Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic study.
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.


METHODS
Case series in a tertiary care center.


METHODS
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.
Lossos
A
A
Department of Neurology, Hadassah-Hebrew University Hospital and Medical School, Jerusalem, Israel. alos@md2.huji.ac.il
Schlesinger
I
I
Okon
E
E
Abramsky
O
O
Bargal
R
R
Vanier
M T
MT
Zeigler
M
M
D000328:Adult; D017668:Age of Onset; D001853:Bone Marrow / Q000473:pathology; D002788:Cholesterol Esters / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D018895:Microsatellite Repeats / Q000235:genetics; D009542:Niemann-Pick Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D011995:Recombination, Genetic; D013194:Staining and Labeling
D002788:Cholesterol Esters; D004247:DNA