Type C Niemann-Pick disease: spectrum of phenotypic variation in disruption of intracellular LDL-derived cholesterol processing

• Published in: Biochimica et biophysica acta Vol. 1096; no. 4; pp. 328 - 337
• Main Authors: Vanier, M T, Rodriguez-Lafrasse, C, Rousson, R, Gazzah, N, Juge, M C, Pentchev, P G, Revol, A, Louisot, P
• Format: Journal Article
• Language: English
• Published: Netherlands 05.06.1991
• Subjects: Adolescent; Adult; Cells, Cultured; Child; Child, Preschool; Cholesterol Esters - metabolism; Cholesterol, LDL - metabolism; Esterification; Histocytochemistry; Homeostasis; Humans; Kinetics; Niemann-Pick Diseases - genetics; Niemann-Pick Diseases - metabolism; Phenotype; Sphingomyelin Phosphodiesterase - metabolism
• ISSN: 0006-3002
• DOI: 10.1016/0925-4439(91)90069-l

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.