Linlin Wan1, Zhao Chen1,2,3, Na Wan1, Mingjie Liu1, Jin Xue4, Hongsheng Chen5, Youming Zhang6, Yun Peng1, Zhichao Tang1, Yiqing Gong1, Hongyu Yuan1, Shang Wang1, Qi Deng1, Xuan Hou1, Chunrong Wang7, Huirong Peng1, Yuting Shi1, Linliu Peng1, Lijing Lei1, Ranhui Duan4,8, Kun Xia4,8, Rong Qiu9, Lu Shen1,2,3, Beisha Tang1,2,3, Tetsuo Ashizawa10, Hong Jiang1,2,3. 1. Department of Neurology, Xiangya Hospital, Central South University, Changsha, China. 2. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China. 3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China. 4. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China. 5. Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China. 6. Department of Radiology, Xiangya Hospital, Central South University, Changsha, China. 7. Department of Pathology, Xiangya Hospital, Central South University, Changsha, China. 8. Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, China. 9. School of Computer Science and Engineering, Central South University, Changsha, China. 10. Neuroscience Research Program, Methodist Hospital Research Institute, Houston, TX, USA.
Abstract
OBJECTIVE: A recessive biallelic repeat expansion, (AAGGG)exp , in the RFC1 gene has been reported to be a frequent cause of late-onset ataxia. For cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG)exp genotype was present in ~92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA), which shares a spectrum of symptoms with CANVAS. METHODS: In this study, we screened the pathogenic (AAGGG)exp repeat and 5 other PNRs in 104 Chinese sporadic adult-onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients, and 203 unaffected individuals. Multiple molecular genetic tests were used, including long-range polymerase chain reaction (PCR), repeat-primed PCR (RP-PCR), Sanger sequencing, and Southern blot. Comprehensive clinical assessments were conducted, including neurological examination, neuroimaging, nerve electrophysiology, and examination of vestibular function. RESULTS: We identified biallelic (AAGGG)exp in 1 SAOA patient and 3 MSA patients. Additionally, 1 MSA patient had the (AAGGG)exp /(AAAGG)exp genotype with uncertain pathogenicity. We also described the carrier frequency for different PNRs in our cohorts. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG)exp in RFC1 could be associated with MSA and should be screened routinely in the MSA diagnostic workflow. INTERPRETATION: Our results expanded the clinical phenotypic spectrum of RFC1-related disorders and raised the possibility that MSA might share the same genetic background as CANVAS, which is crucial for re-evaluating the current CANVAS and MSA diagnostic criteria. ANN NEUROL 2020;88:1132-1143.
OBJECTIVE: A recessive biallelic repeat expansion, (AAGGG)exp , in the RFC1 gene has been reported to be a frequent cause of late-onset ataxia. For cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), the recessive biallelic (AAGGG)exp genotype was present in ~92% of cases. This study aimed to examine whether the pentanucleotide repeat (PNR) was related to multiple system atrophy (MSA), which shares a spectrum of symptoms with CANVAS. METHODS: In this study, we screened the pathogenic (AAGGG)exp repeat and 5 other PNRs in 104 Chinese sporadic adult-onset ataxia of unknown aetiology (SAOA) patients, 282 MSA patients, and 203 unaffected individuals. Multiple molecular genetic tests were used, including long-range polymerase chain reaction (PCR), repeat-primed PCR (RP-PCR), Sanger sequencing, and Southern blot. Comprehensive clinical assessments were conducted, including neurological examination, neuroimaging, nerve electrophysiology, and examination of vestibular function. RESULTS: We identified biallelic (AAGGG)exp in 1 SAOA patient and 3 MSA patients. Additionally, 1 MSA patient had the (AAGGG)exp /(AAAGG)exp genotype with uncertain pathogenicity. We also described the carrier frequency for different PNRs in our cohorts. Furthermore, we summarized the distinct phenotypes of affected patients, suggesting that biallelic (AAGGG)exp in RFC1 could be associated with MSA and should be screened routinely in the MSA diagnostic workflow. INTERPRETATION: Our results expanded the clinical phenotypic spectrum of RFC1-related disorders and raised the possibility that MSA might share the same genetic background as CANVAS, which is crucial for re-evaluating the current CANVAS and MSA diagnostic criteria. ANN NEUROL 2020;88:1132-1143.
Authors: T Bogdan; T Wirth; A Iosif; A Schalk; S Montaut; C Bonnard; G Carre; O Lagha-Boukbiza; C Reschwein; E Albugues; S Demuth; H Landsberger; M Einsiedler; T Parratte; A Nguyen; F Lamy; H Durand; P Fahrer; P Voulleminot; K Bigaut; J B Chanson; G Nicolas; J Chelly; C Cazeneuve; M Koenig; C Bund; I J Namer; S Kremer; N Calmels; C Tranchant; M Anheim Journal: J Neurol Date: 2022-07-23 Impact factor: 6.682
Authors: Marie Beaudin; Mario Manto; Jeremy D Schmahmann; Massimo Pandolfo; Nicolas Dupre Journal: Nat Rev Neurol Date: 2022-03-24 Impact factor: 42.937