Niemann-Pick type C is frequent in adult ataxia with cognitive decline and vertical gaze palsy

Schicks, Julia; Hagen, Jennifer Müller vom; Bauer, Péter; Beck-Wödl, Stefanie; Biskup, Saskia; Krägeloh‐Mann, Ingeborg; Schöls, Lüdger; Synofzik, Matthis

doi:10.1212/wnl.0b013e31828869f9

Cited by 30 publications

(29 citation statements)

References 4 publications

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“…In the present study, we could not unveil any misdiagnosed NPC in 563 patients with PD, 133 patients with FTLD, and 94 patients with PSP by means of a mutational screen. This negative result notwithstanding, it seems important to note that NPC patients might be identified in adult neurologic disease cohorts, for example when testing larger numbers of patients or including individuals exhibiting more exceptional clinical presentations, as recently demonstrated [11], [12]. Besides, it is possible that NPC diagnoses could have been missed because sensitivity of HRM is not 100%, and there was no exploration of large deletions or deep intronic mutations, which were shown to be rarely responsible for NPC [49], [50] [Latour and Vanier, unpublished data].…”

Section: Discussionmentioning

confidence: 99%

“…As a result of its broad phenotypic spectrum, NPC is thought to be significantly under-diagnosed, which is momentous given that an orally applied enzyme inhibitor has proven to be an effective treatment option for slowing neurologic disease progression [1], [2], [10]. Recently, a remarkable proportion of NPC cases were found in adult patients with the concurrence of degenerative ataxia and presenile dementia (17% of 24 patients) [11]. Furthermore, corroborating the existence of an unrecognized pool of NPC, a multicentre study identified three NPC patients in 250 adult individuals (1.2%) suffering from psychosis and/or early-onset cognitive decline combined with neurological symptoms suggestive of NPC by NPC1 / 2 gene sequencing [12].…”

Section: Introductionmentioning

confidence: 99%

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Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders

et al. 2013

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Niemann-Pick type C (NPC) disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95%) or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563), FTLD (n = 133) and PSP (n = 94), and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1%) and seven control subjects (0.8%), but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders

et al. 2013

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“…The proportion of patients with moderate or high scores on the SI across the diagnostic groups in this study was between 83 and 100%, which is appreciably higher than the proportion of patients scoring at this level in the much broader patient population on which the NP-C SI developmental study was based (6). In addition, the NP-C SI threshold for high suspicion was defined for screening purposes in unselected populations, and therefore its poor predictive value in a selected adult patient sample such as that in ZOOM is not surprising (4). …”

Section: Discussionmentioning

confidence: 99%

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

Bauer

Balding

Klünemann

et al. 2013

Human Molecular Genetics

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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.

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“…Furthermore, storage diseases, such as Niemann-Pick type C disease, Tay-Sachs disease, Krabbe disease, and other forms of recessive ataxias, such as ataxia with ocular apraxia and ataxia-telangiectasia may rarely present with adult onset ataxia 2,36,55 . Finally, sporadic ataxia may be the clinical presentation of new mutations recently described in autosomal recessive ataxias with adult onset of symptoms, such as SYNE1 mutations 56 .…”

Section: Mitochondrial and Other Genetic Diseasesmentioning

confidence: 99%

Adult onset sporadic ataxias: a diagnostic challenge

Barsottini

Albuquerque

Neto

et al. 2014

Arq. Neuro-Psiquiatr.

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Patients with adult onset non-familial progressive ataxia are classified in sporadic ataxia group. There are several disease categories that may manifest with sporadic ataxia: toxic causes, immune-mediated ataxias, vitamin deficiency, infectious diseases, degenerative disorders and even genetic conditions. Considering heterogeneity in the clinical spectrum of sporadic ataxias, the correct diagnosis remains a clinical challenge. In this review, the different disease categories that lead to sporadic ataxia with adult onset are discussed with special emphasis on their clinical and neuroimaging features, and diagnostic criteria.Keywords: ataxia, sporadic ataxia, clinical features, diagnostic criteria. RESUMOPacientes com ataxia progressiva que se inicia na idade adulta, e sem histórico familiar da doença, são classificados no grupo das ataxias esporádicas. Existem várias categorias de doenças que podem se manifestar com ataxia esporádica, tais como: causas tóxicas, ataxias imunomediadas, deficiência de vitaminas, doenças infecciosas, doenças degenerativas e até mesmo condições genéticas. Considerando a heterogeneidade no espectro clínico das ataxias esporádicas, a definição da etiologia constitui um desafio diagnóstico. Neste artigo de revisão, realizamos uma discussão sobre as diferentes categorias de doenças que causam ataxia com início na idade adulta sem histórico familiar, com ênfase nas características clínicas, aspectos de imagem e critérios diagnósticos.Palavras-chave: ataxia, ataxias esporádicas, aspectos clínicos, critérios diagnósticos.

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Niemann-Pick type C is frequent in adult ataxia with cognitive decline and vertical gaze palsy

Cited by 30 publications

References 4 publications

Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders

Niemann-Pick C Disease Gene Mutations and Age-Related Neurodegenerative Disorders

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

Adult onset sporadic ataxias: a diagnostic challenge

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