leukodystrophies

Leukodystrophies are a heterogeneous group of inherited disorders characterized by abnormal development or destruction of the brain’s white matter due to defects in myelin formation, maintenance, or catabolism. Most are caused by mutations in genes encoding enzymes, structural myelin proteins, or proteins involved in lipid metabolism. Inheritance can be autosomal recessive, X-linked, or, less commonly, autosomal dominant.

Common subtypes include metachromatic leukodystrophy ( ARSA deficiency), Krabbe disease (GALC deficiency), X-linked adrenoleukodystrophy (ABCD1 mutations), Canavan disease (ASPA deficiency), Pelizaeus–Merzbacher disease (PLP1 mutations), and Alexander disease (GFAP mutations). The disorders are diverse in onset and progression, ranging from infancy to adulthood.

Pathophysiology generally involves defective myelin formation or progressive demyelination, often accompanied by the accumulation of toxic lipids or other metabolites in white matter. This leads to a cascade of neurological symptoms and eventually disability.

Clinically, leukodystrophies commonly present with developmental delay or regression, motor dysfunction (hypotonia evolving to spasticity or ataxia), speech and coordination problems, vision or hearing loss, seizures, or behavioral changes. Onset varies by subtype and individual, with some forms appearing in infancy and others later in childhood or adulthood.

Diagnosis relies on clinical suspicion supported by neuroimaging and laboratory testing. MRI typically shows symmetric or characteristic patterns of white matter involvement. Subtype confirmation is by biochemical assays and genetic testing; for example, elevated plasma very long-chain fatty acids support ALD, reduced ARSA activity supports MLD, and reduced GALC activity supports Krabbe disease.

Management is largely supportive and multidisciplinary. No cure exists for most leukodystrophies; disease-modifying options are available in select conditions (for example, hematopoietic stem cell transplantation in early cerebral forms of ALD and certain other subtypes, along with emerging gene therapies and clinical trials). Prognosis varies widely by subtype and age of onset, underscoring the importance of genetic counseling and family planning.