyeloneuropathy (AMN) predominated in males, with low mortality (<10%) and rare cerebral progression (7%) across 18 years, suggesting protective factors. An intermediate phenotype, adrenoleukomyeloneuropathy (ALMN), showed earlier onset, demyelinating MRI changes without cerebral symptoms at baseline and higher mortality than AMN (HR 4.75, 95% CI 1.60 to 14.11). In females, symptom prevalence increases with age, affecting 57% over 60, although only 37% required walking aids. Males had higher very long-chain fatty acid (VLCFA) levels than females, but intrasex correlations with phenotype were absent. Brainstem auditory evoked potentials (BAEPs) were consistently abnormal, whereas nerve conduction studies were abnormal in ~half of male patients (less often in females). CONCLUSIONS: Adult adrenoleukodystrophy comprises distinct phenotypes with variable prognosis. Recognition of ALMN as an intermediate form and the low cerebral progression rate in Italian AMN refine disease classification. Sex-related VLCFA differences may influence severity, although standard assays lack sensitivity. Neurophysiological testing, particularly BAEPs, can support differential diagnosis in patients with hereditary spastic paraplegias. TRIAL REGISTRATION NUMBER: NCT04880356.

Source: Journal of Neurology Neurosurgery & Psychiatry

DOI: 10.1136/jnnp-2025-337540