Systematic Review Of Spinocerebellar Ataxias And Clinical Study Of Spinocerebellar Ataxias In The Three Gorge Reservoir Area

Spinocerebellar ataxias (SCAs) are rare (incidence between 8 and 10 per 100,000) autosomal dominant hereditary neurological disorders with unified characteristic of progressive ataxia due to the cerebellar degeneration and its connections. Since the first identification of the gene, spinocerebellar ataxia type 1 (SCA 1), involved in dominant ataxia in 1992, twenty-eight genetically distinct subtypes (designated from SCA2 to SCA30,without SCA9 and SCA24) have been described. Because of the clinical overlap among various SCAs and the phenotypic variability of single subtypes, it is difficult to predict the SCA genotype in individual patients.To clarify the clinical characteristics of the Three Gorge Reservoir Area, the following three parts of work were performed: (1) Systemic review about spinocerebellar ataxias, especially in China; (2)Study on clinical features and image characteristics of spinocerebellar ataxias in Three Gorge Reservoir Area; (3) Study on gene diagnosis and antenatal diagnosis of spinocerebellar ataxia patients and presymptomatic patients in Three Gorge Reservoir Area.Part I: Systematic review about spinocerebellar ataxiasObjectives: The aim of this study was to clearify the prevalence, distribution, clinical features and therapy progress of spinocerebellar ataxias in China and other countries.Methods:Chinese articles: Chinese articles were researched online from CNKI full-text databases and Vip databases and were obtained by manual retrieval for other related articles out of the two main databases. Those words were formulated for the retrieval that spinocerebellar ataxia OR MJD OR Machado-Joseph disease.Foreign languages articles: English articles were retrieved online from PUBMED, while those not included in the databases were obtained manually. Search formulas were spinocerebellar ataxia OR MJD OR Machado-Joseph disease OR Machado disease OR Joseph disease.The following information of the enrolled articles were investigated: 1) the country or area, institutes or hospitals where the studies were performed and the publishing dates; 2) presence or absence of genetic diagnosis, genotypes, numbers of pedigrees, numbers of the familial or sporadic patients and asymptomatic patients; 3) gender, age at onset, duration and clinical features of the patients with spinocerebellar ataxia.Results:1. Research history of spinocerebellar ataxiasTwo hundred and three research institutes or hospitals in thirty-nine countries or areas reported spinocerebellar ataxias patients. Among them, one hundred institutes or hospitals in 21 countries or areas used genetic approaches for diagnosis. In totally, there are 28 types of spinocerebellar ataxias in the world.In China, spinocerellar ataxias cases were reported in forty research institutes or hospitals in 20 provinces. Twenty five units are able to perform a genetic diagnosis., Six types of spinocerebellar ataxias were reported in mainland including SCA1, SCA2, MJD/SCA3, SCA6, SCA7 and SCA12, 3 types were reported in Hong Kong of SCA1, SCA3 and SCA6, and 8 types in Taiwan of SCA1, SCA2, MJD/SCA3, SCA6, SCA7, SCA8, SCA17 and SCA22. However, there was no report in Macao.2. Distribution of spinocerebellar ataxiasFrom the first patient reported in Caucasia Area in 1861, the cases of spinocerebellar ataxia had been reported in 39 counties or area in six continents (North America, South America, European, Asia, Africa and Oceania).In China, patients of spinocerebellar ataxia have been diagnosed in 20 provinces or areas, distributed mainly in east and south of China.3. Clinical characteristics of spinocerebellar ataxiasThere was no significant difference on gender in family patients and sporadic patients of spinocerebellar ataxia. Many spinocerebellar ataxia onset after 30 years old, except SCA6 which often occurs after 50 years old.Disease duration of SCA2 was longer than other types of spinocerebellar ataxias, while SCA1 and SCA7 were shorter than others with a possible faster progress.Every subtype of spinocerebellar ataxias has some own special characters, so physicians could estimate the gene type of patient.4. Diagnosis of spinocerebellar ataxiasThere were 482 Chinese pedigrees of spinocerebellar ataxias in mainland, 13 in Hong Kong and 251 in Taiwan.There were 1,750 patients of spinocerebellar ataxias in China. Among them, 1,133, 16 and 601 were reported in mainland, Hong Kong and Taiwan, respectively, including 288 and 68 sporadic patients in mainland and Taiwan.There were 45 asymptomatic patients in mainland of China and 41 in Taiwan and there are no any reports of asymptomatic patients with SCA6 in China.5. Therapy of spinocerebellar ataxiasThere are no effective drugs for spinocerebellar ataxias.Conclusions:1. Spinocerebellar ataxias is a global disease which were reported in 6 continents including 39 countries or areas. Spinocerebellar ataxia type 3 is the main subtype in 28 types of spinocerebellar ataxias.2. In mainland of China, there were 6 types of spinocerebellar ataxia reported which were SCA1-3, SCA6-7 and SCA12. In Hong Kong, 3 types of SCA1, SCA3 and SCA6 were observed. In Taiwan, there were 8 types of spinocerebellar ataxia reported which were SCA1-3,SCA6-8,SCA17 and SCA22.3. In mainland of China, there were 482 pedigrees,1133 familial patients,288 sporadic patients and 45 presymptomatic patients of spinocerebellar ataxias.4. In Taiwan, there were 251 pedigrees, 601 familial patients, 68 sporadic patients and 41 presymptomatic patients of spinocerebellar ataxias.Part II: Clinical and imaging characteristics of spinocerebellar ataxias in Three Gorge Reservoir Area.Objectives: To investigate the clinical and imaging characteristics of spinocerebellar ataxias patients in the Three Gorges Reservoir Area.Methods: All the patients of spinocerebellar ataxias in the Neurology Department of the Chongqing Daping Hospital were assessed. To analysis the 33 familial patients in the 6 unrelated Chinese pedigrees and 9 sporadic patients from the Three Gorge Reservoir Area, all of them were evaluated by International Cooperative Ataxia Rating Scale (ICARS), in addition to neurological examination and brain MRI scans at our hospital,.Results:1. Clinical features of spinocerebellar ataxias patients in the Three Gorge Reservoir AreaThere were not differences in onset age and disease duration of familial and sporadic patients in the Three Gorges Reservoir Area.Early-onset symptoms of some sporadic patients of spinocerebellar ataxias in Three Gorge Reservoir Area were tongue trips and vision impaired.Genetic anticipations were not clearly in all familial patients. But our 2 SCA3 pedigrees in Three Gorge Reservoir Area had significant genetic anticipation.Nystagmus and abnormal muscle tension were common in familial patients in the Three Gorge Reservoir Area.2. Image characters of spinocerebellar ataxias patients in the Three Gorge Reservoir AreaAll familial and sporadic patients had the imaging results of cerebellum atrophy. Some sporadic patients could have pons and medulla oblongata atrophy.Enlargement of fourth ventricle of familial patients were more significant compared to sporadic patients, whereas cerebellum and brain stem atrophy was more severe in sporadic patients.3. Risk factors of spinocerebellar ataxia patients in the Three Gorges Reservoir Area.Most spinocerebellar ataxia patients lived in countryside and got low education degree. Most spinocerebellar ataxia patients were Han Chinese.Poor traffics and consanguineous marriage were potential reasons in fist generation patients. With the improvement of those factors, disease genes of spinocerebellar ataxias were gradually weakened for the genetic dilution.Disease duration was associated with ICARS in the familial patients, but not in sporadic patients as well as the onset age.Conclusions:1. Onset symptom of spinocerebellar ataxias was gait instability and some sporadic patients featured of tongue trips and vision impaired in the Three Gorge Reservoir Area.2. The rate of nystagmus and abnormal muscle tension in familial patients was higher than sporadic patients in the Three Gorge Reservoir Area.3. The atrophy of cerebellum in head MRI of sporadic patients were more severe than those in familial patients in the Three Gorge Reservoir Area.4. By enlarging marriage circle and improving traffic condition, the incidence of spinocerebellar ataxias in pedigrees might be gradually decreased in the Three Gorge Reservoir Area.5. The disease duration was correlated to ICARS in familial patients of spinocerebellar ataxias in the Three Gorge Reservoir Area.Part III: Gene diagnosis and antenatal diagnosis of spinocerebellar ataxias in the Three Gorge Reservoir AreaObjectives: To develop a method of gene diagnosis and antenatal diagnosis and to build database of spinocerebellar ataxias in the Three Gorge Reservoir Area.Methods: Five ml whole blood was obtained from each health member and patient in the affected family, sporadic patient of spinocerebellar ataxias. In addition, 5ml amniotic fluid was collected from every of 20 normal pregnant women. Gene DNA extracting from blood cell and cast-off cell in amniotic fluid were used to perform polymerase chain reaction. It was a way of antenatal diagnosis and gene diagnosis for patients with or without symptom of spinocerebellar ataxias.Results:The gene types of spinocerebellar ataxias could be a preliminary determined by 3% agarose gel electrophoresis. The polymerase chain reactions were useful to perform gene diagnosis of spinocerebellar ataxias type 1-3, 6-7 and 12.We totally observed the only type (type 3) of spinocerebellar ataxia, in the Three Gorges Reservoir Area, including 2 SCA3 pedigree, 20 familial patients and 1 sporadic patient.In the Three Gorge Reservoir Area, 5 asymptomatic patients of spinocerebellar ataxia type 3 were diagnosed. Gene DNA extracting from cast-off cell in amniotic fluid could be used for antenatal diagnosis, the same way as the blood cell for diagnosis making in asymptomatic patients.Conclusions:1.3% agarose gel electrophoresis could be used for a preliminary determination of gene type in spinocerebellar ataxias type 1-3, 6-7 and 12.2. We diagnosised 2 spinocerebellar ataxia type 3 pedigrees, including 20 familial patients, for the first time in the Three Gorge Reservoir Area.3. We diagnosised 1 sporadic patients of spinocerebellar ataxia type 3 for the first time in the Three Gorge Reservoir Area.4. We diagnosised 5 asymptomatic patients of spinocerebellar ataxia type 3 for the first time in the Three Gorge Reservoir Area.5. Gene DNA extracting from cast-off cell in amniotic fluid could be used to perform antenatal diagnosis of spinocerebellar ataxia type 1-3, 6-7 and 12.