{
  "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 We performed a combined retrospective-prospective observational study of adults (≥18 years) with confirmed ABCD1 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 The cohort comprised 140 patients (64 males, 76 females) from 58 families, carrying 50 ABCD1 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.",
  "authors": [
    {
      "affiliations": [
        "Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy",
        "Translational Medicine PhD Programme, University of Milan, Milan, Italy"
      ],
      "name": "Chiara Benzoni"
    },
    {
      "affiliations": [
        "Unit of Neuroradiology, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy",
        "Department of Biomedical Sciences for Health, University of Milan, Milan, Italy"
      ],
      "name": "Marco Moscatelli"
    },
    {
      "affiliations": [
        "Unit of Neurophysiology, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Paola Lanteri"
    },
    {
      "affiliations": [
        "Unit of Medical Genetics and Neurogenetics, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Viviana Pensato"
    },
    {
      "affiliations": [
        "Unit of Neurophysiology, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Chiara Calò"
    },
    {
      "affiliations": [
        "Unit of Medical Genetics and Neurogenetics, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Simona Allievi"
    },
    {
      "affiliations": [
        "Unit of Medical Genetics and Neurogenetics, Department of Diagnostic and Applied Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Cinzia Gellera"
    },
    {
      "affiliations": [
        "Unit of Child Neurology, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Anna Ardissone"
    },
    {
      "affiliations": [
        "Unit of Child Neurology, Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Isabella Moroni"
    },
    {
      "affiliations": [
        "Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Silvia Fenu"
    },
    {
      "affiliations": [
        "Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Eleonora Cavalca"
    },
    {
      "affiliations": [
        "Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Davide Pareyson"
    },
    {
      "affiliations": [
        "Unit of Rare Neurological Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy"
      ],
      "name": "Ettore Salsano"
    }
  ],
  "title": "Adrenoleukodystrophy in adults: phenotypic characterisation and natural history in a large cohort",
  "uid": "255104aa-5dc1-5bd8-a13e-b14942d69d70"
}