Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study

Abstract

Niemann–Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3β,5α,6β-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18–90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3β,5α,6β-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…Accumulation of sphingomyelin in Npc1 nih liver has been extensively documented [24,54,56]. Npc1 Recently increased levels of GlcSph have been reported in NPC patient cohorts [57,58]. Our investigation confirms that the lyso-GSL tends to be elevated in the majority of patients analyzed.…”

Neurological Dysfunction in Early Maturity of a Model for Niemann–Pick C1 Carrier Status

“…The anxiety-like phenotype of Npc1 +/-mice thus warrants assessment in additional paradigms, such as elevated plus maze, light-dark exploration, and fear conditioning, to further characterize the nature of their anxiety-like behavior. Nevertheless, our findings suggest that NPC1 carriers may be more prone to anxiety, which would be consistent with the report of an apparent enrichment of NPC1 carriers in adult patients with neurological and psychiatric symptoms [23].…”

“…Consistent with these animal studies, there are also some case reports of tremor, parkinsonism, and increased foamy storage cell in bone marrow manifesting in aging NPC1 carriers [20][21][22]. Also, an international genetic screen for the prevalence of NP-C1 in adults with neurological and psychiatric disorders revealed an apparent enrichment of NPC1 carriers within this patient population [23]. However, it is unclear in these cases whether pathogenic NPC1 allele carrier status alone can cause neurological and psychiatric symptoms, or whether a neuropsychiatric phenotype is the consequence of a vulnerability induced by NPC1 allele carrier status that emerges only after interaction with other genetic defects and/or environmental factors.…”

Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann–Pick disease type C in a retrospective study

“…This led to the hypothesis that a panel of lysosphingolipids may be useful as biomarkers in NP-C. This hypothesis was previously tested in the ZOOM study, a multicentre genetic screening study of adult patients with neurological and psychiatric symptoms [4]. The three adult NP-C patients identified in the ZOOM study appeared to have elevated plasma levels of both lysosphingomyelin (SPC) and hexosylsphingosine (GlcSph) (Figure 1) when compared to NP-C negative patients.…”

“…The most recent analysis found a significant discrepancy between average on-set of neurological symptoms (10.9¡9.8 years) and diagnosis (15.0¡12.2 years) [3]. Additionally, there is increasing evidence from epidemiological studies that there may be a pool of patients who only become symptomatic later in-life and consequently remain undiagnosed [2,4].…”