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Leukodystrophies: An Overview

Leukodystrophies represent a large group of rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord, and often the peripheral nerves. The word leukodystrophy comes from the Greek roots and means: leuko = “white”; dys = “lack of”; and troph = “growth.” Each type of leukodystrophy (see Table L-1) is caused by a specific gene that leads to an abnormal development or destruction of the myelin sheath of the white matter of specific areas of the brain. The neurological manifestations are directly associated to the brain area where the myelin sheath is affected. In general, the symptoms are characterized by a decreased motor function, muscular spasticity, and progressive loss of sight and auditory. When the age of onset is during infancy, it is usually associated with a life expectancy between 2 and 8 years. When it affects adults, they typically live more than a decade after the onset. The diagnosis is made with magnetic resonance imaging showing the degeneration of the white matter. Overall, the general incidence is estimated at 1:7,600 live births. The mode of inheritance is either recessive, dominant, or X-linked for most medical associated conditions. However, spontaneous mutations have been reported.

TABLE L-1Leukodystrophy Classification
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TABLE L-1 Leukodystrophy Classification
Name Synonyms Inheritance Defective Protein/Gene
☞Adrenoleukodystrophy ☞Schilder Disease; Bronze-Schilder Syndrome; sudanophilic leukodystrophy X-linked ALD protein
Adrenomyeloneuropathy (minor form of adrenoleukodystrophy) X-linked ALD protein
☞Aicardi-Goutieres Syndrome Autosomal recessive Unknown
☞Alexander Syndrome Autosomal recessive Unknown
☞CACH Childhood ataxia with central nervous system hypomyelination; vanishing white matter disease Autosomal recessive Unknown
☞CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy Autosomal dominant Chromosome 19p13.1 (Notch3 gene)
☞Canavan Syndrome (several clinical forms reported) Spongy degeneration of the brain Autosomal recessive Deficiency of aspartoacylase (accumulation of N-acetylaspartic acid)
Cerebrotendinous Xanthomatosis Autosomal recessive Unknown (accumulation of cholestanol)
Krabbe disease (several clinical forms reported) Globoid cell leukodystrophy Autosomal recessive Chromosome 14; deficiency of galactocerebrosidase (GALC)
☞Metachromatic Leukodystrophies (many subtypes) Autosomal recessive

Chromosome 22; deficiency in arylsulfatase A (also called sulfatase A or cerebroside sulfate sulfohydrolase)

Occasionally chromosome 10; deficiency in cerebroside sulfatase activator (or saponin B)
Ovarioleukodystrophy Syndrome Possibly autosomal recessive Unknown
☞Pelizaeus-Merzbacher Disease (several subtypes) X-linked spastic paraplegia; PMD/SPG2 X-linked Duplication of or other mutation in the proteolipid protein gene
☞Refsum Disease Refsum Syndrome Autosomal recessive Deficiency in phytanoyl-CoA hydroxylase (accumulation of phytanic acid)
Van der Knaap Syndrome Vacuolating leukoencephalopathy with subcortical cysts Autosomal recessive Unknown
☞Zellweger Syndrome   Autosomal recessive At least 10 different gene abnormalities (resulting in decreased or missing peroxisomes in liver, kidney, and brain cells)

Classification

Clinically, there are several specific types of leukodystrophies that are described in length elsewhere in the book (indicated with ☞preceding the name of the syndrome). A short description of each condition is given here to facilitate consultation:

  • Adrenoleukodystrophy (X-Linked Adrenoleukodystrophy, ALD, X-ALD, Siemerling-Creutzfeldt Disease, and Bronze Schilder Disease): X-linked adrenoleukodystrophy (ALD) is the most ...

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