Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica / Friedreich's ataxia, review and literature update with a systematic search for cases in Latin America

La Ataxia de Friedreich (AF) es una enfermedad neurodegenerativa autosómica recesiva con compromiso multisistémico. En esta revisión, se actualizan aspectos epidemiológicos, fisiopatológicos y clínico-terapéuticos y se conduce una búsqueda sistemática de casos de AF reportados en Latinoamérica. La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países. Causada por la expansión anormal de repeticiones GAA en el gen FXN, la etiopatogenia está asociada a una reducción en los niveles de la proteína frataxina (que altera el metabolismo energético) y el acúmulo de hierro mitocondrial. El fenotipo clásico de AF suele comenzar antes de los 25 años, aunque hay otros de inicio tardío y retención de reflejos. La sintomatología se caracteriza por ataxia progresiva, alteración sensitiva, arreflexia, disartria, y alteraciones oculomotoras, además de compromiso cardiaco, endocrino y musculoesquelético. El diagnóstico requiere evaluación neurológica detallada, estudios neurofisiológicos, neuroimágenes y pruebas bioquímicas pero el enfoque determinante es el estudio genético que demuestre variantes genéticas bialélicas en el gen FXN. El manejo es multidisciplinario, orientado a aminorar los síntomas, prevenir complicaciones y brindar asesoramiento genético apropiado. Recientemente se ha aprobado el primer tratamiento farmacológico para AF con varios más en fases de experimentación.

SUMMARY Friedreich Ataxia (FA) is an autosomal recessive neurodegenerative disease with multisystemic involvement. This update of epidemiological, pathophysiological, and clinico-therapeutic aspects of FA, includes a systematic review of cases in Latin America. The estimated FA prevalence in Caucasian populations is between 2 to 5 cases per 100 000. In Latin America, 1481 cases have been published in 35 articles from six different countries. Caused by an abnormally repeated expansion of GAA trinucleotide inside the FXN gene, FA's etiopathogenesis is associated with reduced levels of the frataxin protein, which disturb the energy metabolism and result in mitochondrial iron accumulation. The classic phenotype usually shows symptoms before the age of 25, although there are others with a later onset. The main symptoms of AF are progressive ataxia, sensory disturbances, areflexia, dysarthria, and oculomotor alterations, in addition to cardiac, endocrine, and musculoskeletal compromise. Diagnostic workup requires a detailed neurological examination, neuroconduction studies, neuroimaging, and biochemical tests. The definitive diagnosis is provided by genetic testing showing biallelic variants within the FXN gene. The management is multidisciplinary, aimed at reducing symptoms, preventing complications, and providing an appropriate genetic counseling. Recently, the first pharmacological treatment for AF has been approved, with several others in clinical assessment trials.

Review on Molecular Diagnostic Techniques in Friedreich’s Ataxia.

Friedreich’s ataxia is a commonly inherited neurodegenerative disease with an autosomal recessive pattern of inheritance, and was described by Nikolaus Friedreich first in 1863. Friedreich’s ataxia is caused due to hyperexpansion of the intronic GAA trinucleotide repeats or mutations in the FXN gene on chromosome 9q13. This gene codes for a mitochondrial protein, frataxin, which is highly conserved in many species and has functions in iron-sulfur cluster biosynthesis. Friedreich’s ataxia mainly results from a deficiency of the frataxin protein, due to mutations in the FXN gene. Formation of sticky DNA, formation of DNA-RNA hybrid and epigenetic changes, including methylation of DNA and histone modifications, are the proposed mechanisms for disruption of FXN gene expression. Most cases of Friedreich’s ataxia are homozygous and caused due to expansion of the GAA trinucleotide repeat in the first intron of the FXN gene, however, some cases can be heterozygous, with GAA expansion in one allele and point mutation or deletion in the FXN gene on the other allele. Therefore, diagnosis of the disease based on only the clinical symptoms becomes difficult. Molecular diagnosis is, therefore, important, in order to detect GAA repeat expansions as well as mutations in the FXN gene. This review represents an overview of the molecular diagnostic studies in Friedreich’s ataxia, including an overview of the disease, as well as the gene and protein involved in the disease and techniques that can be useful in diagnosis of the Friedreich’s ataxia. The described methods include tools that are based on analysis of DNA as well as analysis of mRNA and protein levels. A brief description of mutations found in compound heterozygous Friedreich’s ataxia patients, is also provided.