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.

Cancer in Machado-Joseph disease patients-low frequency as a cause of death.

Since polyglutamine diseases have been related to a reduced risk of cancer, we aimed to study the 15 years cumulative incidence of cancer (CIC) (arm 1) and the proportion of cancer as a cause of death (arm 2) in symptomatic carriers of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). SCA3/MJD and control individuals from our state were invited to participate. A structured interview was performed. CIC as published by the Brazilian National Institute of Cancer, was used as populational control. Causes of death were obtained from the Public Information System on Mortality. We interviewed 154 SCA3/MJD patients and 80 unrelated controls: CIC was 7/154 (4.5%) and 5/80 (6.3%), respectively. The interim analysis for futility showed that the number of individuals required to detect a significant difference between groups (1938) would be three times larger than the existing local SCA3/MJD population (625), for an absolute risk reduction of 1.8%. Then this study arm was discontinued due to lack of power. In the same period, cancer was a cause of death in 9/101 (8.9%) SCA3/MJD and in 52/202 (26.2%) controls, with an absolute reduction risk of 17.3% (OR 0.27, 95%CI 0.13 to 0.58, p = 0.01). A significant reduction of cancer as cause of death was observed in SCA3/MJD, suggesting a common effect to all polyglutamine diseases.

Curva de crescimento usando modelo misto: uma aplicação na progressão da Doença de Machado-Joseph / Growth curve using mixed model: an application on Machado-Joseph Disease progression

Introdução: A obtenção dos dados por meio de medidas repetidas em diversas ocasiões no tempo em um mesmo sujeito torna possível o ajuste de curvas que descrevam padrões de evolução e identificam preditores de evolução. O objetivo deste trabalho foi ajustar curvas para descrever a progressão da doença de Machado-Joseph (DMJ), quantificada pelo escore NESSCA (Neurological Examination Score for Spinocerebellar Ataxia), utilizando modelos mistos. Métodos: Os dados foram obtidos de uma coorte de pacientes da DMJ acompanhada no Hospital de Clínicas de Porto Alegre (HCPA) durante um período de 10 anos. Nas avaliações clínicas realizadas, o comprometimento clínico do paciente foi mensurado várias vezes através do escore NESSCA. Esse escore foi considerado como desfecho, e a progressão da doença poderia ser influenciada pelas variáveis explicativas: idade no início da doença e comprimento da mutação. O procedimento Proc MIXED do software SAS foi utilizado para realizar o ajuste dos modelos. Resultados: Progressão da doença ocorre mais lentamente com o aumento na idade de início da doença, por outro lado, com o aumento do comprimento da mutação, mais rápida é a progressão da doença. Conclusão: Uma maior idade no início da doença é fator de proteção para a progressão da DMJ e um maior comprimento da mutação é fator de risco. Ressalta-se que as atribuições de proteção e risco estão relacionadas exclusivamente com a velocidade de progressão da doença, não sendo observados efeitos significativos dessas variáveis para o escore no início da doença.

Background: Obtaining data with repeated measures in different occasions, from the same patient, makes the growth curve adjustment possible. These curves describe evolution patterns and identify evolution predictors. The main purpose of this study was to adjust growth curve to describe Machado-Joseph disease progression (MJD), quantified by the NESSCA score (Neurological Examination Score for Spinocerebellar Ataxia) using linear mixed model. Methods: the data were obtained from a cohort of MJD patients observed at Hospital de Clínicas de Porto Alegre (HCPA) during 10 years. In the clinical evaluation performed, the clinical implications of these patients were measured by the NESSCA score. In order to accomplish the data analysis, the NESSCA score was used as an outcome and it was considered that the disease progression could be influenced by explaining variables such as age at onset and CAG length. The procedure Proc MIXED of the software SAS was used to perform the models adjustment. Results: the disease progression is slower with the increase of age at onset, on the other hand, the progression of the disease is faster with CAG length increase. Conclusion: a higher age at onset is a protection factor to the MJD progression and a higher CAG length is a risk factor. It is highlighted that the attributions of protection and risk are exclusively related with the progression speed of the disease, since there were no significant effects of these variables to the score at the beginning of the disease.

Survival estimates for patients with Machado-Joseph disease (SCA3).

Machado-Joseph disease (MJD), one of the most prevalent autosomal dominant cerebellar ataxias, is a neurodegenerative disease that starts during adulthood, with patients showing difficulties in gait, later becoming bedridden, and ultimately presenting premature death. There is, however, scarce data quantifying disease impact on patient survival. We investigated the overall survival of a large series of MJD patients and compared it with the survival of their asymptomatic relatives. A total of 412 affected and 413 unaffected individuals were ascertained from a consecutive sample of 82 families with a molecular diagnosis of MJD. Estimated mean survival time was 63.96 years [95% confidence interval (CI), 62.09-65.83] for the affected group and 78.61 years (95% CI, 74.75-82.47) for the unaffected group (p < 0.001). For a subset of 366 patients, mean age at onset was 36.37 years (95% CI, 35.21-37.53) and survival after disease onset was estimated as 21.18 years. Early onset and large CAG length predicted shorter overall survival times. This study presents quantitative data on the impact of MJD on overall survival, a phenomenon that is related to CAG length, age at onset, and year of birth.

Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly inherited neurodegenerative disorder caused by the expansion of a CAG repeat in the MJD1 gene resulting in an expanded polyglutamine repeat in the ataxin-3 protein. To study the course of the disease, we generated transgenic mice for SCA3 using full-length ataxin-3 constructs containing 15, 70, or 148 CAG repeats, respectively. Control mice (15 CAGs) were phenotypically normal and had no neuropathological findings. However, mice transgenic for ataxin-3 with expanded polyglutamine repeats were severely affected by a strong neurological phenotype with tremor, behavioral deficits, strongly reduced motor and exploratory activity, a hunchback, and premature death at 3 to 6 months of age. Neuropathological examination by immunohistochemical staining revealed ubiquitin- and ataxin-3-positive intranuclear inclusion bodies in a multitude of neurons. Directing ataxin-3 with 148 CAGs to the nucleus revealed an even more pronounced phenotype with more inclusions and earlier death, whereas mice transgenic with the same construct but attached to a nuclear export signal developed a milder phenotype with less inclusions. These studies indicate that nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3 in vivo.

Natural selection at the MJD locus: phenotypic diversity, survival and fertility among Machado-Joseph Disease patients from the Azores.

Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival. nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0.22 among Type 1 patients, to 0.40 in Type 2 and 0.95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors' interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.

Causes of death in Machado-Joseph disease: a case-control study in the Azores (Portugal).

BACKGROUND: Machado-Joseph disease (MJD) is an autosomal dominant cerebellar ataxia of adult onset with a high prevalence in the islands of Azores (Portugal). The genetic epidemiological studies presently under way in these islands are based on the genealogical reconstruction of the affected families, thus partially depending on the reference of patients using family history. A considerable effort has been made to obtain genealogies that are as complete as possible, making use of different types of data. The utility of the death causes contained in the death registers of the patients with MJD was determined in this study. OBJECTIVES: To estimate the extent to which the cause of death reported in the death register can confirm other reports of an individual's status for the disease (ie, oral information), and to determine the accuracy of the death certificates in listing MJD in patients whose disease was clinically diagnosed. DESIGN: Case-control study. METHODS: The death registers of 113 patients with MJD (82 whose disease was identified by history and 31 whose disease was clinically diagnosed) were examined and compared with those of controls matched by sex and date and place of death. RESULTS: There were significant differences in the causes of death between cases and controls, both for those whose disease was identified by history (chi(2) = 51.69, P < .001) and for those whose disease was identified by examination (chi(2) = 27.78, P = .004). However, the cause of death was in accord with the presence of the disease in only 40% of the cases reported as being identified only by family history. In the cases in which the disease was clinically diagnosed, only nearly 38% of the registers provided reliable information as to MJD being the direct cause of death. CONCLUSIONS: The fact that only nearly 40% of the patients with clinically confirmed MJD had a cause of death compatible with MJD precludes the use of cause of death as a means of identifying affected individuals in the Azorean MJD pedigrees.