Prediction of Survival With Long-Term Disease Progression in Most Common Spinocerebellar Ataxia.

BACKGROUND: Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. OBJECTIVE: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. METHODS: Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. RESULTS: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. CONCLUSION: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society.

Predictors of survival in spinocerebellar ataxia type 2 population from Southern Italy.

One hundred-eighteen spinocerebellar ataxia type 2 patients from 35 distinct families personally observed between 1973 and 2016 were retrospectively reviewed. The time point of data collection was 1 January 2017. Thirty-one patients were confined to wheelchair. The median time to wheelchair was 21 years (95% CI, 17.5-24.6). Thirty-seven patients were deceased. The median time to death was 25 years (95% CI, 22.9-27.1). CAG repeat number and ataxia score at first visit influenced the time to wheelchair and death.

Survival in patients with spinocerebellar ataxia types 1, 2, 3, and 6 (EUROSCA): a longitudinal cohort study.

BACKGROUND: Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias. Survival was defined as the time from enrolment to death for any reason. We used the Cox regression model adjusted for age at baseline to analyse survival. We used prognostic factors with a p value less than 0·05 from a multivariate model to build nomograms and assessed their performance based on discrimination and calibration. The EUROSCA study is registered with ClinicalTrials.gov, number NCT02440763. FINDINGS: Between July 1, 2005, and Aug 31, 2006, 525 patients with SCA1 (n=117), SCA2 (n=162), SCA3 (n=139), or SCA6 (n=107) were enrolled and followed up. The 10-year survival rate was 57% (95% CI 47-69) for SCA1, 74% (67-81) for SCA2, 73% (65-82) for SCA3, and 87% (80-94) for SCA6. Factors associated with shorter survival were: dysphagia (hazard ratio 4·52, 95% CI 1·83-11·15) and a higher value for the Scale for the Assessment and Rating of Ataxia (SARA) score (1·26, 1·19-1·33) for patients with SCA1; older age at inclusion (1·04, 1·01-1·08), longer CAG repeat length (1·16, 1·03-1·31), and higher SARA score (1·15, 1·10-1·20) for patients with SCA2; older age at inclusion (1·44, 1·20-1·74), dystonia (2·65, 1·21-5·53), higher SARA score (1·26, 1·17-1·35), and negative interaction between CAG and age at inclusion (0·994, 0·991-0·997) for patients with SCA3; and higher SARA score (1·17, 1·08-1·27) for patients with SCA6. The nomogram-predicted probability of 10-year survival showed good discrimination (c index 0·905 [SD 0·027] for SCA1, 0·822 [0·032] for SCA2, 0·891 [0·021] for SCA3, and 0·825 [0·054] for SCA6). INTERPRETATION: Our study provides quantitative data on the survival of patients with the most common spinocerebellar ataxias, based on a long follow-up period. These results have implications for the design of future interventional studies of spinocerebellar ataxias; for example, the prognostic survival nomogram could be useful for selection and stratification of patients. Our findings need validation in an external population before they can be used to counsel patients and their families. FUNDING: European Union 6th Framework programme, German Ministry of Education and Research, Polish Ministry of Scientific Research and Information Technology, European Union 7th Framework programme, and Fondation pour la Recherche Médicale.

[THE ANALYSIS OF LIFE SPAN AND MORTALITY OF PATIENTS WITH SPINOCEREBELLAR ATAXIA TYPE I].

The article presents results of investigation of certain unclear aspects of mortality of patients with spinocerebellar ataxia type I including patients with the same number of CAG-repetitions. The analysis of mortality of patients observed from 1993 to nowadays was implemented. Sampling included 112 patients during that period 53 patients died. The comparative analysis was implemented concerning received data and results of analysis of mortality of patients died prior to 1980. According received data, average value of CAG-repetitions of normal allele was equal to 30.2, and ofpathologic allele--48.7. The average life span made up to 52.8 years, average age of disease onset--38 years and natural duration of disease--14.8 years. The analysis of life span of patients with equal length of repetitions demonstrated that range of life span of patients makes up to from 8 to 23 years. It is established that life of patients becomes shorter because of accidents, cancer and concomitant diseases of cardiovascular system. The presence of such concomitant disease as tuberculosis of lungs results in no shortening of life of patients. The comparative analysis of mortality during the period over 34 years demonstrated that age of disease onset turned out to be more conservative and stable indicator of morbidity. Despite of lacking of effective methods of treatment of disease, the natural duration of disease increased statistically reliable up to 1.8 times during period of observation. The analysis of life span ofpatients with spinocerebellar ataxia type I demonstrated that their life span except length of CAG-expansion depends on a number of factors accelerating and retarding development of disease. At that, life span of patients with the same number of CAG-repetitions can significantly differ The malignant neoplasms, diseases of cardiovascular system and external causes are to be referred to factors accelerating and retarding development of main disease. The addition oftuberculosis in our case resulted in no alteration of natural course of disease. The other factors exist prolonging life of patients, including factors of social economic and medical character They require additional specification and thorough investigation with the purpose of developing methods ofpreventive correction of neuro-degeneration processes.

Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1.

DNA damage repair is implicated in neurodegenerative diseases; however, the relative contributions of various DNA repair systems to the pathology of these diseases have not been investigated systematically. In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1). We identified genes previously unknown to be involved in CAG-/polyQ-related pathogenesis that function in multiple DNA damage repair systems. Beyond the significance of each repair system, systems biology analyses unraveled the core networks connecting positive genes in the gene screen that could contribute to SCA1 pathology. In particular, RpA1, which had the largest effect on lifespan in the SCA1 fly model, was located at the hub position linked to such core repair systems, including homologous recombination (HR). We revealed that Atxn1 actually interacted with RpA1 and its essential partners BRCA1/2. Furthermore, mutant but not normal Atxn1 impaired the dynamics of RpA1 in the nucleus after DNA damage. Uptake of BrdU by Purkinje cells was observed in mutant Atxn1 knockin mice, suggesting their abnormal entry to the S-phase. In addition, chemical and genetic inhibitions of Chk1 elongated lifespan and recovered eye degeneration. Collectively, we elucidated core networks for DNA damage repair in SCA1 that might include the aberrant usage of HR.

Degeneration of the inferior olive in spinocerebellar ataxia 6 may depend on disease duration: report of two autopsy cases and statistical analysis of autopsy cases reported to date.

This report concerns a clinicopathological study of two autopsied patients with spinocerebellar ataxia 6 (SCA6), and a statistical analysis between neuronal loss of the inferior olive and disease duration of 15 SCA6 autopsy cases reported to date, including the two cases reported in this study. Cases 1 and 2 came from independent Japanese families. Case 1 developed gait disturbance at age 35 years and died at age 78 years; she had a CAG-repeat expansion of the SCA6 gene (25/13). Case 2 presented with gait disturbance at age 68 years and died at age 78 years; he had an expanded CAG-repeat of the SCA6 gene (22/13). Neuropathological examination of both cases disclosed not only neuronal loss of the Purkinje cells and inferior olive, but also some unnoticed features, including cactus-like expansion of the dendrite of Purkinje cells and relative preservation of Golgi cells in the granular layer of the cerebellum. Exploratory statistical analysis between 11 SCA6 autopsy cases with neuronal loss in the inferior olive (average disease duration: 27 years) and four SCA6 autopsy cases without neuronal loss in the olive (average disease duration: 14.5 years) was investigated by Kaplan-Meier estimates of survival and log-rank test, retrospectively. Kaplan-Meier estimates of survival revealed an obvious difference between the two groups. Survival of 10 years after the disease onset was 90.9% in the former 11 SCA6 autopsy cases, but was 50% in the latter four SCA6 autopsy cases. Furthermore, a log-rank test on the two groups disclosed a significant difference (P=0.0450). We postulate that the neuronal loss of the inferior olive in SCA6 may depend on disease duration.