Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic study
A. Lossos, I. Schlesinger, E. Okon, O. Abramsky, R. Bargal, M. T. Vanier and M. Zeigler
Department of Neurology, Hadassah-Hebrew University Hospital and Medical School, Jerusalem, Israel. alos@md2.huji.ac.il
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 low-density 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 4 1/2
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.
