Genetic Analysis of Inherited Leukodystrophies

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Abstract
The leukodystrophies are a clinically and pathologically heterogeneous group of white matter diseases of the central nervous system. Recent genotypic and phenotypic advances have allowed a more specific classification of the leukodystrophies but there remain many difficulties in the diagnosis.1 Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a progressive autosomal dominant leukodystrophy with an onset typically occurring in the fourth or fifth decade of life (although with a wide spread in age at onset between 15-78 years). The clinical presentation is variable and patients have been described with dementia, seizures, parkinsonian features, spastic paraplegia, personality/behavioral changes, and dystonia.2-4 A definitive diagnosis of HDLS has therefore relied on the characteristic pathological features being seen at brain biopsy or post mortem, ie, loss of myelin sheaths and axonal destruction, axonal spheroids, gliosis, and autofluorescent lipid-laden macrophages.4-11 There is definite clinical overlap between HDLS and pigmentary orthochromatic leukodystrophy. The pathological hallmarks of the 2 diseases, axonal spheroids in HDLS and pigmented macrophages in pigmentary orthochromatic leukodystrophy, can be identified in both conditions and this supports HDLS and pigmentary orthochromatic leukodystrophy being referred to collectively, in a review of these 2 conditions, as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.2

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