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

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.

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

“…The prevalence of NP-C in the general population has been estimated at 1/150,000 live births (Patterson, et al, 2001). This estimate may be low, as about 50% of NP-C cases may present with neonatal liver disease (Kelly, et al, 1993,Vanier, et al, 1988. Thus, the true prevalence of NP-C is likely to be greater than 1/150.000.…”

Genetic Disorders Associated with Gingival Enlargement

“…The buildup of undigested material, secondary to lysosomal enzyme dysfunction, results in the formation of typical histochemical and ultrastructural changes. Light microscopy often reveals engorged macrophages with a characteristic appearance, such as that of 'sea-blue histiocytes' in Niemann-Pick disease (Vanier et al, 1988).…”

Pearls & Oy-sters: Niemann-Pick disease type C in a 65-year-old patient

“…5 Our patient had onset of neurologic symptoms at age 55 years, second only to a case reported with onset of symptoms at 59 years of age. 7 The heterogeneous clinical manifestations of NPC include systemic, neurologic, and psychiatric features. 1 Systemic features like neonatal jaundice, hepatosplenomegaly, or isolated splenomegaly are common in early-onset disease, and always precede neurologic manifestations.…”