There is a later-onset form of the disease in which the course is more protracted and the neurologic manifestations (rigidity and spasticity, cerebellar ataxia, and myoclonus) are more pronounced. In these cases, the mental regression is slow. Vision may be retained but retinal degeneration has been documented. Some of the late-onset cases are indistinguishable from PKAN (formerly Hallervorden-Spatz) disease.
In early infantile forms there is a mutation in a lysosomal hydrolase. The primary mutation in the infantile form is in the PLA2G6 gene.
As stated earlier, Gaucher disease usually develops in early infancy, but some cases, so-called Gaucher disease type III, may begin in childhood, between 3 and 8 years of age. The clinical picture is variable and combines features of infantile Gaucher disease—such as abducens palsies, dysphagia, trismus, rigidity of the limbs, and dementia—with features of the late childhood–early adult form, such as palsies of horizontal gaze, diffuse myoclonus, generalized seizures, and a chronic course. The diagnosis is established by the finding of splenomegaly, Gaucher cells, glucocerebroside storage, and deficient activity of glucocerebrosidase in leukocytes or cultured fibroblasts.
Niemann-Pick disease is a subacute or chronic neurovisceral storage disease with early signs of hepatosplenomegaly and later signs (2 to 4 years) of neurologic involvement. These later-onset types have been termed C and D, and formerly, III and IV, to differentiate them from infantile forms discussed earlier. The neurologic disorder consists of progressive dementia, dysarthria, ataxia, rarely extrapyramidal signs (choreoathetosis), and paralysis of horizontal and vertical gaze, the latter being a distinguishing feature of the later-onset types. On attempting to look to the side, some of the patients make head-thrusting movements of the same type that one observes in ataxia- telangiectasia and the oculomotor apraxia of Cogan. Lateral eye movements are full on passive movement of the head (oculocephalic maneuver). Convergence is also deficient. A subtype called juvenile dystonic lipidosis is characterized by extrapyramidal symptoms and paralysis of vertical eye movements. The syndrome of the “sea-blue histiocyte” (liver, spleen, and bone marrow contain histiocytes with sea-blue granules)—in which there is retardation in mental and motor development, grayish macular degeneration, and, in rare cases, posterior column and pyramidal degeneration—may be another variant.
The diagnosis is made by measuring the defect in cholesterol esterification in cultured skin fibroblasts.