Leukoencephalopathy and leukodystrophy

Leukodystrophies can be classified according to neuroimaging, cellular, metabolic, or molecular characteristics. Magnetic resonance imaging (MRI) plays a central role in distinguishing major subtypes, particularly demyelinating and hypomyelinating forms, and serves as a key diagnostic tool alongside genetic testing. Leukodystrophies arise from dysfunction of various central nervous system cell types and molecular pathways involved in myelin formation, maintenance, and white matter homeostasis. Pathogenic mechanisms often extend beyond myelin itself and affect interconnected biological processes. The clinical presentation is highly heterogeneous and depends on both the underlying genetic defect and the age at disease onset, which may range from infancy to adulthood. Disease severity generally correlates with earlier onset, particularly in hypomyelinating disorders, and most leukodystrophies follow a progressive course, although atypical cases with partial clinical and radiological improvement have been reported. Leukodystrophies commonly present with a broad range of neurological manifestations, most notably motor and cognitive impairment. Frequent clinical features include pyramidal and extrapyramidal signs, gait disturbances, peripheral neuropathy, bulbar dysfunction, seizures, and neurobehavioral abnormalities. Additional findings such as autonomic dysfunction, macrocephaly, or microcephaly may provide important diagnostic clues and help distinguish specific leukodystrophy subtypes.

The incidence of leukodystrophies shows marked geographic variability, with estimates ranging from 1 in 100,000 to 1 in 6,000-7,700 live births in Western populations and approximately 3 per 100,000 live births in Asian cohorts.

The distribution of genetic leukoencephalopathies varies considerably according to age at onset. In paediatric cohorts, metachromatic leukodystrophy (ARSA, lysosomal sulfatide accumulation) is among the most prevalent disorders, followed by adrenoleukodystrophy (ABCD1, peroxisomal very-long-chain fatty-acid accumulation), , mitochondrial leukoencephalopathies, vanishing white matter disease, Pelizaeus-Merzbacher disease, and . Adult patients exhibit a distinct diagnostic spectrum, in which cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy () constitutes a leading cause of inherited white matter disease.

A wide range of inheritance patterns has been described for leukodystrophies, including autosomal recessive, autosomal dominant, X-linked, mitochondrial, and sporadic forms. Nevertheless, the majority of leukodystrophies follow an autosomal recessive mode of inheritance.

• Where leukoencephalopathy or leukodystrophy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Ceravolo G, Zhelcheska K, Squadrito V, Pellerin D, Gitto E, Hartley L, et al. Update on leukodystrophies and developing trials. J Neurol. 2024;271(1):593-605. PMID: .
• Muthusamy K, Sivadasan A, Dixon L, Sudhakar S, Thomas M, Danda S, et al. Adult-onset leukodystrophies: a practical guide, recent treatment updates, and future directions. Front Neurol. 2023;14:1219324. PMID: .
• Wu C, Wang M, Wang X, Li W, Li S, Chen B, et al. The genetic and phenotypic spectra of adult genetic leukoencephalopathies in a cohort of 309 patients. Brain. 2023;146(6):2364-2376. PMID: .