Niemann-Pick Disease Type C. Chronic neuronopathic form. Juvenile form.
Incidence
It is an autosomal recessive disease. It is due to an abnormality of intracellular processing of exogenous cholesterol which may result in a secondary partial reduction of sphyngomyelinase activity.
Clinical Characteristics
The onset of this condition in 1/3 of the cases is on the second year of life (late infancy) with symptoms similar to Niemann-Pick disease type A. There is normal vision, normal NCV and CSF. Death occur by the age of three to five years. In 2/3 of the cases, the onset is in childhood to adolescence (juvenile). Symptoms start between 3 to 8 years of age in 70 % of the cases and less often between 10 and 15 years of age (30 %) and rarely in adulthood. The major symptoms are ataxia, incoordination, tremor, dysarthria. There is dystonia and choreoathetosis prominent in some patients. The hallmark of the disease is supranuclear palsy of vertical eye movements. Patients cannot see low placed objects so the head is tilted downward. Occasionally the eye gaze is fixed upward. Vertical doll's eyes movement are normal. Optokinetic nystagmus vertically is absent but it is normal horizontally. The vertical supranuclear palsy always is present in children above the age of seven years. Seizures occur in one third of the cases. Cataplexic attack (falling when excited) may occur. There is late spasticity and late mental retardation with behavioral problems. Spleen is moderately enlarged more than liver but not always occur hepatosplenomegaly. A history of prolonged neonatal jaundice is present in 50% of the patients which is gone by the age of two to four months. There are peculiar storage cells in the bone marrow called blue-sea histocytes and there are also vacuolated cells. There is no X-ray deformities observed. MRI of the brain shows cerebellar atrophy. No retinal changes, no visual failure and no polyneuropathy is seen. CSF is normal. Death occur by the second or third decade from aspiration pneumonia. Diagnosis is made by the association of vertical supranuclear gaze palsy, foam cells and sea-blue histiocytes in the bone marrow, hepatosplenomegaly and when present, an antecedent history of prolonged neonatal or transient infantile jaundice. Skin, rectal or conjunctival biopsy may be of some help to detect intralysosomal lamellar cytoplasmic bodies. The activity of sphyngomyelinase in leukocytes is normal but a partial deficiency may be found in cultured fibroblasts, a secondary consequence of lysosomal cholesterol sequestration. Diagnosis rests in the demonstration of unique abnormalities of intracellular translocation of exogenous cholesterol, done in cultured skin fibroblasts or lymphocytes, demonstrating an impaired cholesterol esterification and the intralysosomal storage of unesterified cholesterol. There is no specific therapy available. A diet restricted in cholesterol and administration of cholesterol lowering agents have resulted in reduction of hepatic and plasma cholesterol levels but its effect on the course of neurological disorders remains to be seen.
Precipitants
no
Provocation Tests
no
Diagnostic Procedures
Diagnosis is made by the association of vertical supranuclear gaze palsy, foam cells and sea-blue histiocytes in the bone marrow, hepatosplenomegaly and when present, an antecedent history of prolonged neonatal or transient infantile jaundice. Skin, rectal or conjunctival biopsy may be of some help to detect intralysosomal lamellar cytoplasmic bodies. The activity of sphyngomyelinase in leukocytes is normal but a partial deficiency may be found in cultured fibroblasts, a secondary consequence of lysosomal cholesterol sequestration. Diagnosis rests in the demonstration of unique abnormalities of intracellular translocation of exogenous cholesterol, done in cultured skin fibroblasts or lymphocytes, demonstrating an impaired cholesterol esterification and the intralysosomal storage of unesterified cholesterol.