Leukodystrophies and Mitochondrial Disorders

LEUKODYSTROPHIES

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The leukodystrophies are diseases that affect the white matter of the CNS (Table 31–1). These diseases can begin in infancy, childhood, or adulthood. Infantile-onset leukodystrophies are generally characterized by initial hypotonia followed by spasticity and mental retardation. Seizures may also occur. In childhood-onset leukodystrophies, there is typically developmental and motor regression. Adult-onset leukodystrophies are characterized by dementia, psychiatric symptoms, and development of spasticity.

TABLE 31–1Clinical and Laboratory Features of the Leukodystrophies.

			Neuroimaging
	Age of Onset	Unique Clinical Features	White Matter Changes	U Fibers	Gene Mutation	Inheritance	Diagnosis	Other
Adrenoleukodystrophy	Childhood (most commonly 4–8 years old) or adulthood	Visual and/or behavioral problems in children Adrenal insufficiency Adrenomyelo-neuropathy can occur in adults	Posterior predominance	Spared	ABCD1	XL	Plasma very long chain fatty acids	Treatments: Bone marrow transplant Lorenzo’s oil
Alexander disease	Any age	Macrocephaly Seizures	Frontal predominance	Involved	GFAP	Sporadic or AD	Genetic testing	Pathology: Rosenthal’s fibers
Canavan disease	Infancy	Macrocephaly	Diffuse	Involved	Aspartoacylase	AR	Urine NAA Decreased aspartoacylase activity in skin fibroblasts	Increased NAA peak on MR-spectroscopy
Krabbe disease	Any age (but most commonly infancy)	Irritability Peripheral neuropathy	Posterior predominance	Spared	Galactocerebrosidase	AR	Decreased galactocerebrosidase activity in skin fibroblasts	Globoid cells on pathology Treatment with bone marrow transplant
Metachromatic leukodystrophy	Any age	Peripheral neuropathy	Frontal predominance	Spared	Arylsulfatase A	AR	Decreased arylsulfatase A activity in skin fibroblasts	Treatment with bone marrow transplant
Pelizaeus-Merzbacher disease	Infancy or childhood	Eye movement abnormalities	Diffuse	Spared	PLP1	XL	Genetic testing	Pathology: tigroid appearance of white matter
Vanishing white matter disease	Any age	Ataxia and/or spasticity Spared cognition Ovarian failure may be seen in affected women	White matter hypointense (“vanished”) rather than hyperintense as in other leukodystrophies	Involved	eIF2B	AR	Genetic testing