Metabolic leukodystrophies should be considered in all patients with patterns of white matter abnormalities that are not evocative of an inflammatory or vascular process. Metabolic leukodystrophies typically present with bilateral and symmetrical white matter involvement, either fascicular or confluent. Biochemical analyses should be conducted as first-line investigations, including blood tests for cholestanol, homocysteine, very long-chain fatty acids, lactate, and a few enzymes—particularly arylsulfatase A and galactocerebrosidase.
Diagnosing metabolic leukodystrophies is crucial, as some are treatable with small molecules — such as cerebrotendinous xanthomatosis and homocysteine remethylation disorders — or with hematopoietic stem cell transplantation, as in X-linked adrenoleukodystrophy, metachromatic leukodystrophy, and CSF1R-related leukodystrophy.