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December 1997

Adult-Onset Niemann-Pick Type C Disease: Clinical, Biochemical, and Genetic Study

Author Affiliations

From the Departments of Neurology (Drs Lossos, Schlesinger, and Abramsky), Pathology (Dr Okon), and Human Genetics (Ms Bargal and Dr Zeigler), Hadassah-Hebrew University Hospital and Medical School, Jerusalem, Israel; and the Department of Biochemistry, Lyon-Sud School of Medicine, Oullins, France (Dr Vanier).

Arch Neurol. 1997;54(12):1536-1541. doi:10.1001/archneur.1997.00550240084016

Background:  Niemann-Pick type C disease is an autosomal recessive neurometabolic disorder of unknown origin mapped to chromosome 18q11-12 in most of the studied families. In contrast to the sphingomyelin lipidoses, in Niemann-Pick type C disease, fibroblasts are impaired in intracellular homeostatic responses to exogenous lowdensity lipoprotein (LDL) cholesterol. Biochemical heterogeneity of the disorder in relation to abnormal LDL processing is associated with various clinical presentations, but adult-onset Niemann-Pick type C disease is rare and has not been comprehensively characterized.

Objective:  To describe clinical, biochemical, and genetic features of adult-onset Niemann-Pick type C disease in 3 siblings.

Design and Setting:  Case series in a tertiary care center.

Patients:  The 3 siblings manifested a variable combination of vertical supranuclear ophthalmoplegia, ataxia, and splenomegaly. Brain magnetic resonance imaging showed cerebellar atrophy; brainstem auditory evoked responses were unobtainable, and bone marrow examination disclosed typical foam cells. The patients were 20, 26, and 28 years old and belonged to a sibship of 13 born of consanguineous healthy parents.

Methods:  Esterification of exogenous LDL cholesterol in cultured skin fibroblasts and filipin staining for free intracellular cholesterol. Polymerase chain reaction—based DNA linkage study using AC microsatellite markers D18S40, D18S44, D18S480, and D18S66.

Results:  Fibroblasts of the 3 patients showed a 23% to 58% block in the induced cholesterol esterification after 4½ hours and a mild to moderate accumulation of free cholesterol. DNA study demonstrated linkage to the major 18q11-12 Niemann-Pick type C locus and identified unaffected carriers.

Conclusions:  These results confirm the diagnosis of the least biochemically affected Niemann-Pick type C phenotype in this family with adult-onset disease and support a correlation between the mild laboratory and clinical findings in this age group.