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At a glance

Group of rare inherited disorders of fat metabolism with varying degrees of lipid storage and foam cell infiltration in tissues. Clinical features include jaundice, progressive loss of motor skills, feeding difficulties, learning disabilities, and hepatosplenomegaly. Lysosomal storage disorder caused by deficient activity of the enzyme acid sphingomyelinase (Types A and B) or due to defective function in cholesterol transport (Type C).

Synonyms

Lipid Histiocytosis; Sphingomyelinase Deficiency.

History

Named after German pediatrician, Albert Niemann and German pathologist, Ludwig Pick.

Incidence

Type A 1:500,000; Type B 1:200,000; Type C 1:100,000.

Genetic inheritance

Autosomal recessive.

  • Types A and B: The gene (SMPD1) for lysosomal sphingomyelinase is located on chromosome 11p15.1-p15.4. More than 180 mutations have been described. The different phenotypes may be in part due to inheritance of specific mutations on the maternal versus paternal alleles. Three mutations have been account for more than 90% in the Ashkenazi Jewish population carrying Type A. Other mutations cause Type B phenotype and are found in southern Europe and in the Mediterranean region.

  • Type C: Mutations of the NPC1 gene on chromosome 18q11 are responsible Niemann-Pick Disease Type C (95%) and mutations in the NPC2 gene (5%). The term Type D (found in Nova Scotia) is no longer used.

Pathophysiology

Types A and B: Sphingomyelin accumulates in the brain, viscera, and reticuloendothelial system. Type C: Dysfunction of cellular cholesterol trafficking and other lipids in the late endosomal/post-lysosomal stage of lipid transport resulting in tissue accumulation of multiple lipids. 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.

Diagnosis

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.

Clinical aspects

  • 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. Bone marrow transplant or enzyme ...

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