Isolated Corticospinal Tract Lesions as an Early Manifestation of Adrenoleukodystrophy in Children.

PURPOSE: X-linked adrenoleukodystrophy (ALD) encompasses a wide range of neurological manifestations, classically described as distinct phenotypes including childhood cerebral adrenoleukodystrophy and adult-onset adrenomyeloneuropathy (AMN). Corticospinal tract (CST) and cerebellar involvement on brain magnetic resonance imaging (MRI) are typically attributed to long-tract axonopathy in AMN, yet the extent to which these features span the ALD spectrum is unclear. To explore whether CST and infratentorial lesions reflect discrete phenotypes or a continuous disease spectrum, we examined their onset and prevalence across the lifespan. METHODS: We retrospectively analyzed 1189 brain MRIs from 218 male patients diagnosed with ALD evaluated at Massachusetts General Hospital from 2005 to 2024. Imaging reports were screened for CST and infratentorial lesion presence, and serial scans were reviewed to determine chronological patterns of involvement. In pediatric patients with isolated CST lesions, treatment data and post-treatment imaging were assessed. RESULTS: Isolated CST lesions were identified in 8.7% of pediatric and 11.4% of adult patients. All but one adult with cerebellar lesions also demonstrated CST lesions, which preceded or occurred concurrently with the cerebellar abnormalities. Among pediatric patients with isolated CST lesions, 38.5% underwent lentiviral gene therapy, and 23.1% received hematopoietic stem cell transplantation. Imaging post-treatment revealed lesion size reduction in 87.5%. CONCLUSION: CST involvement, including isolated lesions and those preceding cerebellar involvement, occurs across age groups and may represent a continuous ALD disease spectrum rather than a strictly phenotype-specific feature. These findings support the importance of dedicated CST assessment in routine MRI review and highlight its potential role in earlier diagnosis and therapeutic decision-making.