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Souza G.N.,Federal University of Rio Grande do Sul | Kersting N.,Federal University of Rio Grande do Sul | Krum-Santos A.C.,Federal University of Rio Grande do Sul | Santos A.S.P.,Federal University of Rio Grande do Sul | And 16 more authors.
Clinical Genetics | Year: 2016

Controversies about Mendelian segregation and CAG expansion (CAGexp) instabilities during meiosis in spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) need clarification. Additional evidence about these issues was obtained from the cohort of all SCA3/MJD individuals living in South Brazil. A survey was carried out to update information registered since 2001. Deaths were checked with the Public Information System, and data was made anonymous. Anticipation and delta-CAGexp from parent–offspring pairs, and delta-CAGexp between siblings were obtained. One hundred and fifty-nine families (94% of the entire registry) were retrieved, comprising 3725 living individuals as of 2015, 625 of these being symptomatic. Minimal prevalence was 6:100,000. Carriers of a CAGexp represented 65.6% of sibs in the genotyped offspring (p < 0.001). Median instability was larger among paternal than maternal transmissions, and instabilities correlated with anticipation (r = 0.38; p = 0.001). Age of the parent correlated to delta-CAGexp among 115 direct parent–offspring CAGexp transmissions (ρ = 0.23, p = 0.014). In 98 additional kindreds, the delta-CAGexp between 269 siblings correlated with their delta-of-age (ρ = 0.27, p < 0.0001). SCA3/MJD was associated with a segregation distortion favoring the expanded allele in our cohort. Instability of expansion during meiosis was weakly influenced by the age of the transmitting parent at the time of conception. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Donis K.C.,Federal University of Rio Grande do Sul | Donis K.C.,Hospital Of Clinicas Of Porto Alegre | Saute J.A.M.,Hospital Of Clinicas Of Porto Alegre | Krum-Santos A.C.,Federal University of Rio Grande do Sul | And 11 more authors.
Neurogenetics | Year: 2016

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. © 2016 Springer-Verlag Berlin Heidelberg

Selistre S.G.A.,Federal University of Rio Grande do Sul | Selistre S.G.A.,Hospital Of Clinicas Of Porto Alegre Hcpa | Maestri M.K.,Ophthalmology Service | Santos-Silva P.,Federal University of Rio Grande do Sul | And 12 more authors.
BMC Pediatrics | Year: 2016

Background: Retinoblastoma (Rb) is the most common intraocular tumor diagnosed in children in Brazil. However, detailed information is lacking regarding patient clinical demographics. This study aimed to determine the clinical profile of patients with Rb who were treated in a public university hospital in southern Brazil from 1983 to 2012. Methods: Patients' medical records were reviewed to retrospectively identify patients with a principal diagnosis of Rb. Rb was classified as hereditary or non-hereditary. Clinical staging was reviewed by an ophthalmologist. Statistical analysis was performed using SPSS. Results: Of 165 patients with a diagnosis of Rb during this period, 140 were included in the study. Disease was unilateral in 65.0% of patients, bilateral in 32.9%, and trilateral in 2.1%. The mean age at onset of the first sign/symptom was 18.1month, and 35.7% of patients were diagnosed during the first year of life. The most common presenting signs were leukocoria (73.6%) and strabismus (20.7%). The mean age at diagnosis was 23.5months, and time to diagnosis was 5.4months. In patients with clinical features of hereditary Rb, both onset of the first sign/symptom and diagnosis were at an earlier age than in patients without these features (12.3 vs 21.6months [P=0.001] and 15.9 vs 28.0months [P<0.001], respectively). However, there was no significant difference in overall survival between the two groups. Ocular stage at diagnosis was advanced in 76.5% (Reese V) and 78.1% (International Classification D or E). Of patients with unilateral and bilateral disease, 35.2% and 34.8%, respectively, had extraocular disease at diagnosis; 10.7% had metastatic disease at diagnosis. Enucleation was observed in 88.1% and exenteration in 11.9% of patients; 93.6% patients were followed until 2012, and 22.9% relapsed. Overall survival was 86.4%. Conclusions: Most Rb diagnoses are still diagnosed in advanced stages of the disease, considerably reducing overall survival time and the rate of eye and vision preservation. © 2016 Selistre et al.

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