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

Abstract

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. We performed a combined retrospective-prospective observational study of adults (≥18 years) with confirmed <i>ABCD1</i> 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. The cohort comprised 140 patients (64 males, 76 females) from 58 families, carrying 50 <i>ABCD1</i> 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). 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. NCT04880356.