Ismael Araujo-Aliaga

Objetivo: Comparar la frecuencia de crisis epilépticas entre pacientes con SCA10 y otras SCA en una muestra de la población peruana. Materiales y métodos: Estudio observacional con componente retrospectivo con revisión de historias clínicas y prospectivo con entrevista previo consentimiento informado. Se reclutaron pacientes con diagnóstico genético de SCA atendidos entre enero de 2014 y diciembre de 2023 en un centro de referencia nacional de Perú. Resultados: Se identificaron 125 casos/87 familias con diagnóstico de seis tipos de SCA (SCA1, SCA2, MJD/SCA3, SCA6, SCA7 y SCA10), con una frecuencia global de 11,2 % de crisis epilépticas. Estas predominaron en el subgrupo SCA10 (16 %), en contraste con el subgrupo de otras SCA (4 %), donde se hallaron dos casos de SCA2 con crisis epilépticas. Conclusiones: Las crisis epilépticas son significativamente más frecuentes en SCA10 respecto de las otras SCA en la población estudiada. Predominan las crisis de inicio desconocido tipo motor tónico-clónicas en SCA10 y las crisis de inicio focales motoras en SCA2, ambas con buena respuesta a medicación anticrisis.

Las ataxias hereditarias representan un grupo diverso de enfermedades neurogenéticas caracterizadas por alteraciones en la coordinación motora, debido a la disfunción del cerebelo o sus vías asociadas. Estas enfermedades incluyen formas autosómicas dominantes, recesivas, ligadas al cromosoma X y mitocondriales. El diagnóstico y el tratamiento son complejos, más aún en regiones con recursos limitados como Perú y otros países de Latinoamérica, donde se presentan desafíos adicionales. Esta revisión propone un enfoque diagnóstico estructurado para las ataxias hereditarias que consiste en cinco ejes: 1) confirmación del tipo de ataxia (cerebelosa o no cerebelosa); 2) edad de inicio; 3) forma de presentación (predominantemente pura o plus); 4) historia familiar; y 5) exclusión de causas reversibles o secundarias. Los estudios auxiliares más útiles en el diagnóstico diferencial, dependiendo de la información recolectada de los 5 ejes, incluyen análisis séricos, neuroimagen, estudios neurofisiológicos, evaluaciones neurooftalmológicas, pruebas vestibulares y estudios genéticos (genes específicos, paneles genéticos, exoma y genoma clínico). La implementación de un enfoque diagnóstico basado en estos pilares optimiza tanto el diagnóstico como el manejo clínico de esta enfermedad, especialmente en contextos con recursos limitados.

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by intronic expansions of pentanucleotide repeats in the ATXN10 gene. While various repeat motifs have been described, emerging evidence suggests that specific repeat motifs, rather than repeat length alone, can modify disease features such as seizure prevalence and penetrance. We used a novel multiplex 20-gene panel with Cas9-targeted, amplification-free long-read sequencing (LRS) and optical genome mapping to elucidate ATXN10 repeat motif patterns and investigated genotype-phenotype correlations in index cases of 6 multigenerational SCA10 kindreds from Peru. We detected ATXN10 repeat expansions ranging from 990 to 2,002 pentanucleotide repeats (4.9–10 kb) across 6 families. It is important to note that we identified 3 mixed repeat motif patterns and ratios of (ATTCT)_n(ATTCC)_n, which were associated with differences in age at disease onset and anticipation. Our key novel finding is the prominence of the alternate ATTCC motif alongside the common ATTCT motif. While repeat length alone does not appear to drive disease onset in SCA10, we uncovered that the ratio of the ATTCC motif within distinct repeat patterns might correlate with disease onset. These findings underscore the need to adapt LRS clinical workflows to fully characterize large repeat expansions at the nucleotide level.

The Spinocerebellar Ataxias (SCAs) are a group of autosomal dominant neurodegenerative disorders characterized by progressive cerebellar ataxia, affecting motor coordination. SCAs are reported globally with large geographical and ethnic differences. This systematic review and meta-analysis aimed to update the frequency, and geographic distribution of SCAs in Latin America, including recently identified SCAs like SCA27B. We conducted a systematic search in PubMed, Scopus, LILACS, SciELO, and Web of Science databases, including studies published from inception to January 2025. We included 27 studies for the systematic review and 18 studies for the meta-analysis that met the inclusion criteria, representing a total of 5859 participants across eleven countries. Our meta-analysis revealed that about 50% (95% CI 26–74%) of hereditary ataxias in Latin America were confirmed to have a genetic diagnosis of SCA. The included participants with a known SCA have the following proportions: MJD/SCA3 (15%), SCA2 (11%), SCA7 (4%), SCA10 (3%), and SCA1 (3%). Geographic distributions were notable, MJD/SCA3 in Brazil, SCA2 in Cuba, Argentina and Mexico, SCA10 predominating in Peru, and SCA7 in Venezuela. Recently identified SCA types, like SCA27B and one case of SCA4, were identified in Brazil. In 22 countries there are no published studies on the epidemiology of SCAs. The distribution of SCAs in Latin America reflects the influence of historical migrations, founder effects, and ancestries, emphasizing regional heterogeneity. Our findings underscore the critical need for further epidemiological studies, particularly in understudied countries in the region.

Objectives: Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant disorder caused by large intronic expansions of pentanucleotide repeats in the ATXN10 gene. While various repeat motifs have been described, emerging evidence suggests that specific repeat motifs—rather than merely repeat length alone—can significantly modify disease features such as seizure prevalence and penetrance. Methods: We employed a novel multiplex 20-gene panel with Cas9-targeted, amplification-free long-read sequencing and optical genome mapping to elucidate ATXN10 repeat motif patterns and investigate potential genotype-phenotype correlations in index cases of six clinically well-characterized multigenerational SCA10 kindreds from Peru. Results: We detected ATXN10 repeat expansions ranging from 990 to 2002 pentanucleotide repeats (4.9 to 10 kb expansions) across six families. Importantly, we identified three mixed repeat motif patterns and ratios of (ATTCT)ₙ(ATTCC)ₙ, which were associated with differences in age at disease onset and anticipation. Discussion: Specific ATXN10 repeat motif patterns and (ATTCT)_n(ATTCC)_n motif ratios may serve as modifiers of SCA10 age at onset rather than repeat length. ATXN10 repeat composition can only be fully resolved with long-read sequencing and makes it a fundamental diagnostic for clinical practice and genetic counseling. These findings underscore the need to adapt long-read sequencing clinical workflows to fully characterize large repeat expansions at the nucleotide level.

The Spinocerebellar Ataxias (SCAs) are a group of autosomal dominant neurodegenerative disorders characterized by progressive cerebellar ataxia, affecting motor coordination. SCAs are reported globally with large geographical and ethnic differences. This systematic review and meta-analysis aimed to update the frequency, and geographic distribution of SCAs in Latin America, including recently identified SCAs like SCA27b. We conducted a systematic search in PubMed, Scopus, LILACS, SciELO and Web of Science databases, including studies published from inception to January 2025. We included 25 studies for the systematic review and 17 studies for the meta-analysis that met the inclusion criteria, representing a total of 5,546 participants across eleven countries. Our meta-analysis revealed that about 61% (95% CI 31–84%) of hereditary ataxias in Latin America were confirmed to have a genetic diagnosis of SCA. The included participants with a known SCA have the following proportions: MJD/SCA3 (34%), SCA2 (30%), SCA10 (9%), SCA7 (9%) and SCA1 (4%). Geographic distributions were notable, MJD/SCA3 in Brazil, SCA2 in Cuba, Argentina and Mexico, SCA10 predominating in Peru, and SCA7 in Venezuela. Recently identified subtypes, like SCA27B and one case of SCA4, were identified in Brazil. In 22 countries there are no published studies on the epidemiology of SCAs. The distribution of SCAs in Latin America reflects the influence of historical migrations, founder effects, and ancestries, emphasizing regional heterogeneity. Our findings underscore the critical need for further epidemiological studies, particularly in understudied countries in the region.

La Ataxia-Telangiectasia (AT) es una rara enfermedad de herencia autosómica recesiva y de afección multisistémica, caracterizada por ataxia progresiva, inmunodeficiencia variable con infecciones recurrentes, riesgo incrementado de neoplasias con o sin telangiectasias óculo-cutáneas. La AT es causada por variantes patogénicas bialélicas en el gen ATM. Su diagnóstico se basa en la sospecha de un cuadro clínico compatible, niveles elevados de alfafetoproteína, atrofia cerebelosa y estudios genéticos. No existe tratamiento curativo de AT y su manejo se basa en medidas de soporte y prevención de complicaciones y asesoramiento genético. En esta revisión, actualizamos la epidemiología, manifestaciones clínicas, diagnóstico y tratamiento de AT incluyendo una búsqueda de casos publicados en el Perú.