RESUMEN
BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the pathogenesis of several neurodegenerative disorders, including Machado-Joseph disease (MJD), an autosomal dominant late-onset polyglutamine ataxia that results from an unstable expansion of a CAG tract in the ATXN3 gene. The size of the CAG tract only partially explains age at onset (AO), highlighting the existence of disease modifiers. Mitochondrial DNA (mtDNA) haplogroups have been associated with clinical presentation in other polyglutamine disorders, constituting potential modifiers of MJD phenotype. METHODS: A cross-sectional study, using 235 unrelated patients from Portugal, Brazil, India and Japan, was performed to investigate if mtDNA haplogroups contribute to AO of MJD. mtDNA haplogroups were obtained after sequencing the mtDNA hypervariable region I. Patients were classified in 15 phylogenetically related haplogroup clusters. RESULTS: The AO was significantly different among populations, implying the existence of other non-CAG factors, which seem to be population specific. In the Portuguese population, patients classified as belonging to haplogroup JT presented the earliest onset (estimated onset 34.6 years of age). Haplogroups W and X seem to have a protective effect, causing a delay in onset (estimated onset 47 years of age). No significant association between haplogroup clusters and AO was detected in the other populations or when all patients were pooled. Although haplogroup JT has already been implicated in other neurodegenerative disorders, no previous reports of an association between haplogroups W and X and disease were found. CONCLUSIONS: These findings suggest that haplogroups JT, W and X modify AO in MJD. Replication studies should be performed in European populations, where the frequency of the candidate modifiers is similar.
Asunto(s)
ADN Mitocondrial/genética , Haplotipos , Enfermedad de Machado-Joseph/genética , Adulto , Edad de Inicio , Brasil , Estudios Transversales , Femenino , Humanos , India , Japón , Masculino , Persona de Mediana Edad , PortugalRESUMEN
BACKGROUND AND PURPOSE: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the length of CAG repeat expansions in ATXN3 shows an inverse correlation with age at onset (AO). Recently, a formula for predicting AO based on CAG expansion was developed for European carriers. We tested this formula in SCA3/MJD carriers from distinct origins and developed population-specific models to predict AO. METHODS: This was a parametric survival modelling study. RESULTS: The European formula (EF) was tested in 739 independent SCA3/MJD carriers from South Brazil, Taiwan and the Portuguese Azorean islands, and it largely underestimated AO in South Brazilian and Taiwanese test cohorts. This finding challenged the universal use of the EF, leading us to develop and validate population-specific models for AO prediction. Using validation cohorts, we showed that Brazilian and Taiwanese formulas largely outperformed the EF in a population-specific manner. Inversely, the EF was more accurate at predicting AO among Portuguese Azorean patients. Hence, specific prediction models were required for each SCA3/MJD ethnic group. CONCLUSIONS: Our data strongly support the existence of as yet unknown factors that modulate AO in SCA3/MJD in a population-dependent manner, independent of CAG expansion length. The generated models are made available to the scientific community as they can be useful for future studies on SCA3/MJD carriers from distinct geographical origins.
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Edad de Inicio , Enfermedad de Machado-Joseph/fisiopatología , Adulto , Algoritmos , Pueblo Asiatico , Brasil , Portador Sano , Estudios de Cohortes , Femenino , Humanos , Enfermedad de Machado-Joseph/genética , Masculino , Persona de Mediana Edad , Población , Portugal , Valor Predictivo de las Pruebas , Taiwán , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Spinocerebellar ataxia type 10 is a neurodegenerative disorder that is due to an expanded ATTCT repeat tract in the ATXN10 gene. Our aim was to describe clinical characteristics and intragenic haplotypes of patients with spinocerebellar ataxia type 10 from Brazil and Peru. METHODS: Expanded alleles were detected by repeat-primed polymerase chain reaction. Disease progression was measured by the Scale for the Assessment and Rating of Ataxia, and the Neurological Examination Score for Spinocerebellar Ataxias when possible. Haplotypes were constructed based on polymorphic markers within and outside the gene. RESULTS: Thirteen new families were diagnosed (three from Peru). Patients from three Brazilian families diagnosed previously were also reassessed. In total, 25 individuals (16 families) were evaluated. Mean (± SD) age at onset and disease duration were 34.8 ± 10.2 and 12 ± 8 years, respectively. Common findings were ataxia, dysarthria/dysphagia, nystagmus, pyramidal signs, ophthalmoparesis and seizures. No associations were found between clinical findings and geographical origins. Twelve patients living in remote regions were examined only once. In the remaining individuals, the Scale for the Assessment and Rating of Ataxia score, and Neurological Examination Score for Spinocerebellar Ataxias worsened by 0.444 (95% CI, -0.088 to 0.800) and 0.287 (95% CI, -0.061 to 0.635) points/year, respectively. A common haplotype, 19CGGC14, was found in 11/13 of Brazilian and in 1/3 of Peruvian families. CONCLUSIONS: The progression rate was slower than in other spinocerebellar ataxias. A consistently recurrent intragenic haplotype was found, suggesting a common ancestry for most, if not all, patients.
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Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/patología , Adolescente , Adulto , Edad de Inicio , Alelos , Ataxina-10/genética , Brasil/epidemiología , Niño , ADN/genética , Progresión de la Enfermedad , Femenino , Genotipo , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , Perú/epidemiología , Convulsiones/epidemiología , Convulsiones/etiología , Adulto JovenRESUMEN
We aimed to present a systematic review on Huntington's disease (HD) in Latin America (LA). PubMed and LILACS were searched up to March 2015, reporting confirmed HD cases in LA. Case series, cross-sectional, case-control, and prospective studies were included. From 534 communications, 47 were eligible. Population-based studies were not found; minimal prevalence of 0.5-4/100,000 was estimated for Venezuela and Mexico. Geographical isolates were well characterized in Venezuela and in Peru. CAG repeats at HTT gene varied between 7-33 and 37-112 in normal and expanded alleles, respectively. Intermediate alleles were found in 4-10% of controls. Ages at onset and the expanded CAG repeats correlated with r from - 0.55 to -0.91. While haplotype patterns of Venezuelan and Brazilian chromosomes were similar to those observed in Europeans, haplotypes from Peruvian HD patients did not match the same pattern. The limited number of papers found suggests that HD is poorly diagnosed in LA. Minimal prevalence seemed to be halfway between those of Caucasians and Asians. Range of CAG repeats was similar to those of Europeans. Haplotype studies indicate that majority of HD patients might be of Caucasian descent; an Asian origin for some Peruvian patients was proposed.
Asunto(s)
Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Edad de Inicio , Anciano , Pueblo Asiatico/genética , Niño , Preescolar , Haplotipos , Humanos , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/etnología , América Latina/etnología , Persona de Mediana Edad , Prevalencia , Población Blanca/genética , Adulto JovenRESUMEN
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.
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Ataxina-3/genética , Inestabilidad Genómica , Patrón de Herencia , Enfermedad de Machado-Joseph/genética , Proteínas Represoras/genética , Expansión de Repetición de Trinucleótido , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Alelos , Enfermedades Asintomáticas , Segregación Cromosómica , Femenino , Frecuencia de los Genes , Heterocigoto , Humanos , Enfermedad de Machado-Joseph/patología , Masculino , Meiosis , Linaje , Índice de Severidad de la Enfermedad , Factores Sexuales , HermanosRESUMEN
The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis.
Asunto(s)
Corea/genética , Demencia/genética , Trastornos Heredodegenerativos del Sistema Nervioso/genética , Enfermedad de Huntington/genética , Ataxias Espinocerebelosas/genética , Adulto , Brasil , Corea/diagnóstico , Corea/epidemiología , Corea/patología , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Demencia/diagnóstico , Demencia/epidemiología , Demencia/patología , Femenino , Trastornos Heredodegenerativos del Sistema Nervioso/diagnóstico , Trastornos Heredodegenerativos del Sistema Nervioso/epidemiología , Trastornos Heredodegenerativos del Sistema Nervioso/patología , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/patología , Masculino , Persona de Mediana Edad , Fenotipo , Ataxias Espinocerebelosas/diagnóstico , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/patología , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
BACKGROUND: Cândido Godói (CG) is a small town in South Brazil, which has the highest prevalence of twin births in Brazil. Recently, a number of studies have shown that p53 plays an important role in reproduction through blastocyst implantation and intra utero embryo survival. Thus, gene polymorphisms in the p53 pathway were investigated in this population. METHODS: Single nucleotide polymorphisms from five genes in the p53 pathway were investigated, as well as background characteristics of 42 mothers of twins (cases) and 101 mothers of singletons (controls), all residents from CG. RESULTS: Mothers of twins have higher number of pregnancies and higher frequencies of P72 allele at TP53 and T allele at MDM4 genes compared with controls. Logistic regression shows that both TP53 and number of pregnancies maintained their association with twinning (P =0.004 and P =0.002, respectively), with TP53 having a higher odds ratio than number of pregnancies (2.73 versus 1.70, respectively). No interactive effect between TP53 and MDM4 (P =0.966) is observed. As expected, mothers of twins have three times more cases of cancer in their first-degree relatives than control mothers (P =0.011). CONCLUSIONS: Our results suggest that the P72 allele of TP53 is a strong risk factor for twinning in CG, while the number of pregnancies and the T allele at MDM4 may represent weaker risk factors. These two alleles are associated with infertility, but the anti-apoptotic effect of low levels of p53 in general, and of the P72 allele in particular, may play a role after implantation, enhancing the chance for a double pregnancy to succeed to term.
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Fertilidad/genética , Fertilidad/fisiología , Genes p53 , Proteína p53 Supresora de Tumor/genética , Gemelos/genética , Adulto , Alelos , Blastocisto , Brasil , Estudios de Casos y Controles , Implantación del Embrión , Femenino , Humanos , Infertilidad , Oportunidad Relativa , Polimorfismo Genético , Embarazo , Prevalencia , Factores de RiesgoAsunto(s)
Edad de Inicio , Metilación de ADN , Enfermedad de Machado-Joseph , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Adolescente , Adulto , Ataxina-3 , Niño , Regulación del Desarrollo de la Expresión Génica , Humanos , Enfermedad de Machado-Joseph/diagnóstico , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/fisiopatología , Persona de Mediana Edad , Análisis de Secuencia , Expansión de Repetición de Trinucleótido , Adulto JovenRESUMEN
Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder inherited as an autosomal recessive trait. MLD is caused by the deficiency of arylsulfatase A (ARSA), a lysosomal enzyme that catalyzes the first step in the degradation of sulfated glycolipids, which are essential components of the myelin sheet. Notably, between 7% and 15% of healthy individuals show in vitro deficiency of ARSA, a condition called ARSA pseudodeficiency (ARSA-PD). To date, 151 ARSA-MLD mutations have been reported in the gene encoding ARSA (ARSA), among which IVS2+1G>A and P426L occur at high frequencies in most of the studied populations. The aim of this work was to identify ARSA mutant alleles in a cohort of 27 unrelated Brazilian MLD patients. The most frequent ARSA-MLD mutation, IVS2+1G>A, and the ARSA-PD polymorphisms, N350S and 1524+95A>G, were detected using real-time PCR, while the remaining mutations were detected using direct sequencing of ARSA. In concordance with previous reports, IVS2+1G>A and P426L were the most common ARSA-MLD mutations in our cohort of MLD patients, found at frequencies of 0.05 and 0.08, respectively. Interestingly, two mutations previously reported as rare, 103_110del8 and 1190_1191insC, were found at higher frequencies in our cohort of MLD patients, 0.08 and 0.06, respectively. Additionally, 11 other rare ARSA-MLD mutations were found at lower frequencies in our cohort of MLD patients. To our knowledge, this is the first systematic genotypic characterization of MLD patients from Latin America. This work highlights the genetic heterogeneity of MLD, and supports genotype-phenotype associations, which become more important as specific treatments are being developed for this devastating disorder.
Asunto(s)
Leucodistrofia Metacromática/genética , Brasil , Cerebrósido Sulfatasa/genética , Niño , Preescolar , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Lactante , Masculino , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
Polymorphisms of hormone receptor genes have been linked to modifications in reproductive factors and to an increased risk of breast cancer (BC). In the present study, we have determined the allelic and genotypic frequencies of the ERα-397 PvuII C/T, ERα-351 XbaI A/G and PGR PROGINS polymorphisms and investigated their relationship with mammographic density, body mass index (BMI) and other risk factors for BC. A consecutive and unselected sample of 750 Brazilian BC-unaffected women enrolled in a mammography screening program was recruited. The distribution of PGR PROGINS genotypic frequencies was 72.5, 25.5 and 2.0% for A1A1, A1A2 and A2A2, respectively, which was equivalent to that encountered in other studies with healthy women. The distribution of ERα genotypes was: ERα-397 PvuII C/T: 32.3% TT, 47.5% TC, and 20.2% CC; ERα-351 XbaI A/G: 46.3% AA, 41.7% AG and 12.0% GG. ERα haplotypes were 53.5% PX, 14.3% Px, 0.3% pX, and 32.0% px. These were significantly different from most previously published reports worldwide (P < 0.05). Overall, the PGR PROGINS genotypes A2A2 and A1A2 were associated with fatty and moderately fatty breast tissue. The same genotypes were also associated with a high BMI in postmenopausal women. In addition, the ERα-351 XbaI GG genotype was associated with menarche ≥ 12 years (P = 0.02). ERα and PGR polymorphisms have a phenotypic effect and may play an important role in BC risk determination. Finally, if confirmed in BC patients, these associations could have important implications for mammographic screening and strategies and may be helpful to identify women at higher risk for the disease.
Asunto(s)
Neoplasias de la Mama/genética , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Receptor alfa de Estrógeno/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético/genética , Receptores de Progesterona/genética , Adulto , Anciano , Índice de Masa Corporal , Brasil , Densidad de la Mama , Neoplasias de la Mama/diagnóstico , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Glándulas Mamarias Humanas/anomalías , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
UNLABELLED: Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) may rarely presents a parkinsonian phenotype. Considering that mutations in the glucocerebrosidase (GBA) gene have been associated with Parkinson disease, we investigated whether these would be more prevalent in MJD/SCA3 patients with parkinsonian manifestations than in those without them. METHODS: MJD/SCA3 patients with parkinsonian features were identified and compared to relatives and to a MJD/SCA3 control group with no such features. The GBA gene was sequenced and, in a subset of patients and in normal volunteers, GBA enzyme activity was measured. RESULTS: We have identified nine index MJD/SCA3 patients with parkinsonian manifestations. Overall, GBA sequence variations were found in 3/9 MJD/SCA3 index cases with parkinsonian manifestations (33%) and in 0/40 MJD/SCA3 controls without parkinsonism (p=0.03, Fisher exact test). The GBA sequence variations found were p.K(-27)R, p.E326K, and p.T369M. The latter two sequence variations were also found in two symptomatic relatives with no parkinsonian manifestations. A MJD/SCA3 relative belonging to the first positive pedigree and carrier of the p.K(-27)R mutation also presented parkinsonian manifestations. GBA activity in MJD/SCA3 patients was similar to those found in the normal control group. CONCLUSION: Sequence variations at the GBA gene may play a role as a minor, modifying gene of MJD/SCA3 phenotype. This hypothetical role was not related to changes in GBA activity in peripheral leukocytes.
Asunto(s)
Variación Genética , Glucosilceramidasa/genética , Enfermedad de Machado-Joseph/enzimología , Enfermedad de Machado-Joseph/genética , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/genética , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeAsunto(s)
Proteínas Portadoras/genética , Colestanoles/sangre , Filipina/química , Glicoproteínas/genética , Hexosaminidasas/sangre , Glicoproteínas de Membrana/genética , Enfermedad de Niemann-Pick Tipo C/diagnóstico , Coloración y Etiquetado , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/uso terapéutico , Brasil , Hexosaminidasas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/sangre , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/genética , Proteínas de Transporte VesicularRESUMEN
Several studies have identified the single nucleotide polymorphism STK15 F31I as a low-penetrance risk allele for breast cancer, but its prevalence and risk association in the Brazilian population have not been determined. The goal of this study was to identify the frequency of this polymorphism in the Brazilian setting. Considering the high degree of admixture of our population, it is of fundamental importance to validate the results already reported in the literature and also to verify the relationship between this variant and breast cancer risk. A total of 750 women without breast cancer were genotyped using the TaqMan PCR assay for STK15 F31I polymorphism. Clinical information was obtained from review of the medical records and mammographic density from the images obtained using the BI-RADS System. The estimated risk of developing cancer was calculated according to the Gail model. The genotypic frequencies observed in this study were 4.5, 38.7, and 56.6%, respectively, for the STK15 F31I AA, AT and TT genotypes. The AT and AA genotypes were encountered significantly more often in premenopausal women with moderately dense, dense and heterogeneously dense breast tissue (P = 0.023). In addition, the presence of the TT genotype was significantly associated with age at menarche ≥12 years (P = 0.023). High mammographic density, associated with increased breast cancer risk, was encountered more frequently in premenopausal women with the risk genotypes STK15 F31I AA and AT. The genotypic frequencies observed in our Brazilian sample were similar to those described in other predominantly European populations.
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Neoplasias de la Mama/genética , Mamografía , Polimorfismo de Nucleótido Simple/genética , Proteínas Serina-Treonina Quinasas/genética , Adulto , Anciano , Aurora Quinasa A , Aurora Quinasas , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/enzimología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prevalencia , Factores de RiesgoRESUMEN
Occupational therapy (OT) is a profession concerned with promoting health and well-being through occupation, by enabling handicapped people to participate in the activities of everyday life. OT is part of the clinical rehabilitation of progressive genetic neurodegenerative diseases such as spinocerebellar ataxias; however, its effects have never been determined in these diseases. Our aim was to investigate the effect of OT on both physical disabilities and depressive symptoms of spinocerebellar ataxia type 3 (SCA3) patients. Genomically diagnosed SCA3 patients older than 18 years were invited to participate in the study. Disability, as evaluated by functional independence measurement and Barthel incapacitation score, Hamilton Rating Scale for Depression, and World Health Organization Quality of Life questionnaire (WHOQOL-BREF), was determined at baseline and after 3 and 6 months of treatment. Twenty-six patients agreed to participate in the study. All were treated because OT prevents blinding of a control group. Fifteen sessions of rehabilitative OT were applied over a period of 6 months. Difficult access to food, clothing, personal hygiene, and leisure were some of the main disabilities focused by these patients. After this treatment, disability scores and quality of life were stable, and the Hamilton scores for depression improved. Since no medication was started up to 6 months before or during OT, this improvement was related to our intervention. No association was found between these endpoints and a CAG tract of the MJD1 gene (CAGn), age, age of onset, or neurological scores at baseline (Spearman test). Although the possibly temporary stabilization of the downhill disabilities as an effect of OT remains to be established, its clear effect on depressive symptoms confirms the recommendation of OT to any patient with SCA3 or spinocerebellar ataxia.
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Depresión/rehabilitación , Enfermedad de Machado-Joseph/rehabilitación , Terapia Ocupacional , Calidad de Vida/psicología , Adulto , Depresión/psicología , Femenino , Estudios de Seguimiento , Humanos , Enfermedad de Machado-Joseph/psicología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Parkinson's disease (PD) has been related to mutations associated with spinocerebellar ataxias (SCA); the frequency of the diagnosis of these mutations is low in general late-onset PD cases. Our aim was to investigate a selected high-risk group of PD patients. METHODS: PD patients with autosomal dominant inheritance or atypical neurological manifestations were enrolled, underwent a full neurological examination and had the CAG tracts of their SCA1, 2, 3, 6 and 7 genes analyzed. RESULTS: Of the 23 studied families, two SCA3 and one SCA2 cases were identified. All had autosomal dominant inheritance. In the SCA2 pedigree, four affected sibs had a homogeneous PD phenotype. CAG repeats varied between 35 and 44 with CAA interruptions. Intrafamilial phenotypic heterogeneity was identified in the SCA3 pedigrees; parkinsonian and ataxic phenotypes coexisted in both kindreds. CAGn varied between 69 and 71 repeats. Age of onset was lower in the SCA3 patients than in the remaining 24 cases (38 versus 46.7+/-12 years of age, p=0.003). CONCLUSIONS: SCA2 and SCA3 mutations were detected in 13% of the present sample: the strategy of selecting a high-risk group increased the rate of making these diagnoses. The SCA2 cases confirmed an association between PD and interrupted expansions, as well as PD intrafamilial phenotypic homogeneity. Clinical heterogeneity of SCA3 pedigrees suggests that disease-modifying agents outside the MJD1 gene may play a role in determining PD symptoms in this disorder.
Asunto(s)
Expansión de las Repeticiones de ADN , Familia , Variación Genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Adulto , Edad de Inicio , Antiparkinsonianos/uso terapéutico , Ataxina-3 , Ataxinas , Femenino , Genes Dominantes , Humanos , Levodopa/uso terapéutico , Enfermedad de Machado-Joseph/genética , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Linaje , Fenotipo , Proteínas Represoras/genética , Degeneraciones Espinocerebelosas/genéticaRESUMEN
BACKGROUND: Machado-Joseph disease (MJD SCA3), a spinocerebellar ataxia related to expansion of a CAG tract, has already been related to anticipation and meiotic drift. However, fitness of MJD carriers has been little studied. OBJECTIVE: To analyze genetic fitness of MJD patients, comparing them to their unaffected relatives and to the general population (GP) of origin. SUBJECTS AND METHODS: 182 informants, belonging to 82 MJD families, agreed to participate in the study. Informants supplied data about 828 MJD patients. Number of children (NC), gender, age, school attainment, menarche and menopause were compared between general and emeritus (older than 45 years of age or deceased) groups. RESULTS: Mean NC of the GP and of MJD patients were respectively 1.90 and 2.93+/-2.3 (p = 0.0037). Comparisons within families also showed differences: the mean NC of unaffected and affected emeritus MJD women were, respectively, 2.68 and 3.89 (p = 0.0037). Affected MJD women had earlier mean ages at the delivery of their first child and menopause (p < 0.011 and 0.07, respectively). Among affected women those who did not have children had larger CAG tracts than those who had children (p < 0.05). CONCLUSION: MJD enhances the fitness of its carriers, and this phenomenon seems to have a biological basis.
Asunto(s)
Enfermedad de Machado-Joseph/genética , Grupos de Población , Edad de Inicio , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Enfermedad de Machado-Joseph/epidemiología , Enfermedad de Machado-Joseph/patología , PrevalenciaRESUMEN
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.
Asunto(s)
Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/mortalidad , Adolescente , Adulto , Edad de Inicio , Anciano , Ataxina-3 , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Tasa de Supervivencia , Expansión de Repetición de TrinucleótidoRESUMEN
OBJECTIVES: It was the aim of this study to determine the depression scores of Machado-Joseph disease (MJD) patients, their spouses, and individuals at 50% risk for MJD, and second, to verify the existence of a correlation between depressive symptoms and the degree of motor incapacitation. SUBJECTS AND METHODS: Two hundred and forty-six individuals aged > or =18 years were studied: 79 MJD patients (group 1), 43 spouses of MJD patients (group 2), 80 individuals at risk for MJD (group 3), and a control group (group 4) composed of 44 patients with multiple sclerosis (MS). The following two tools were applied: the Beck Depression Inventory and the Barthel index of physical incapacitation, both in an adapted Brazilian Portuguese version. RESULTS: Moderate to severe depressive scores were found in 33.5% of patients in the MJD families, in 16.3% of the spouses, and in 6.3% of the individuals at risk. This linear reduction between MJD family members was statistically significant (p < 0.0001, ANOVA). Depressive scores were also associated with age and the female sex. A direct correlation between Beck Depression Inventory scores and motor incapacitation was found in MJD patients (r = 0.507, Pearson correlation, p < 0.0001). Although the depressive symptoms in the control group with MS were higher than those found in MJD patients (59% of MS patients showed moderate to severe scores), depression did not correlate with physical incapacitation, age, or education attainment in the MS group. CONCLUSIONS: Depressive symptoms are rather common in MJD patients and in their spouses (caregivers). In this condition, depression seemed to be more reactive than primarily related to the disease process itself.
Asunto(s)
Depresión/diagnóstico , Enfermedad de Machado-Joseph/psicología , Adulto , Ataxina-3 , Cuidadores , Depresión/psicología , Familia , Femenino , Humanos , Enfermedad de Machado-Joseph/fisiopatología , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Represoras/metabolismo , Índice de Severidad de la EnfermedadRESUMEN
Polymorphisms of hormone receptor genes have been linked to modifications in reproductive factors and to an increased risk of breast cancer (BC). In the present study, we have determined the allelic and genotypic frequencies of the ERα-397 PvuII C/T, ERα-351 XbaI A/G and PGR PROGINS polymorphisms and investigated their relationship with mammographic density, body mass index (BMI) and other risk factors for BC. A consecutive and unselected sample of 750 Brazilian BC-unaffected women enrolled in a mammography screening program was recruited. The distribution of PGR PROGINS genotypic frequencies was 72.5, 25.5 and 2.0% for A1A1, A1A2 and A2A2, respectively, which was equivalent to that encountered in other studies with healthy women. The distribution of ERα genotypes was: ERα-397 PvuII C/T: 32.3% TT, 47.5% TC, and 20.2% CC; ERα-351 XbaI A/G: 46.3% AA, 41.7% AG and 12.0% GG. ERα haplotypes were 53.5% PX, 14.3% Px, 0.3% pX, and 32.0% px. These were significantly different from most previously published reports worldwide (P < 0.05). Overall, the PGR PROGINS genotypes A2A2 and A1A2 were associated with fatty and moderately fatty breast tissue. The same genotypes were also associated with a high BMI in postmenopausal women. In addition, the ERα-351 XbaI GG genotype was associated with menarche ≥12 years (P = 0.02). ERα and PGR polymorphisms have a phenotypic effect and may play an important role in BC risk determination. Finally, if confirmed in BC patients, these associations could have important implications for mammographic screening and strategies and may be helpful to identify women at higher risk for the disease.
Asunto(s)
Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Neoplasias de la Mama/genética , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Receptor alfa de Estrógeno/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético/genética , Receptores de Progesterona/genética , Índice de Masa Corporal , Brasil , Neoplasias de la Mama/diagnóstico , Frecuencia de los Genes , Genotipo , Glándulas Mamarias Humanas/anomalías , Prevalencia , Factores de RiesgoRESUMEN
Several studies have identified the single nucleotide polymorphism STK15 F31I as a low-penetrance risk allele for breast cancer, but its prevalence and risk association in the Brazilian population have not been determined. The goal of this study was to identify the frequency of this polymorphism in the Brazilian setting. Considering the high degree of admixture of our population, it is of fundamental importance to validate the results already reported in the literature and also to verify the relationship between this variant and breast cancer risk. A total of 750 women without breast cancer were genotyped using the TaqMan PCR assay for STK15 F31I polymorphism. Clinical information was obtained from review of the medical records and mammographic density from the images obtained using the BI-RADS System. The estimated risk of developing cancer was calculated according to the Gail model. The genotypic frequencies observed in this study were 4.5, 38.7, and 56.6 percent, respectively, for the STK15 F31I AA, AT and TT genotypes. The AT and AA genotypes were encountered significantly more often in premenopausal women with moderately dense, dense and heterogeneously dense breast tissue (P = 0.023). In addition, the presence of the TT genotype was significantly associated with age at menarche ≥12 years (P = 0.023). High mammographic density, associated with increased breast cancer risk, was encountered more frequently in premenopausal women with the risk genotypes STK15 F31I AA and AT. The genotypic frequencies observed in our Brazilian sample were similar to those described in other predominantly European populations.