The adult form of Niemann-Pick disease type C

Abstract

Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids and other molecules but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. Based upon a comprehensive study of 13 unrelated adult patients diagnosed in France over the past 20 years as well as the analysis of the 55 other cases published since 1969, we have attempted to delineate the major clinical, radiological, biochemical and genotypic characteristics of adult NPC. Overall, mean age at onset (+/-SD) of neuropsychiatric symptoms was 25 +/- 9.7 years. The diagnosis of NPC was established after a mean delay of 6.2 +/- 6.4 years and the mean age at death (calculated from 20 cases) was 38 +/- 10.2 years. Major clinical features included cerebellar ataxia (76%), vertical supranuclear ophthalmoplegia (VSO, 75%), dysarthria, (63%), cognitive troubles (61%), movement disorders (58%), splenomegaly (54%), psychiatric disorders (45%) and dysphagia (37%). Less frequent signs were epilepsy and cataplexy. During the course of the disease, clinical features could be subdivided into (i) visceral signs (hepatomegaly or splenomegaly), (ii) cortical signs (psychiatric cognitive disorders and epilepsy); and (iii) deep brain signs (VSO, ataxia, movement disorders, dysarthria, dysphagia, cataplexy) which exhibited different evolution patterns. Asymptomatic and non-evolutive visceral signs were often noticed since early childhood (38.5% of our patients), followed by mild cortical signs in childhood (learning difficulties) and early adulthood (62% of cases among which 38% were psychiatric disorders). Deep brain signs were observed in 96% of patients and were usually responsible for death. In general, there was a good correlation between clinical signs and the localization of brain atrophy on MRI. The 'variant' biochemical phenotype characterized by mild abnormalities of the cellular trafficking of endocytosed cholesterol was over-represented in the adult form of NPC and seemed associated with less frequent splenomegaly in childhood and lesser psychiatric signs. Involvement of the NPC1 gene was shown in 33 families and of the NPC2 gene in one. Improving the knowledge of the disease among psychiatrists and neurologists appears essential since emerging treatments should be more efficient at the visceral or cognitive/psychiatric stages of the disease, before the occurrence of widespread deep brain neurological lesions.

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

“…The incidence is about 1/150,000 live births (Vanier and Millat 2003). The clinical spectrum is broad, with presenting symptoms ranging from lethal fetal ascites to psychiatric disease in adults, but progressive neurodegeneration is the major problem (Imrie et al 2007;Sevin et al 2007;Yerushalmi et al 2002). Most patients have mutations in the NPC1 gene that encodes a membrane protein involved in intracellular cholesterol transport (Ory 2004).…”

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

“…Inborn defects in cholesterol metabolism such as the Smith-Lemli-Opitz syndrome (Tint et al, 1994) and the Niemann-Pick type C disease (Sévin et al, 2007) disturb brain development profoundly. The exact molecular and cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown.…”

“…Fourth, it has been suggested that the deleterious effects of ethanol on the developing brain might be due, at least in part, to an effect on cholesterol homeostasis (Guzzetti and Costa, 2007). Last, there are inborn defects in cholesterol metabolism such as the Smith-Lemli-Opitz syndrome (Tint et al, 1994), a failure in cholesterol production accompanied by microcephaly, and the NiemannPick type C disease, a failure in cholesterol degradation accompanied by neurodegeneration (Sévin et al, 2007). Taken together, there is good evidence that brain cholesterol and its metabolism are important for the formation and maintenance of neural tissue as well as for neural functions.…”

Niemann–Pick disease type C1 presenting with psychosis in an adolescent male

“…On a cellular level, NPC is characterized by accumulation of unesterified cholesterol and glycolipids in the endosomal/lysosomal system [7], due to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol from the endosomal/lysosomal compartment to the cytosolic compartment. The symptomatology, which generally encompasses hepatosplenomegaly, cerebellar ataxia, dysarthria, vertical gaze palsy, cognitive difficulties and progressive neurological deterioration, is polymorphic with various epiphanies and great variety in the progress [2,10]. NPC is difficult to diagnose, particularly when it presents as a pure psychiatric disorder [1,4,10].…”

“…The symptomatology, which generally encompasses hepatosplenomegaly, cerebellar ataxia, dysarthria, vertical gaze palsy, cognitive difficulties and progressive neurological deterioration, is polymorphic with various epiphanies and great variety in the progress [2,10]. NPC is difficult to diagnose, particularly when it presents as a pure psychiatric disorder [1,4,10].…”