RESUMO
INTRODUCTION: Synaptophysin, already related to X-linked intellectual disability, is expressed mainly in the central nervous system. Studies in humans indicate that the downregulation of synaptophysin could be involved in the development of dementia. Our study presents the first familial case of behavioral variant frontotemporal dementia associated with the co-occurrence of the repeat expansion in C9orf72 and a pathogenic variant in the SYP gene. METHODS: Exome sequencing and repeat-primed PCR for C9orf72 were performed for two siblings with clinical and imaging findings suggestive of slowly progressive behavioral frontotemporal dementia. RESULTS: We found that both siblings have the hexanucleotide expansion in C9orf72 and a null variant in the SYP gene. The most affected sibling presents the putative variant in a hemizygous state. With milder symptoms, his sister has the same pathogenic variant in heterozygosis, compatible with X-linked inheritance. DISCUSSION: Our results strengthened previous suggestive evidence that the phenotypes associated with C9orf72 repeat expansion are variable and probably influenced by additional genetic modifiers. We hypothesized that the pathogenic variant in the SYP gene might have modified the typical phenotype associated with the C9orf72 mutation.
Assuntos
Esclerose Lateral Amiotrófica , Demência Frontotemporal , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Humanos , Mutação/genética , Proteínas/genética , Sinaptofisina/genéticaRESUMO
OBJECTIVES: Limitations of functional capacity and balance are common features of the natural history of spinocerebellar ataxias (SCA). However, their onset and progression patterns differ according to subtype. The aim of our study was to compare physical functionality and balance parameters in SCA10 and SCA3 patients, correlating with clinical variables. MATERIALS & METHODS: Cross-sectional study evaluating ninety-five SCA patients (60 with SCA3 and 35 with SCA10) with validated scales for functional independence, balance and the severity of signs and symptoms. RESULTS: The groups were similar in terms of age and gender, and results were adjusted for age at symptom onset. The SCA10 patients had better results for balance and functional independence (p < 0.007). They also had lower scores for disease severity (p < 0.0002) and the subitems gait (p < 0.0005), posture (p < 0.0021) and sitting balance (p < 0.0008). Symptom progression in both groups was similar for patients with a disease duration of up to ten years, but there was a more marked decline in SCA3 patients after this period. CONCLUSIONS: We have shown that disease progression as assessed by balance and physical functioning is slower in SCA10 patients than SCA3 patients, particularly after 10 years of disease. These findings are important as they can help to characterize the disease, assisting in the development of new therapies and rehabilitation programs.
Assuntos
Progressão da Doença , Desempenho Físico Funcional , Equilíbrio Postural/fisiologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/fisiopatologia , Adulto , Estudos Transversais , Expansão das Repetições de DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Ataxias Espinocerebelares/genéticaRESUMO
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder in which patients have a slowly progressive cerebellar ataxia, with dysarthria, dysphagia, and epilepsy. The aims of this study were to characterize the phenotypic expression of SCA10 and to examine its genotype-phenotype relationships. Ninety-one Brazilian patients with SCA10 from 16 families were selected. Clinical and epidemiological data were assessed by a standardized protocol, and severity of disease was measured by the Scale for the Assessment and Rating of Ataxia (SARA). The mean age of onset of symptoms was 34.8 ± 9.4 years. Sixty-two (68.2%) patients presented exclusively with pure cerebellar ataxia. Only 6 (6.6%) of the patients presented with epilepsy. Patients with epilepsy had a mean age of onset of symptoms lower than that of patients without epilepsy (23.5 ± 15.5 years vs 35.4 ± 8.7 years, p = 0.021, respectively). All cases of intention tremor were in women from one family. This family also had the lowest mean age of onset of symptoms, and a higher percentage of SCA10 cases in women. There was a positive correlation between duration of disease and severity of ataxia (rho = 0.272, p = 0.016), as quantified by SARA. We did not find a statistically significant correlation between age of onset of symptoms and expansion size (r = - 0.163, p = 0.185). The most common clinical presentation of SCA10 was pure cerebellar ataxia. Our data suggest that patients with epilepsy may have a lower age of onset of symptoms than those who do not have epilepsy. These findings and the description of a family with intention tremor in women with earlier onset of symptoms draw further attention to the phenotypic variability of SCA10.
Assuntos
Ataxina-10/genética , Epilepsia/epidemiologia , Epilepsia/genética , Testes Genéticos/métodos , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Adolescente , Adulto , Brasil/epidemiologia , Expansão das Repetições de DNA/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico , Adulto JovemRESUMO
Spinocerebellar ataxia type 10 (SCA10) is a repeat expansion disease occurring mostly in Latin America, suggesting that the mutation spread with the peopling of the Americas, or that Amerindian populations, have a higher ATXN10 mutability. High frequency of large normal alleles is associated with prevalence and relative frequency of other repeat expansion diseases. To test whether the allele distribution of the SCA10-causing ATXN10 microsatellite in an Amerindian Peruvian population differs from that of other populations. The ATXN10 allele distribution in a Quechua Peruvian population from Puno, Peru, is similar to that of Finland. Mean allele size and mode were also similar to those of Mexico, Japan, and white Europeans. ATXN10 allele distribution in a healthy Amerindian population from Peru does not differ from that of other populations.
Assuntos
Alelos , Ataxina-10/genética , Repetições de Microssatélites/genética , Vigilância da População , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genética , Expansão das Repetições de DNA/genética , Europa (Continente)/epidemiologia , Humanos , Japão/epidemiologia , México/epidemiologia , Peru/epidemiologia , Vigilância da População/métodos , Ataxias Espinocerebelares/diagnósticoRESUMO
Although the main clinical manifestations of spinocerebellar ataxias (SCAs) result from damage of the cerebellum, other systems may also be involved. Olfactory deficits have been reported in other types of ataxias, especially in SCA3; however, there are no studies on olfactory deficits in SCA type 10 (SCA10). To analyze olfactory function of SCA10 patients compared with that of SCA3, Parkinson's, and healthy controls. Olfactory identification was tested in three groups of 30 patients (SCA10, SCA3, and Parkinson's disease (PD)) and 44 healthy controls using the Sniffin' Sticks (SS16) test. Mean SS16 score was 11.9 ± 2.9 for the SCA10 group, 12.3 ± 1.9 for the SCA3 group, 6.6 ± 2.8 for the PD group, and 12.1 ± 2.0 for the control group. Mean SS16 score for the SCA10 group was not significantly different from the scores for the SCA3 and control groups but was significantly higher than the score for the PD group (p < 0.001) when adjusted for age, gender, and history of smoking. There was no association between SS16 scores and disease duration in the SCA10 or SCA3 groups or number of repeat expansions. SS16 and Mini Mental State Examination scores were correlated in the three groups: SCA10 group (r = 0.59, p = 0.001), SCA3 group (r = 0.50, p = 0.005), and control group (r = 0.40, p = 0.007). We found no significant olfactory deficits in SCA10 in this large series.
Assuntos
Doença de Machado-Joseph/fisiopatologia , Transtornos do Olfato/fisiopatologia , Doença de Parkinson/fisiopatologia , Olfato , Ataxias Espinocerebelares/fisiopatologia , Expansão das Repetições de DNA/genética , Feminino , Humanos , Doença de Machado-Joseph/genética , Masculino , Pessoa de Meia-Idade , Transtornos do Olfato/genética , Estudos Prospectivos , Ataxias Espinocerebelares/genéticaRESUMO
G4C2 hexanucleotide repeat expansions in the C9orf72 gene seem to be the cause of numerous cases of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). In this study, we investigated the presence of the G4C2 repeat expansion in 463 Brazilian probands, of whom 404 had ALS/motor neuron disease and 67 FTD, and in 63 healthy controls in the southeastern region of Brazil. The highest frequencies of the C9orf72 mutation were in the ALS-FTD group (50% of familial and 17.6% of sporadic cases), although it was also present in 5% of pure ALS/motor neuron disease patients (11.8% of familial and 3.6% of sporadic cases) and in 7.1% of pure familial FTD. Among G4C2 repeat mutation carriers, 68.8% of the subjects who developed dementia symptoms were females. This frequency was significantly higher than the percentage reached by men with C9orf72 expansion who had this phenotype (p = 0.047). No abnormal repeat expansion was found in control groups. Inclusion of the C9orf72 genetic test in the molecular panels for Brazilian populations with these neurodegenerative diseases should be strongly considered.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Estudos de Associação Genética , Doença dos Neurônios Motores/genética , Mutação , Esclerose Lateral Amiotrófica/epidemiologia , Brasil/epidemiologia , Feminino , Demência Frontotemporal/epidemiologia , Testes Genéticos , Humanos , Masculino , Doença dos Neurônios Motores/epidemiologia , FenótipoRESUMO
Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5' untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.
Assuntos
Pé Torto Equinovaro/genética , RNA Helicases DEAD-box/genética , Fator de Iniciação 4A em Eucariotos/genética , Deformidades Congênitas da Mão/genética , Laringe/fisiopatologia , Deformidades Congênitas dos Membros/genética , Síndrome de Pierre Robin/genética , Adolescente , Adulto , Alelos , Brasil/epidemiologia , Criança , Pé Torto Equinovaro/epidemiologia , Pé Torto Equinovaro/fisiopatologia , Expansão das Repetições de DNA/genética , Inglaterra/epidemiologia , Extremidades/fisiopatologia , Feminino , Genótipo , Deformidades Congênitas da Mão/epidemiologia , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Laringe/anormalidades , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Fenótipo , Síndrome de Pierre Robin/epidemiologia , Síndrome de Pierre Robin/fisiopatologia , Mutação Puntual/genética , Adulto JovemRESUMO
Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND) may share similar pathogenic mechanisms. An abnormal hexanucleotide expansion in C9orf72 gene is the most common genetic abnormality of these conditions and explains their concurrence in the same family. We report a 77-year-old female presenting with non-fluent aphasia leading to mutism and a mild Parkinsonism. A magnetic resonance imaging showed a severe atrophy of frontal and temporal lobes. Several family members of the patient suffered of atypical Parkinsonism, lateral amyotrophic sclerosis and dementia. We identified an abnormal hexanucleotide expansion in the C9orf72 gene in the proband. To the extent of our knowledge, this is the first time that this diagnosis is confirmed in our country. The knowledge of the genetic basis of neuro degenerative disorders improves diagnosis and opens expectatives for future treatments of these disabling conditions.
Assuntos
Proteína C9orf72/genética , Expansão das Repetições de DNA/genética , Demência Frontotemporal/genética , Mutação/genética , Idoso , Atrofia , Feminino , Demência Frontotemporal/patologia , Predisposição Genética para Doença , Humanos , Imageamento por Ressonância Magnética , Masculino , LinhagemRESUMO
Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene on chromosome 22q13.3. SCA10 has shown a geographical distribution throughout America with a likely degree of Amerindian ancestry from different countries so far. Currently available data suggest that SCA10 mutation might have spread out early during the peopling of the Americas. However, the ancestral origin of SCA10 mutation remains under speculation. Samples of SCA10 patients from two Latin American countries were analysed, being 16 families from Brazil (29 patients) and 21 families from Peru (27 patients) as well as 49 healthy individuals from Indigenous Quechua population and 51 healthy Brazilian individuals. Four polymorphic markers spanning a region of 5.2 cM harbouring the ATTCT expansion were used to define the haplotypes, which were genotyped by different approaches. Our data have shown that 19-CGGC-14 shared haplotype was found in 47% of Brazilian and in 63% of Peruvian families. Frequencies from both groups are not statistically different from Quechua controls (57%), but they are statistically different from Brazilian controls (12%) (p < 0.001). The most frequent expanded haplotype in Quechuas, 19-15-CGGC-14-10, is found in 50% of Brazilian and in 65% of Peruvian patients with SCA10. These findings bring valuable evidence that ATTCT expansion may have arisen in a Native American chromosome.
Assuntos
Ataxina-10/genética , Efeito Fundador , Indígenas Sul-Americanos/genética , Mutação , Ataxias Espinocerebelares/genética , África/etnologia , População Negra/genética , Brasil/epidemiologia , Expansão das Repetições de DNA/genética , Europa (Continente)/etnologia , Frequência do Gene , Haplótipos/genética , Migração Humana , Humanos , Peru/epidemiologia , Ataxias Espinocerebelares/etnologia , População Branca/genéticaRESUMO
Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND) may share similar pathogenic mechanisms. An abnormal hexanucleotide expansion in C9orf72 gene is the most common genetic abnormality of these conditions and explains their concurrence in the same family. We report a 77-year-old female presenting with non-fluent aphasia leading to mutism and a mild Parkinsonism. A magnetic resonance imaging showed a severe atrophy of frontal and temporal lobes. Several family members of the patient suffered of atypical Parkinsonism, lateral amyotrophic sclerosis and dementia. We identified an abnormal hexanucleotide expansion in the C9orf72 gene in the proband. To the extent of our knowledge, this is the first time that this diagnosis is confirmed in our country. The knowledge of the genetic basis of neuro degenerative disorders improves diagnosis and opens expectatives for future treatments of these disabling conditions.