title: Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing.
abstract: To investigate biochemical heterogeneity within Niemann-Pick type C disease (NPC), the two most characteristic abnormalities, namely (1) kinetics of LDL-stimulated cholesteryl ester formation and (2) intravesicular accumulation of LDL-derived unesterified cholesterol, evaluated by histochemical filipin staining, were studied in cultured skin fibroblasts from a population of 125 NPC patients. Profound alterations (esterification rates less than 10% of normal, very numerous and intensely fluorescent cholesterol-filipin granules) were demonstrated in 86% of the cases, depicting the 'classical' NPC phenotype. The remaining cell lines showed a graded less severe impairment and more transient delay in the induction of LDL-mediated cholesteryl esterification, along with an attenuated accumulation of unesterified cholesterol. In particular, cells from a small group (7%) of patients, which have been individualized as representative of a 'variant' phenotype, showed only slight alterations of esterification, restricted to the early phase of LDL uptake and undistinguishable from those in heterozygotes. In these cells, an abnormal cytochemical distribution of LDL-derived cholesterol, although moderate, was still evident provided rigorous experimental conditions were followed. A third, less clearly individualized group (7%), differing from the classical phenotype mostly by higher rates of cholesteryl ester formation, has been designated as an 'intermediary' phenotype to reflect a more difficult diagnosis of such patients. These findings have an important bearing with regard to diagnosis and genetic counselling, although the significance of such a phenotypic variation in terms of genetic heterogeneity has still to be demonstrated. A given biochemical phenotype was however a constant observation within a family (14 pairs of siblings tested so far). The unique feature of LDL-cholesterol processing alterations in NPC has been further established from comparative studies in Wolman disease and I-cell disease, showing normal or different intracellular distribution of unesterified LDL-derived cholesterol in the latter disorders. Correlation between biochemical and clinical NPC phenotypes was only partial, but a correlation between the severity of alterations in cholesterol processing and sphingomyelin catabolism could be established.
authors.affiliation: Department of Biochemistry, Faculté de Médecine Lyon-Sud, Oullins, France.
authors.forename: M T
authors.initials: MT
authors.lastname: Vanier
authors.forename: C
authors.initials: C
authors.lastname: Rodriguez-Lafrasse
authors.forename: R
authors.initials: R
authors.lastname: Rousson
authors.forename: N
authors.initials: N
authors.lastname: Gazzah
authors.forename: M C
authors.initials: MC
authors.lastname: Juge
authors.forename: P G
authors.initials: PG
authors.lastname: Pentchev
authors.forename: A
authors.initials: A
authors.lastname: Revol
authors.forename: P
authors.initials: P
authors.lastname: Louisot
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002788:Cholesterol Esters / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism*; D004951:Esterification; D006651:Histocytochemistry; D006706:Homeostasis; D006801:Humans; D007700:Kinetics; D009542:Niemann-Pick Diseases / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D013108:Sphingomyelin Phosphodiesterase