title: Identification of novel senataxin mutations in Chinese patients with autosomal recessive cerebellar ataxias by targeted next-generation sequencing.
abstract: BACKGROUND
  Autosomal recessive cerebellar ataxias (ARCA) are a group of neurodegenerative disorders characterized by early onset of gait impairment, disturbed limb coordination, dysarthria, and eye movement abnormalities, most likely due to the degeneration of cerebellum, brainstem, and spinal cord. Despite of the rarity, ARCA are both clinically and genetically heterogeneous. To date, more than 30 culprit genes have been identified in ARCA. Unraveling the specific causative mutation in cases with ARCA remains challenging so far.
  
  
  METHODS
  Three ARCA pedigrees of Chinese ancestry were recruited. Clinical features were evaluated and peripheral blood was collected after obtaining the written inform. Laboratory examinations, brain MRI, and EMG were performed for all the affected individuals. Genomic DNA was extracted, followed by the screening of GAA repeat expansion in FXN gene to exclude Friedreich's ataxia. Targeted next-generation sequencing combining Sanger sequencing was performed in each proband of these families.
  
  
  RESULTS
  Compound heterozygous mutations, c.3190G > T (p.E1064X) and c.4883C > G (p.S1628X) of senataxin (SETX) gene were identified in one family with two affected cases. Both of the patients presented with early onset of unsteady walk, dysarthria, and diplopia. EMG test revealed decreased conduction velocity and evoked potential of both motor and sensory nerve. Moreover, elevated serum alpha-fetoprotein (AFP) and apparent cerebellar atrophy were observed. These features were typical features of ataxia with oculomotor apraxia type 2 (AOA2) and in line with the genetic results. However, no specific mutation was identified in the other two pedigrees.
  
  
  CONCLUSIONS
  We identified novel compound heterozygous mutations of SETX in Chinese AOA2 pedigree, which broaden the mutation spectrum of SETX. To our knowledge, this is the first report concerning Chinese AOA2 cases with SETX mutations.
authors.affiliation: Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China.|Department of Neurology and Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Lu
authors.affiliation: The High School Affiliated to Fudan University-WLSA Fudan Academy, Shanghai, China.
authors.forename: Yi-Cen
authors.initials: YC
authors.lastname: Zheng
authors.affiliation: Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China. hongfuli@zju.edu.cn.
authors.forename: Hong-Fu
authors.initials: HF
authors.lastname: Li
mesh_terms: D000328:Adult; D044466:Asian People / Q000235:genetics; D002524:Cerebellar Ataxia / Q000235:genetics*; D002681:China; D004265:DNA Helicases; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D064251:Multifunctional Enzymes; D009154:Mutation; D015835:Ocular Motility Disorders / Q000235:genetics*; D010375:Pedigree; D020365:RNA Helicases / Q000235:genetics*; D055815:Young Adult
chemical_list: D064251:Multifunctional Enzymes; C484368:SETX protein, human; D004265:DNA Helicases; D020365:RNA Helicases
keywords: Ataxia with oculomotor apraxia type 2; Autosomal recessive cerebellar ataxias; Senataxin; Targeted next-generation sequencing