Niemann‐Pick disease group C: clinical variability and diagnosis based on defective cholesterol esterification: A collaborative study on 70 patients
- 1 May 1988
- journal article
- research article
- Published by Wiley in Clinical Genetics
- Vol. 33 (5), 331-348
- https://doi.org/10.1111/j.1399-0004.1988.tb03460.x
Abstract
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.Keywords
This publication has 28 references indexed in Scilit:
- Ophthalmoplegic Neurolipidosis - Storage Cells in HeterocygotesNeuropediatrics, 1985
- Biochemical studies in Niemann‐Pick disease. III: In vitro and in vivo assays of sphingomyelin degradation in cultured skin fibroblasts and amniotic fluid cells for the diagnosis of the various forms of the diseaseClinical Genetics, 1985
- Clinical heterogeneity in a sibship with Niemann‐Pick disease type CClinical Genetics, 1983
- Cataplexy in variant forms of Niemann‐Pick diseaseAnnals of Neurology, 1982
- Lactosyl Ceramidosis: Normal Activity for Two Lactosyl Ceramide β-GalactosidasesScience, 1975
- A NEUROVISCERAL STORAGE DISEASE WITH VERTICAL SUPRANUCLEAR OPHTHALMOPLEGIA, AND ITS RELATIONSHIP TO NIEMANN-PICK DISEASEBrain, 1973
- Lactosylceramidosis: Lactosylceramide galactosyl hydrolase deficiency and accumulation of lactosylceramide in cultured skin fibroblastsThe Journal of Pediatrics, 1971
- The juvenile form of Niemann-Pick disease.Archives of Disease in Childhood, 1967
- NIEMANN-PICK DISEASEMedicine, 1958
- THE DISTRIBUTION AND CHEMICAL COMPOSITION OF ULTRACENTRIFUGALLY SEPARATED LIPOPROTEINS IN HUMAN SERUMJCI Insight, 1955