Yuh-Cherng Guo1, Juei-Jueng Lin1, Yi-Chu Liao1, Pei-Chien Tsai1, Yi-Chung Lee1, Bing-Wen Soong2. 1. From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan. 2. From the Institute of Clinical Medicine (Y.-C.G.), National Yang-Ming University, Taipei; Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.) and Brain Research Center (P.-C.T., Y.-C. Lee, B.-W.S.), National Yang-Ming University School of Medicine, Taipei; Neuroscience Laboratory (Y.-C.G.), Department of Neurology, China Medical University Hospital, Taichung; School of Medicine (Y.-C.G.), College of Medicine, China Medical University, Taichung; Department of Neurology (J.-J.L.), Chushang Show-Chwan Hospital, Nantou; Department of Neurology (J.-J.L.), Chung-Shan Medical University Hospital, Taichung; and Department of Neurology (Y.-C. Liao, P.-C.T., Y.-C. Lee, B.-W.S.), Taipei Veterans General Hospital, Taiwan. bwsoong@ym.edu.tw ycli@vghtpe.gov.tw.
Abstract
OBJECTIVE: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort. METHODS: Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs. RESULTS: Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6. CONCLUSIONS: SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions.
OBJECTIVE: To elucidate the clinical and cellular characteristics of spinocerebellar ataxia type 35 (SCA35), which is caused by mutations in the TGM6 gene encoding transglutaminase 6 (TG6), in a Taiwanese cohort. METHODS: Mutations in TGM6 were ascertained in 109 unrelated probands of Chinese descent with molecularly unassigned SCA from 512 pedigrees, in whom mutations responsible for 15 other ataxia syndromes had been excluded. The clinical features of all patients with a TGM6 mutation were systematically analyzed. The biological consequences of the newly identified TGM6 mutations were investigated in HEK293 cells transfected with mutant complementary DNA constructs. RESULTS: Two missense mutations (p.R111C and p.D510H) and one 3-base pair deletion (p.E574del) in TGM6 were identified. Among them, p.R111C and p.E574del were novel. The common features of SCA35 include a slowly progressive clinical course, trunk/limb ataxia, and hand tremors. The age at onset varies from adolescence to the fifth decade. Torticollis and intellectual impairment are rare manifestations. Brain MRI reveals diffuse cerebellar atrophy without involvement of the cerebral hemispheres or brainstem. The 3 mutations identified here attenuated the protein stability and catalytic activities of TG6. CONCLUSIONS: SCA35 is an uncommon ataxia syndrome, accounting for 0.6% (3/512) of SCAs among the Han-Chinese descent in Taiwan. This study broadens the mutational spectrum of SCA35 and stresses the importance of TG6 in cerebellar functions.
Authors: David Bargiela; Priya Shanmugarajah; Patrick F Chinnery; Marios Hadjivassiliou; Christine Lo; Emma L Blakely; Robert W Taylor; Rita Horvath; Stephen Wharton Journal: Cerebellum Ataxias Date: 2015-12-04