Identifying Niemann–Pick type C in early-onset ataxia: two quick clinical screening tools

Synofzik, Matthis; Fleszar, Zofia; Schöls, Lüdger; Just, Jennifer; Bauer, Péter; Martin, Juan Vicente Torres; Kolb, Stefan

doi:10.1007/s00415-016-8178-0

Cited by 16 publications

(19 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…P2 also showed limb action myoclonus throughout all prospective longitudinal assessments, thus extending the movement disorder spectrum associated with ITPR1 ataxia. In contrast, none of the patients identified here showed evidence for other nonataxia signs that are frequently observed in other EOAs [10,11] such as epilepsy, pyramidal tract affection or peripheral neuropathy ( Table 2). Cerebellar atrophy was seen only in 2 out of 5 patients where MRI was available (Fig.…”

Section: Phenotype Of Patients With Itpr1 De Novo Variantsmentioning

confidence: 57%

De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

et al. 2018

Self Cite

View full text Add to dashboard Cite

We explored the clinico-genetic basis of spinocerebellar ataxia 29 (SCA29) by determining the frequency, phenotype, and functional impact of ITPR1 missense variants associated with early-onset ataxia (EOA). Three hundred thirty one patients from a European EOA target cohort (n = 120), US-American EOA validation cohort (n = 72), and early-onset epileptic encephalopathy (EOEE) control cohort (n = 139) were screened for de novo ITPR1 variants. The target cohort was also screened for inherited ITPR1 variants. The variants' functional impact was determined by IP3-induced Ca release in HEK293 cells. 3/120 patients (2.5%) from the target cohort and 4/72 patients (5.5%) from the validation cohort, but none from the EOEE control cohort, carried de novo ITPR1 variants. However, most ITPR1 variants (7/10 = 70%) in the target cohort were inherited from a healthy parent, with 3/6 patients carrying disease-causing variants in other genes. This suggests limited or no phenotypic impact of many ITPR1 missense variants, even if ultra-rare and well-conserved. While common bioinformatics tools did not discriminate de novo from other ITPR1 variants, functional characterization demonstrated reduced IP3-induced Ca release for all de novo variants, including the recurrent c.805C>T (p.(R269W)) variant. In sum, these findings show that de novo ITPR1 missense variants are a recurrent cause of EOA (SCA29) across independent cohorts, acting via loss of IP3 channel function. Inherited ITPR1 variants are also enriched in EOA, but often without strong impact, albeit rare and well-conserved. Functional studies allow identifying ITPR1 variants with large impact, likely disease-causing. Such functional confirmation is warranted for inherited ITPR1 variants before making a SCA29 diagnosis.

show abstract

Section: Phenotype Of Patients With Itpr1 De Novo Variantsmentioning

confidence: 57%

De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Autophagy-lysosomal activity, including the genes SPG15, SPG11, 46,47 ATP13A2 (SPG78), 48,49 NPC1, and NPC2 disease. [50][51][52][53][54][55] Toward a Mechanism-Based Classification of Ataxia-Spasticity Spectrum Diseases…”

Section: Common Pathophysiological Pathways and Mechanisms In Ataxiasmentioning

confidence: 99%

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

2017

Self Cite

View full text Add to dashboard Cite

Autosomal-dominant spinocerebellar ataxias, autosomal-recessive spinocerebellar ataxias, and hereditary spastic paraplegias have traditionally been designated in separate clinicogenetic disease classifications. This classification system still largely frames clinical thinking and genetic workup in clinical practice. Yet, with the advent of next-generation sequencing, phenotypically unbiased studies have revealed the limitations of this classification system. Various genes (eg, SPG7, SYNE1, PNPLA6) traditionally rooted in either the ataxia or hereditary spastic paraplegia classification system have now been shown to cause ataxia on the one end of the disease continuum and hereditary spastic paraplegia on the other. Other genes such as GBA2 and KIF1C were almost simultaneously published as both a hereditary spastic paraplegia and an ataxia gene. The variability and fluidity of observed phenotypes along the ataxia-spasticity spectrum warrants a rethinking of the traditional classification system. We propose to replace this divisive diagnosis-driven ataxia and hereditary spastic paraplegia classification system by a descriptive, unbiased approach of modular phenotyping. This approach is also open to expansion of the phenotype beyond ataxia and spasticity, which often occur as part of broader multisystem neuronal dysfunction. The concept of a continuous ataxia-spasticity disease spectrum is further supported by ataxias and hereditary spastic paraplegias sharing not only overlapping phenotypes and underlying genes, but also common cellular pathways and disease mechanisms. This suggests a shared vulnerability of cerebellar and corticospinal neurons for common pathophysiological processes. It might be this mechanistic overlap that drives their clinical overlap. A mechanistically inspired classification system will help to pave the way for mechanism-based strategies for drug development.

show abstract

“…A screening tool, the NPC suspicion index (NPC SI) has been developed to aid the clinician in the early identification of patients. 7,8 But there is still no single biomarker which could serve as a reliable screening tool. In some suspected cases only one pathogenic mutation in NPC1 or NPC2 gene can be found.…”

Section: Introductionmentioning

confidence: 99%

Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C

et al. 2019

Self Cite

View full text Add to dashboard Cite

Aim The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC). Systematic MRI analyses in this rare lysosomal storage disease are lacking in the infantile and juvenile onset forms. Methods Thirty-two cerebral MRI scans from 19 patients with NPC were assessed using a newly established and validated scoring system which addresses white matter changes and supratentorial versus infratentorial atrophy. Results Seven scans were from six NPC patients with early infantile onset (<2 years of age), six scans were from three patients with late infantile onset (2–6 years), six scans from four with juvenile onset (6–15 years), and 13 from six with adult onset (>15 years). While supratentorial atrophy was the leading sign in the infantile groups, the juvenile and adult forms were characterized by both, infra- and supratentorial atrophy. White matter changes were found in nearly every patient; they increased with the disease duration in the earlier forms and were prominent in the later forms already early in the disease course. Conclusion This is the first systematic and comparative MRI analysis in the different onset groups of NPC using a scoring system. Early during disease course, MRI showed different patterns in infantile compared with juvenile and adult onset NPC patients, for example, only supratentorial atrophy in juvenile versus global atrophy in adult onset patients. MRI changes provide an additional, early biomarker for NPC.

show abstract

Identifying Niemann–Pick type C in early-onset ataxia: two quick clinical screening tools

Cited by 16 publications

References 14 publications

De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C

Contact Info

Product

Resources

About