The importance of functional analysis: a cautionary case of cerebellar ataxia
Open Access
- 31 May 2023
- journal article
- research article
- Published by Université Paris Cité in Emerging Neurologist
- Vol. 2 (1) , 5-9
Abstract
Introduction. Cerebellar ataxias are a heterogeneous group of disorders with various cerebellar and extracerebellar manifestations. The underlying aetiology in early-onset, progressive, sporadic ataxia, is often autosomal recessive cerebellar ataxia (ARCA). The advent and rapid clinical integration of next-generation sequencing (NGS) has made it increasingly possible to provide a genetic diagnosis for patients with suspected ARCA. However, one of the greatest challenges of NGS is the interpretation and reclassification of variants of uncertain significance (VUS). Case report. Ataxia telangiectasia was suspected due to progressive teenage-onset ataxia in a 42-year-old woman with a history of breast cancer, ovarian mass, and elevated alpha-fetoprotein and CA-125. ATM sequencing demonstrated a homozygous missense VUS. However, functional studies clarified that this VUS was not pathogenic, but there was reduction in senataxin. This enabled clarification that the diagnosis was ataxia with oculomotor apraxia type 2. Conclusion. Our case highlights the importance of functional studies, where possible, to enable reclassification of VUSs.Keywords
This publication has 10 references indexed in Scilit:
- Inherited Cerebellar Ataxias: 5-Year Experience of the Irish National Ataxia ClinicThe Cerebellum, 2020
- Late-onset ataxia plus syndromesNeurology Clinical Practice, 2020
- Clinical utility of multigene analysis in over 25,000 patients with neuromuscular disordersNeurology Genetics, 2020
- Variants of uncertain significance in the era of high-throughput genome sequencing: a lesson from breast and ovary cancersJournal of Experimental & Clinical Cancer Research, 2020
- Prognostic impact of ATM mutations in patients with metastatic colorectal cancerScientific Reports, 2019
- Genotype, extrapyramidal features, and severity of variant ataxia‐telangiectasiaAnnals of Neurology, 2018
- Ataxia‐telangiectasia: A review of movement disorders, clinical features, and genotype correlationsMovement Disorders, 2018
- Ataxia with oculomotor apraxia type 2: an evolving axonal neuropathyPractical Neurology, 2017
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular PathologyGenetics in Medicine, 2015
- Scale for the assessment and rating of ataxiaNeurology, 2006