BACKGROUND: The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2). METHODS: We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments. FINDINGS: We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively). INTERPRETATION: Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease. FUNDING: Cuban Ministry of Public Health.
BACKGROUND: The effects of ATXN2 expansion on the nervous system arise before the cerebellar syndrome can be diagnosed; however, progression of the underlying early clinical manifestations is unknown. We aimed to assess progression of the main clinical features in early stages of the spinocerebellar ataxia type 2 (SCA2). METHODS: We did this longitudinal study between Aug 12, 1986, and Sept 3, 2013, in carriers and non-carriers of the SCA2 mutation. We enrolled participants aged 6-60 years who were asymptomatic offspring or siblings of patients with SCA2. Participants were repeatedly assessed (two to seven times) until they presented definite cerebellar syndrome. All participants underwent standardised neurological examinations and electrophysiological (nerve conduction tests and somatosensory evoked potentials) and genetic assessments. FINDINGS: We enrolled 40 (73%) of 55 eligible participants to the baseline assessment, of whom 21 (13 women and eight men) were carriers of the SCA2 mutation, and 19 (14 women and five men) were non-carriers. Muscle cramps and sensory abnormalities were the most common clinical features in carriers (n=17 [81%] for both features) compared with controls (n=3 [16%] and n=4 [21%], respectively; χ(2)=84·58; p<0.0001, and χ(2)=72·03; p<0·0001, respectively) Both features showed a notable worsening over time and, in 17 (81%) carriers, age at onset was inversely correlated to CAG repeats (cramps: r -0·76, p=0·0004; sensory abnormalities: r -0·77, p=0·0004). Hyper-reflexia was associated with long time to ataxia onset (mean 5·71 years [SD 5·03]), whereas hyporeflexia was associated with short time (median 1·29 years [range 1-3]). Electrophysiological recordings obtained between 5 and 8 years before ataxia in 11 (52%) carriers showed reduced sensory amplitudes for median nerve (10·34 uV [SD 5·07]) and prolonged mean P40 latency (39·31 ms [2·40]) compared with age-matched and sex-matched controls (20·72 uV [9·08 uV]; p=0·0085, and 35·60 ms [2·05]; p=0·0023, respectively). INTERPRETATION: Early features of SCA2 are detectable before the onset of the cerebellar syndrome, and are associated with expanded CAG repeats and the time to onset of cerebellar syndrome. These findings could aid early diagnosis and genetic counselling, and also offer physiopathological insights that could help in the implementation of clinical trials in early stages of the disease. FUNDING: Cuban Ministry of Public Health.
Authors: Tania Cruz-Mariño; Yaimeé Vázquez-Mojena; Luis Velázquez-Pérez; Yanetza González-Zaldívar; Raúl Aguilera-Rodríguez; Miguel Velázquez-Santos; Annelié Estupiñán-Rodríguez; José Miguel Laffita-Mesa; Luis E Almaguer-Mederos; Milena Paneque Journal: J Community Genet Date: 2015-04-19
Authors: M Mascalchi; N Toschi; M Giannelli; A Ginestroni; R Della Nave; E Nicolai; A Bianchi; C Tessa; E Salvatore; M Aiello; A Soricelli; S Diciotti Journal: AJNR Am J Neuroradiol Date: 2015-04-16 Impact factor: 3.825
Authors: Roberto Rodríguez-Labrada; Ana Carolina Martins; Jonathan J Magaña; Yaimeé Vazquez-Mojena; Jacqueline Medrano-Montero; Juan Fernandez-Ruíz; Bulmaro Cisneros; Helio Teive; Karen N McFarland; Maria Luiza Saraiva-Pereira; César M Cerecedo-Zapata; Christopher M Gomez; Tetsuo Ashizawa; Luis Velázquez-Pérez; Laura Bannach Jardim Journal: Cerebellum Date: 2020-06 Impact factor: 3.847
Authors: José Luiz Pedroso; Pedro Braga-Neto; Marcio Luiz Escorcio-Bezerra; Agessandro Abrahão; Marcus Vinicius Cristino de Albuquerque; Flavio Moura Rezende Filho; Paulo Victor Sgobbi de Souza; Wladimir Bocca Vieira de Rezende Pinto; Franklin Roberto Pereira Borges; Maria Luiza Saraiva-Pereira; Laura Bannach Jardim; Orlando G P Barsottini Journal: Cerebellum Date: 2017-02 Impact factor: 3.847