RESUMO
Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the unstable expansion of a cytosine-adenine-guanine (CAG)/cytosine-adenine-adenine (CAA) repeat in the ATXN2 gene, which normally encodes 22 glutamines (Q22). A large study was conducted to characterize the CAG/CAA repeat intergenerational instability in SCA2 families. Large normal alleles (Q24-31) were significantly more unstable upon maternal transmissions. In contrast, expanded alleles (Q32-750) were significantly more unstable during paternal transmissions, in correlation with repeat length. Significant correlations were found between the instability and the age at conception in paternal transmissions. In conclusion, intergenerational instability at ATXN2 locus is influenced by the sex, repeat length and age at conception of the transmitting parent. These results have profound implications for genetic counseling services.
Assuntos
Fatores Etários , Ataxina-2/genética , Impressão Genômica , Instabilidade Genômica , Ataxias Espinocerebelares/genética , Repetições de Trinucleotídeos , Adulto , Alelos , Feminino , Humanos , MasculinoAssuntos
Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/mortalidade , Expansão das Repetições de Trinucleotídeos/genética , Ataxinas , Cuba/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Ataxias Espinocerebelares/epidemiologia , Taxa de SobrevidaRESUMO
Previous studies have investigated the close association that exists between CAG repeat number and the age at onset in SCA2 = spinocerebellar ataxia type 2. These studies have focused on affected individuals. To further characterize this association and estimate the risk of a carrier developing SCA2 at a particular age as a function of a specific CAG repeat size, we have analyzed a large group of 924 individuals, including 394 presymptomatic and 530 affected individuals with a CAG repeat length of 32-79 units. Using a Kaplan-Meier survival analysis, we obtained cumulative probability curves for disease manifestation at a particular age for each CAG repeat length in the 34-45 range. These curves were significantly different (p < 0.001) and showed small overlap. All these information may be very valuable in predictive-testing programs, in the planning of studies for the identification of other genetic and environmental factors as modifiers of age at onset, and in the design of clinical trials for people at enlarged risk for SCA2.
Assuntos
Ataxias Espinocerebelares/epidemiologia , Adolescente , Adulto , Idade de Início , Idoso , Criança , Pré-Escolar , Cuba/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/genética , Análise de Sobrevida , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
We tested the frequency of the delta F508 mutation and haplotypes linked to the cystic fibrosis (CF) gene in Cuba. The delta F508 deletion was detected in 34.0% of the CF chromosomes. There was a shortage of delta F508 heterozygotes, suggesting non-randomness in mating patterns. Haplotype B (XV2C/KM19 1/2) was found on 40.5% of the CF chromosomes (71.5% of delta F508 chromosomes, 28.3% of non-delta F508 CF chromosomes) against 13.5% of non-CF chromosomes.
Assuntos
Fibrose Cística/genética , Haplótipos , Mutação , Cuba , Ligação Genética , HumanosRESUMO
A refined genetic map of the spinocerebellar ataxia 2 locus was constructed through linkage and haplotype analysis of 11 large pedigrees from the Holguín SCA2 family collective. Three-point analysis makes a localization of the SCA2 mutation in the 6-cM interval D12S84-D12S79 likely. This is consistent with haplotype results indicating a crossover event between two branches of the SCA2 family Rs and placing the mutation on the telomeric side of D12S84. The microsatellite D12S105 within this interval shows a peak two-point lod score of Z = 16.14 at theta = 0.00 recombination and complete linkage disequilibrium among affected individuals. These data together with the observation of a common disease haplotype among all family ancestors support the notion of an SCA2 founder effect in Holguín province.
Assuntos
Cromossomos Humanos Par 12 , Genes , Degenerações Espinocerebelares/genética , Adolescente , Adulto , Idade de Início , Idoso , Criança , Mapeamento Cromossômico , Troca Genética , Cuba/epidemiologia , DNA Satélite/genética , Feminino , Efeito Fundador , Haplótipos/genética , Humanos , Desequilíbrio de Ligação , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Reação em Cadeia da Polimerase , Degenerações Espinocerebelares/epidemiologiaRESUMO
A nationwide programme for the prevention of sickle cell (SS and SC) disorders was initiated in Cuba in 1983. Couples at risk were identified by screening pregnant women and the partners of those who carry an abnormal haemoglobin, followed by genetic counselling and the offer of prenatal diagnosis. Prenatal diagnosis was performed in one laboratory, which had carried out 1068 prenatal tests for Hb SS and SC disorders by the end of 1992. The centralization of the service has permitted rapid identification and resolution of problems.
Assuntos
Anemia Falciforme/diagnóstico , Hemoglobina Falciforme/genética , Diagnóstico Pré-Natal , Amniocentese , Anemia Falciforme/genética , Amostra da Vilosidade Coriônica , Cuba , DNA/análise , Feminino , Globinas/genética , Humanos , Reação em Cadeia da Polimerase , Gravidez , Fatores de RiscoRESUMO
Machado-Joseph disease (MJD) and Holguin ataxia (SCA2) are autosomal dominant multisystem degenerations with spinocerebellar involvement that are predominant among people of Portuguese-Azorean and of Cuban descent, respectively. Their clinical distinction may at times be difficult to make in individual patients, due to significant phenotypic overlapping (similar overall age-of-onset and duration of cerebellar ataxia, eye movement, and, often, other common problems. The recent mapping of SCA2 to chromosome 12q provided another candidate region for linkage studies of MJD. Original data on 10 families with Holguin ataxia show that the locus for phenylalanine hydroxylase (PAH) on chromosome 12q is linked to SCA2 at 4 cM and is thus far its closest marker. The exclusion of linkage 15 cM on each side of PAH in 16 families with MJD shows that these two forms of dominant ataxia are genetically distinct and at different chromosomal locations (nonallelic).
Assuntos
Doença de Machado-Joseph/genética , Degenerações Espinocerebelares/genética , Cuba , Feminino , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Fenilalanina Hidroxilase/genética , Polimorfismo de Fragmento de Restrição , PortugalRESUMO
The autosomal dominant cerebellar ataxias (ADCA) are a group of neurodegenerative disorders characterized by onset with gait ataxia, dysarthria, dysmetria and dysdiadochokinesia. We have demonstrated previously genetic heterogeneity within these disorders by excluding the disease locus from the documented spinocerebellar ataxia locus (SCA1) on chromosome 6p in a large Cuban founder population. We now report the assignment of a second locus for ADCA (SCA2) to chromosome 12q23-24.1 following linkage analyses carried out for the Cuban pedigrees, with probable flanking markers D12S58 and phospholipase A2. Investigation of linkage to the interval containing SCA2 for seven French ADCA families, previously excluded from linkage to SCA1, provides preliminary data suggesting the existence of a third ADCA locus (SCA3).
Assuntos
Cromossomos Humanos Par 12 , Degenerações Espinocerebelares/genética , Mapeamento Cromossômico , Cuba , Feminino , França , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , LinhagemRESUMO
A gene locus for autosomal dominant cerebellar ataxia (ADCA) has been found on chromosome 6p and named spinocerebellar ataxia 1. However, linkage exclusion from chromosome 6p and thus locus heterogeneity has been proven in Cuban ADCA, the largest known collective of ADCA patients, probably due to a founder effect. Two chromosomal regions were analyzed for linkage to Cuban ADCA: chromosome 4, since a pericentromeric inversion has been reported in a member of a European ADCA family, and chromosome 11q22-23, since it is known to contain the gene locus for ataxia telangiectasia, the main autosomal recessive disorder of cerebellar degeneration. In neither region was evidence for linkage found.
Assuntos
Ataxia Cerebelar/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Cuba , Ligação Genética , Marcadores Genéticos , Humanos , Linhagem , Polimorfismo GenéticoRESUMO
The percentage of carriers of the sickle cell gene in Cuba ranges from 3 to 7% in different regions. In 1983 the National Medical Genetics Centre initiated a programme for the control of sickle cell disease, which was started in Havana and later extended nationwide. The programme is based on mass education, screening and supportive genetic counselling, care of affected individuals, and availability of prenatal diagnosis. 806,935 pregnant women had been screened by the end of 1989: 29,913 (3.7%) were heterozygous, homozygous or doubly heterozygous for abnormal haemoglobin. 19,686 fathers (67%) were also tested: 1268 at-risk couples were detected. 531 elected to have prenatal diagnosis; 404 results were obtained and 98 affected fetuses (SS or SC) found. In 72 cases the pregnancy was terminated.