Niemann-Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification. A collaborative study on 70 patients

Clin Genet. 1988 May;33(5):331-48. doi: 10.1111/j.1399-0004.1988.tb03460.x.


Seventy patients were selected to cover the range of variability in clinical expression of Niemann-Pick disease group C (NP-C). Their individual main clinical features and course of the disease (age at discovery and type of visceromegaly, age at onset and first neurological manifestation, later neurological symptoms) are schematically described. In cultured skin fibroblasts from these patients, sphingomyelinase activities measured in vitro showed decreased values only in approximately half of the cases, and when the metabolic fate of [14C]-sphingomyelin was studied in living cell cultures, still 20% of the cases had a normal hydrolysis rate. Esterification of exogenous cholesterol was investigated in cell lines from these and 5 additional patients and in 21 of their parents. Using a non-lipoprotein [3H]cholesterol source, very low esterification rates were obtained in more than 90% of the cases. All the numerous other pathological conditions studied, including Niemann-Pick disease types A and B, gave normal results. A more sensitive method was elaborated, in which the cells were challenged with pure human low density lipoproteins (LDL) and the early rate of esterification studied. With the latter procedure, a pronounced deficiency could also be demonstrated in the few cases which had shown a milder impairment using a [3H]cholesterol source, and intermediate rates of esterification were obtained in heterozygotes. Discrimination of these difficult cases and of heterozygotes could also be achieved replacing LDL with total unfrozen human serum. Correlations were established between given clinical phenotypes and the severity of the biochemical lesion. Defective intracellular cholesterol esterification is further established as an intrinsic feature of NP-C, and demonstration of this metabolic alteration appears as a major advance in diagnosing the condition.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Bone Marrow / pathology
  • Cells, Cultured
  • Cholesterol Esters / biosynthesis*
  • Cholesterol, LDL / metabolism
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Niemann-Pick Diseases / classification*
  • Niemann-Pick Diseases / diagnosis
  • Niemann-Pick Diseases / metabolism
  • Niemann-Pick Diseases / pathology
  • Phenotype
  • Sphingomyelin Phosphodiesterase / metabolism


  • Cholesterol Esters
  • Cholesterol, LDL
  • Sphingomyelin Phosphodiesterase