Niemann-Pick Disease

Group of rare inherited disorders of fat metabolism. Clinical features include jaundice, progressive loss of motor skills, feeding difficulties, learning disabilities, and hepatosplenomegaly. Lysosomal storage disorder caused by a defect in sphingolipid metabolism and involving brain and/or viscera. There are five types of Newman-Pick disease.

Lipid Histiocytosis; Sphingomyelinase Deficiency.

Disorders of sphingomyelin storage were initially grouped together under the eponym Niemann-Pick disease and classified as A, B, C, D, E, and F. However, only types A and B are deficient in sphingomyelinase; types C and D are biochemically and genetically different. Types E and F are not well described. A new nomenclature has been proposed that groups types A and B as type I and types C and D as type II, but this is not yet universally adopted. Types A and B: Deficiency in sphingomyelinase. Types C and D: Basic defect not yet identified.

Autosomal recessive.

Types A and B: The gene for lysosomal sphingomyelinase is located on chromosome 11p15.1-p15.4. Three mutations have been identified in Ashkenazi Jews carrying type A. Other mutations cause type B phenotype and are found in southern Europe and in the Mediterranean region.

Types C and D: The NPC1 gene on chromosome 18q11-12 is Niemann-Pick disease type C1 gene (found worldwide) and mutated in type D (called Nova Scotia variant because of the high incidence in the province of Nova Scotia, Canada); another gene, NPC2, has been identified.

Types A and B: Sphingomyelin accumulates in the brain, viscera, and reticuloendothelial system. Types C and D: Still unknown but there is accumulation of unesterified cholesterol and glucosylceramide in lysosomes. Sphingomyelinase activity is normal in most tissues but is partially deficient in fibroblasts. In the brain, this anomaly leads to swelling of the proximal neurite segment in the cerebral cortex and accumulation of paired helical filaments, as reported in Alzheimer disease.

Sphingomyelinase assay in leukocytes or in fibroblasts shows residual activity that tends to be higher in type B than in type A. Cultured fibroblasts obtained from skin biopsy allow staining with filipin to demonstrate accumulated cholesterol.

Type A: Infantile type. Sphingomyelin accumulates mainly in the brain. Starts with feeding difficulties, hepatomegaly. Respiratory infections are common, with a chest radiograph similar to that seen in miliary tuberculosis. Neurologic deterioration in the second part of the first year of life, with loss of contact, hypotonia, and spastic paresis. In 50% of cases, a cherry-red spot is seen in the macula; it is a normal macula surrounded with grayish-colored retina caused by storage compounds. Vacuolized lymphocytes are found in the blood, and foam cells are present in the bone marrow. Anemia and thrombocytopenia are late signs. Death usually occurs by age 3 years. No treatment available.

Type B: Chronic form. Unlike type A, sphingomyelin accumulates mainly in the viscera and reticuloendothelial system. It presents as hepatosplenomegaly or splenomegaly ...