Article

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

Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
Clinical Genetics (Impact Factor: 3.93). 12/2007; 72(6):543-5. DOI: 10.1111/j.1399-0004.2007.00910.x
Source: PubMed

ABSTRACT

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.

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    • "SCA3/MJD is invariably progressive, leading patients to functional dependency and social withdrawal, with no known treatment. The average survival is 63 years[14]. Descriptions of early childhood onset rarely appeared in literature, with some reports even preceding gene discovery[5,151617. Disease progression of patients whose disease started before 12 years of age has never been described. "
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    ABSTRACT: Onset of Machado-Joseph disease (SCA3/MJD) before adolescence has been rarely reported. This study aims to describe a cohort of SCA3/MJD with onset before 12 years of age, comparing their disease progression with the progression observed in patients with usual disease onset. We identified all cases from our cohort whose onset was before adolescence. After consent, patients were examined with clinical scales Scale for the Assessment and Rating of Ataxia (SARA) and Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). Gender, age, age at onset, disease duration, CAG expanded repeats, transmitting parent, and anticipation of cases with infantile and adult onset were studied. Progression of NESSCA and SARA scores was estimated through a mixed model, and was compared with a historical group with onset after adolescence. Between 2000 and 2014, 461 symptomatic individuals from our region were diagnosed as SCA3/MJD. Onset of eight cases (2.2 %), all heterozygotes, was before adolescence: seven were females (p = 0.054). CAG expanded repeats—75 ± 3 versus 84 ± 4—and anticipations—7 ± 9.7 versus 14.4 ± 7.2 years—were different between early childhood and adult onset groups (p < 0.03). The median survival of early childhood onset group was 23 years of age. The annual progression of SARA—2.3 and 0.6 points/year (p = 0.001)—and NESSCA—2.04 and 0.88 points/year (p = 0.043)—was faster in childhood than in adult onset group. Onset of SCA3/MJD before adolescence was related to larger expanded CAG repeats in heterozygosis; females seemed to be at higher risk. Disease progression was faster than in SCA3/MJD starting after 12 years.
    Full-text · Article · Jan 2016 · Neurogenetics
    • "Minor, but more specific, features such as external progressive ophthalmoplegia (EPO), dystonia, intention fasciculationlike movements of facial and lingual muscles, as well as bulging eyes (BE), may also be of major importance for the clinical diagnosis of MJD (Lima and Coutinho 1980). The mean age at onset is around 40 years, with extremes of 4 (Carvalho et al. 2008) and 70 years (Coutinho 1992), and a mean survival time of 21 years (Range: 7 to 29 years) (Coutinho 1992; Kieling et al. 2007). Gait ataxia and diplopia are reported as initial symptoms in 92.4 and 7.6 % of cases, respectively (Coutinho 1992). "
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    ABSTRACT: This study investigates illness representations of subjects at-risk for 3 autosomal dominant late-onset disorders: Familial Amyloid Polyneuropathy (FAP) TTR V30M, Huntington’s disease (HD) and Machado-Joseph disease (MJD), comparing them with the illness representations of subjects at-risk for Hemochromatosis (HH). The present study included a clinical group that consisted of 213 subjects at genetic risk (FAP, HD and MJD), comprising 174 subjects at-risk for FAP, 34 subjects at-risk for HD and only 5 subjects at-risk for MJD; and the control group consisting of 31 subjects at genetic risk for HH. All subjects at-risk were undergoing the process of genetic counseling to learn their genetic status (carrier or non-carrier). Subjects were assessed through a semi-structured single interview, in order to obtain sociodemographic data and the answer to an open-ended question relating to the illness representation issue: “What does this illness mean to you?/ What is this disease to you?” It was in the subjects’ metaphors that subjects best expressed what they felt regarding the disease and the situation of being at-risk for this disease. Family is their mirror and their source of learning and, therefore, it is inevitable that family is related to the meaning of the disease itself.
    No preview · Article · May 2015 · Journal of Genetic Counseling
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    • "Minor, but more specific, features such as external progressive ophthalmoplegia (EPO), dystonia, intention fasciculation-like movements of facial and lingual muscles, as well as bulging eyes, may also be of major importance for the clinical diagnosis of MJD [34]. The mean age at onset is around 40 years, with extremes of 4 [35] and 70 years [31], and a mean survival time of 21 years (ranging from 7 to 29 years) [31,36]. Gait ataxia and diplopia are reported as first symptoms in 92.4% and 7.6% of cases, respectively [31]. "
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    ABSTRACT: Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis. MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar dentate nucleus. MJD's causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and, among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and dispersion, as well as molecular genetics aspects considered essential for a better understanding of its neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and perspectives on genetic therapy, are also addressed.
    Full-text · Article · Jun 2011 · Orphanet Journal of Rare Diseases
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