RESUMO
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.
Assuntos
Ataxias Espinocerebelares/genética , Ataxias Espinocerebelares/patologia , Adolescente , Adulto , Idade de Início , Alelos , Ataxina-10/genética , Brasil/epidemiologia , Criança , DNA/genética , Progressão da Doença , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Peru/epidemiologia , Convulsões/epidemiologia , Convulsões/etiologia , Adulto JovemRESUMO
Presenilin 1 (PSEN1) gene mutations are found in 30-70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family.
Las mutaciones del gen de presenilina 1 (PSEN1) se encuentran en el 30-70% de los casos de enfermedad de Alzheimer de inicio temprano (EAIP) familiar (inicio <60 años). La prevalencia de estas mutaciones es muy variable, incluidas las diferencias étnicas en todo el mundo. No se han descrito parientes peruanos con EA familiar (EAF). Se realizó una evaluación clínica estandarizada y una evaluación cognitiva en una familia peruana con EAIP grave. El curso clínico se caracterizó por un inicio muy temprano (antes de los 35 años), deterioro cognitivo progresivo con pérdida temprana de memoria, desorientación espacial y disfunción ejecutiva. Secuenciamos todos los exones de PSEN1 en el probando e identificamos un cambio de ADN c.475C>G que resultó en una mutación sin sentido p.L153V en el dominio transmembrana 2 del gen. Esta mutación también está presente en los tres hermanos afectados adicionales, pero no en un miembro de la familia no afectado, lo que es consistente con la segregación de esta mutación con la enfermedad. Este es el primer informe de una familia peruana afectada con EAIP asociada con una mutación PSEN1. Esta misma mutación se ha informado previamente en familias inglesas y francesas, pero una nueva variante muy cercana a la mutación y el análisis de marcadores informativos de ascendencia sugieren que la mutación podría ser de origen amerindio o africano en esta familia peruana.