Metachromatic leukodystrophy (MLD) is a lipidosis causedby deficiency of arylsulfatase that results in demyelination ofthe central nervous system (CNS) and peripheral nervous system. Children with the late-infantile form present between 1and 2 years of age. After a period of normal development, progressive stiffening and ataxia of gait, spasticity, optic atrophy,intellectual deterioration, and absent reflexes occur. Diagnostictesting reveals increased cerebral spinal fluid protein (a sign ofCNS demyelination) and slowing of motor nerve conductionvelocity (a sign of peripheral demyelination). Older school-agechildren with the juvenile form of MLD may present with gradual onset of behavior difficulties and declining academic abilities, succeeded by gait difficulties, clumsiness, slurred speech,and sometimes seizures. Relentless progression is the rule.Bone marrow transplant is a treatment option, particularly if asibling is diagnosed with MLD before symptom onset.
Krabbe disease (globoid cell leukodystrophy) is caused by a deficiency of galactocerebrosidase. Individuals with the infantile form (85% to 90% of cases) appear to be normal during the first months of life. Symptoms begin by 6 months of age and include extreme irritability, hyperpyrexia, vomiting, seizures, hypertonia, and blindness. Demyelination of the CNS and peripheral nervous system results in upper and lower motor neuron signs.
The neuronal ceroid lipofuscinoses are a group of inherited, neurodegenerative lysosomal storage disorders characterized by progressive vision loss, seizures, declining cognitive abilities, motordeterioration, and early death. Ten different types have been characterized, including infantile, late-infantile, and juvenile types.
The adrenoleukodystrophies (ALD) are a group of X-linked neurodegenerative disorders that are often associated with adrenocortical insufficiency. ALD is caused by accumulation of very long chain fatty acids in neuronal and adrenal tissue (Chapter 178) and is diagnosed by abnormal very long chain fatty acid testing. The most common leukodystrophy is classic X-linked adrenoleukodystrophy, caused by a mutation in the ABCD1 gene. Boys present between ages 5 and 15 years with academic difficulties, behavioral disturbances, and gait abnormalities, progressing to seizures, spasticity, ataxia, and swallowing difficulties. Brain MRI demonstrates a classic pattern of symmetric abnormal white matter signal in the parietal-occipital regions, with contrast enhancement at the anterior margin. Symptomatic adrenocortical insufficiency with fatigue, vomiting, and hypotension develops in 20% to 40% of patients with X-linked ALD. ALD should be considered in any male with primary adrenocortical insufficiency, even in the absence of clear-cut neurological abnormalities. Adrenomyeloneuropathy, a chronic disorder of spinal cord and peripheral nerves, presents in the third decade of life. Female carriers of the ABCD1 mutation may also have symptoms similar to adrenomyeloneuropathy, beginning later in life (>35 years of age).