Gaucher disease is a nonneuronopathic and relatively benign form. A less-frequent type III Gaucher disease is neuronopathic. It expresses itself in late childhood or adolescence by a slowly progressive mental decline, seizures, and ataxia, and, later, by spastic weakness and splenomegaly. Vision and retinae remain normal. Highly diagnostic is the defect in voluntary lateral gaze (oculomotor apraxia), with full movements on the oculocephalic (“doll’s-head”) maneuver. These signs help to differentiate Gaucher from Niemann-Pick disease, in which vertical eye movements are lost (see below). The nucleotide sequence of the cloned glucocerebrosidase gene of type I Gaucher disease was found by Tsuji and associates (1987) to be different from that of types II and III. There is no treatment for the latter types.
Infantile Niemann-Pick Disease (Sphingomyelinase Deficiency, NPC Mutation)
This is also an autosomal recessive disease. Two-thirds of the affected infants have been of Ashkenazi Jewish parentage. The onset of symptoms in the usual type A disease is between 3 and 9 months of age, frequently beginning with marked enlargement of liver, spleen, and lymph nodes and infiltration of the lungs; rarely, there is jaundice and ascites. Cerebral abnormalities are definite by the end of the first year, often earlier. The usual manifestations are loss of spontaneous movements, lack of interest in the environment, axial hypotonia with bilateral corticospinal signs, blindness and amaurotic nystagmus, and a macular cherry-red spot (in about one-quarter of the patients). Seizures may occur, but are relatively late. There is no acoustic- induced startle or myoclonus, and head size is normal or slightly reduced. Loss of tendon reflexes and slowed conduction in peripheral nerves have been recorded but are rare. Protuberant eyes, mild hypertelorism, slight yellowish pigmentation of oral mucosa, and dysplasia of dental enamel have also been reported but are rare. Most patients succumb to an intercurrent infection by the end of the second year.
Vacuolated histiocytes (“foam cells”) in the bone marrow and vacuolated blood lymphocytes are the important laboratory findings. A deficiency of sphingomyelinase in leukocytes, cultured fibroblasts, and hepatocytes is diagnostic. Pathologic examination reveals a decrease in the number of neurons; many of the remaining ones are pale and ballooned and have a granular cytoplasm. The most prominent neuronal changes are seen in the midbrain, spinal cord, and cerebellum. The white matter is little affected. The retinal nerve cell changes are similar to those in the brain. The foamy histiocytes (Niemann-Pick cells) that fill the viscera contain sphingomyelin and cholesterol; the distended nerve cells contain mainly sphingomyelin.
There are also less-severe late infantile and juvenile-adult forms of Niemann-Pick disease types C and D. These are discussed in a later section of this chapter.
Infantile Generalized GM1 Gangliosidosis (Type I,
Beta-Galactosidase Deficiency, Pseudo-Hurler Disease, GLB1 Mutation)