ABSTRACT
Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by an expanded pentanucleotide repeat in the ATXN10 gene. This repeat expansion, when fully penetrant, has a size of 850-4,500 repeats. It has been shown that the repeat composition can be a modifier of disease, e.g., seizures. Here, we describe a Mexican kindred in which we identified both pure (ATTCT)n and mixed (ATTCT)n-(ATTCC)n expansions in the same family. We used amplification-free targeted sequencing and optical genome mapping to decipher the composition of these repeat expansions. We found a considerable degree of mosaicism of the repeat expansion. This mosaicism was confirmed in skin fibroblasts from individuals with ATXN10 expansions with RNAScope in situ hybridization. All affected family members with the mixed ATXN10 repeat expansion showed typical clinical signs of spinocerebellar ataxia and epilepsy. In contrast, individuals with the pure ATXN10 expansion present with Parkinson's disease or are unaffected, even in individuals more than 20 years older than the average age at onset for SCA10. Our findings suggest that the pure (ATTCT)n expansion is non-pathogenic, while repeat interruptions, e.g., (ATTCC)n, are necessary to cause SCA10. This mechanism has been recently described for several other repeat expansions including SCA31 (BEAN1), SCA37 (DAB1), and three loci for benign adult familial myoclonic epilepsy BAFME (SAMD12, TNRC6A, RAPGEF2). Therefore, long-read sequencing and optical genome mapping of the entire genomic structure of repeat expansions are critical for clinical practice and genetic counseling, as variations in the repeat can affect disease penetrance, symptoms, and disease trajectory.
ABSTRACT
El signo de Babinski es considerado el más importante de la neurología clínica. Sin embargo a pesar de que ya ha pasado casi un siglo desde su descripción original, desconocemos su verdadero valor diagnóstico. Estudiamos a 49 pacientes con evidencia de lesión de la vía piramidal y a 100 controles sanos. El signo de Babinski estuvo presente en 41/49 pacientes y en ninguno del grupo control; la sensibilidad fue de 84 por ciento y la especialidad del 100 por ciento, con un valor predictivo positivo casi perfecto (99 por ciento, negativo excelente (92 por ciento) y una eficacia global del 94.6 por ciento. La alta sensibilidad y especificidad del signo de Babinski permite al clínico afirmar que la vía piramidal está alterada cuando el signo está presente y confianza, para decir que la vía piramidal está sana, cuando el signo esta ausente. Dificilmente se puede pensar en una prueba clínica, con toda la tecnología moderna, que reúne estas características.
