Myoclonus, epilepsy, and ragged red fibers, dementia, hearing loss, optic nerve atrophy, ataxia, and loss of deep sensation
Neuropathy, ataxia, and retinitis pigmentosa
Tests: testing for mitochondrial disorders is complex and must be tailored to the individual clinical scenario; screening for blood and serum lactate and pyruvate is reasonable
Hypotonia, feeding difficulties, respiratory irregularity, weakness of extraocular movements, and ataxia
Test: depends on clinical phenotype
Loss of purposeful hand movements and communication skills, social withdrawal, gait apraxia, seizures, spasticity, and kyphoscoliosis
Test: MECP2 gene testing
Inborn error of copper metabolism resulting in signs of cerebellar and basal ganglia dysfunction
Test: serum ceruloplasmin levels, urinary copper excretion patient with a degenerative neurologic condition of unknown cause should have leukocytes or skin fibroblasts harvested for measurement of a standard battery of lysosomal, peroxisomal, and mitochondrial enzymes (Chapters 56, 57). Neuroimaging, usually with brain magnetic resonance imaging (MRI), is also typically warranted. The diagnosis of leukodystrophy usually can be made confidently on the basis of extensive cerebral white matter changes on MRI. Histologic and biochemical studies may be normal in gray matter encephalopathy, making the diagnosis much less secure. Acquired lesions (infectious, inflammatory, vascular, toxic) are difficult to exclude completely. Brain biopsy is not likely to be helpful.
The sphingolipidoses are characterized by intracellular storage of lipid substrates resulting from defective catabolism of the sphingolipids comprising cellular membranes. They are inherited in an autosomal recessive pattern. In most cases, there are several forms of these diseases, typically corresponding to the amount of residual activity in the relevant enzyme.
The infantile forms are generally the most severe, usually presenting in the first or second year of life with rapid disease progression; affected individuals have virtually no normal enzyme activity. Juvenile and chronic forms are manifest somewhat later in childhood or even adulthood and have a less fulminant disease course because of some residual enzyme activity.
Classic Niemann-Pick disease is caused by a deficiency of sphingomyelinase and should be suspected in infants who exhibit the combination of hepatosplenomegaly, developmental delay, interstitial lung disease, and retinal cherry-red spots. The ganglion cells of the retina and macula are distended and appear as a large area of white surrounding a small red fovea that is not covered by ganglion cells. Cognitive regression, myoclonic seizures, hypotonia, and jaundice are also noted within the first year of life. Genetic testing for SMPD1 mutations is clinically available.
Although the most common form of Gaucher disease is an indolent illness of adults, there is a rapidly fatal infantile form featuring severe neurologic involvement caused by deficiency of the enzyme glucocerebrosidase. Glucoceramide accumulates in the liver, spleen, and bone marrow. The characteristic neurologic signs are opisthotonos (arching of the trunk), trismus (difficulty opening mouth), eye movement abnormalities, and bulbar signs including difficulty swallowing.
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Tay-Sachs disease (GM2 gangliosidosis) is caused by deficiency of hexosaminidase A and results in the accumulation of GM2 ganglioside in cerebral gray matter and cerebellum. Infants are typically normal except for a marked startle response until 6 months of age, when they develop listlessness, irritability, hyperacusis, intellectual retardation, and retinal cherry-red spots. Within months, blindness, convulsions, spasticity, and opisthotonos develop.