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.

Diabetes mellitus y ataxia de Friedreich en un niño: una difícil coexistencia / Diabetes mellitus and Friedreich´s ataxia in a child: a complicated coexistence

La ataxia de Friedreich, de herencia autosómica recesiva causada por una expansión repetida de trinucleótidos se asocia, entre otras complicaciones sistémicas, con diabetes mellitus. La aparición de torpeza motriz, con dificultad en la carrera y el salto en un varón de 6 años motivaron el estudio genético para ataxia de Friedrich y permitieron confirmar el diagnóstico. Tres años más tarde, se diagnosticó diabetes mellitus y se inició el tratamiento con insulina. Durante el seguimiento, presentó un importante deterioro neurológico, con necesidad de usar silla de ruedas, lo que dificultó un adecuado control metabólico. Se presenta el manejo y la evolución de un paciente con ataxia de Friedreich y diabetes mellitus

Friedreich's ataxia is an autosomal recessive disease caused by trinucleotide repeat expansion, presenting among other systemic complications, diabetes mellitus. The appearance of motor clumsiness, with running and jumping difficulties in a 6-year-old boy prompted the genetic study of Friedreich's ataxia, confirming his diagnosis. After diagnosis,it was evaluated by Pediatric Cardiology, detecting the presence of non-obstructive hypertrophic cardiomyopathy, and by Pediatric Endocrinology, due to overweight. At 9 years of age, he was diagnosed with diabetes mellitus, a regimen of insulin treatment was initiated. During follow-up, he presented significant neurological deterioration, reaching the use of a wheelchair,which hinders adequate metabolic control. This is a report of a pediatric patient with Friedrich ataxia and diabetes mellitus.

Proposta de aplicação da comunicação alternativa para paciente com doença neurodegenerativa e seu impacto na qualidade vida: relato de caso / Proposal of application of alternative communication for patient with neurodegenerative disease and its impact on quality of life: case report / Propuesta de aplicación de comunicación alternativa para paciente com enfermedad neurodegenerativa y su impacto en la calidad de vida: caso clínico

Trata-se de um relato de caso de um indivíduo do sexo masculino com 51 anos, nível superior completo, nível socioeconômico favorável, diagnosticado em 1999 com Ataxia de Friedreich. Chega ao ambulatório de Fonoaudiologia, com ênfase no atendimento de adultos com doenças degenerativas, sob encaminhamento da equipe de genética do serviço do mesmo hospital. Ao exame fonoaudiológico diagnostica-se uma disfagia orofaríngea de moderada a grave e uma disartria grave. A disfagia é reabilitada via home care particular por opção do paciente, e no ambulatório, com objetivo de melhora da qualidade de vida criou-se uma proposta de aplicação da comunicação aumentativa e/ou alternativa para o desenvolvimento das habilidades de comunicação do paciente que já não estava mais se expressando. Foram realizadas duas avaliações (pré e pós terapia) e quatro sessões de intervenção terapêutica para o aprendizado e implementação da prancha de comunicação alternativa. Ao término do processo terapêutico verificou-se baixa adesão ao uso da comunicação aumentativa e/ou alternativa, mesmo com a auto-percepção da ininteligibilidade da sua fala, utilizando a pasta restrita ao atendimento fonoaudiológico. Tanto o paciente quanto seus acompanhantes referiram que mesmo após várias tentativas houve negação ao uso da comunicação alternativa. Embora tenham sido poucas sessões, não houve impacto da qualidade de vida do paciente após uso da comunicação aumentativa e/ou alternativa.

Este es un informe del caso de un hombre de 51 años, con educación universitaria completa, estatus socioeconómico favorable, diagnosticado en 1999 con ataxia de Friedreich. Llega a la clínica de terapia del habla, con énfasis en ayudar a adultos con enfermedades degenerativas, bajo la guía del equipo de genética al servicio del mismo hospital. El examen notas la disfagia orofaríngea moderada a severa y la disartria severa. La disfagia se rehabilita mediante atención domiciliaria privada a elección del paciente y en la clínica ambulatoria con el objetivo de mejorar la calidad de vida, se creó una propuesta para la aplicación de comunicación aumentativa y/o alternativa para desarrollar las habilidades de comunicación del paciente que ya no era más expresándose a sí mismos. Se realizaron dos evaluaciones (pre y post terapia) y cuatro sesiones de intervención terapéutica para aprender e implementar el tablero de comunicación alternativo. Al final del proceso terapéutico, hubo una baja adherencia al uso de comunicación aumentativa y/o alternativa, incluso con la autopercepción de la ininteligibilidad de su discurso, usando la carpeta restringida a la terapia del habla. Tanto el paciente como sus compañeros informaron que incluso después de varios intentos hubo una negación del uso de comunicación alternativa. Aunque hubo pocas sesiones, no hubo impacto en la calidad de vida del paciente después de usar comunicación aumentativa y/o alternativa.

This is a case report of a 51-year-old male, with complete college education, favorable socioeconomic status, diagnosed in 1999 with Friedreich's Ataxia. He arrives at the speech therapy clinic, with an emphasis on assisting adults with degenerative diseases, under the guidance of the genetics team at the service of the same hospital. Speech examination examines moderate to severe oropharyngeal dysphagia and severe dysarthria. Dysphagia is rehabilitated via private home care at the patient's option and in the outpatient clinic with the objective of improving quality of life, a proposal for the application of augmentative and/or alternative communication was created to develop the communication skills of the patient who was no longer expressing himself. Two evaluations (pre and post therapy) and four therapeutic intervention sessions were carried out to learn and implement the alternative communication board. At the end of the therapeutic process, there was low adherence to the use of augmentative and / or alternative communication, even with the self-perception of the unintelligibility of his speech, using the folder restricted to speech therapy. Both the patient and his companions reported that even after several attempts there was a denial of the use of alternative communication. Although there were few sessions, there was no impact on the patient's quality of life after using augmentative and/or alternative communication.

Cardiomyopathy as the first manifestation of Friedreichs ataxia

We present the case of a female patient diagnosed in childhood with Friedreich Ataxia (FA). At the age of 6, she developed left congestive heart failure with cardiomyopathy, as evident on echocardiogram. Neurologic signs only appeared at age 7, including marked loss of muscle mass, gait instability, muscle clonus, and Babinski's signal. At age 27, she had a stroke and was hospitalized; a few days later, she had a cardiorespiratory arrest with asystole, leading to death. The autopsy disclosed severe cardiomyopathy and significant myocardial replacement with fibrosis; therefore, the cause of death was assumed to be heart failure. Compared to the literature, our case has some unique features, such as cardiac disease as the presenting manifestation instead of gait instability, which is the major initial sign in most FA cases. Since our patient was submitted to an autopsy, it was an opportunity to retrieve important data to confirm the diagnosis and to evaluate the pathophysiology of this entity, such as myocardium fibrosis and cerebellar degeneration. In summary, our case demonstrates that cardiac disease can be the first manifestation of FA, with eventual diagnostic and prognostic implications. In addition, the autopsy provided findings of severe cardiomyopathy associated with FA.

Safety and Biodistribution of Human Bone Marrow-Derived Mesenchymal Stromal Cells Injected Intrathecally in Non-Obese Diabetic Severe Combined Immunodefi ciency Mice: Preclinical Study

BACKGROUND: Mesenchymal stromal cells (MSCs) have potent immunomodulatory and neuroprotective properties, and have been tested in neurodegenerative diseases resulting in meaningful clinical improvements. Regulatory guidelines specify the need to perform preclinical studies prior any clinical trial, including biodistribution assays and tumourigenesis exclusion. We conducted a preclinical study of human bone marrow MSCs (hBM-MSCs) injected by intrathecal route in Non-Obese Diabetic Severe Combined Immunodeficiency mice, to explore cellular biodistribution and toxicity as a privileged administration method for cell therapy in Friedreich's Ataxia. METHODS: For this purpose, 3 × 10⁵ cells were injected by intrathecal route in 12 animals (experimental group) and the same volume of culture media in 6 animals (control group). Blood samples were collected at 24 h (n = 9) or 4 months (n = 9) to assess toxicity, and nine organs were harvested for histology and safety studies. Genomic DNA was isolated from all tissues, and mouse GAPDH and human β2M and β-actin genes were amplified by qPCR to analyze hBM-MSCs biodistribution. RESULTS: There were no deaths nor acute or chronic toxicity. Hematology, biochemistry and body weight were in the range of normal values in all groups. At 24 h hBM-MSCs were detected in 4/6 spinal cords and 1/6 hearts, and at 4 months in 3/6 hearts and 1/6 brains of transplanted mice. No tumours were found. CONCLUSION: This study demonstrated that intrathecal injection of hBM-MSCs is safe, non toxic and do not produce tumors. These results provide further evidence that hBM-MSCs might be used in a clinical trial in patients with FRDA.

Características clínicas de 63 pacientes con ataxia / Clinical features of 63 patients with ataxia

Background: Ataxia can be classified as genetic, sporadic or acquired. Aim: To report the clinical features of a group of patients with ataxia. Material and Methods: Review of medical records of patients consulting in a specialized center in movement disorders. Those records in which the diagnosis of "ataxia" or "ataxic syndrome" appeared, were selected for the review. Results: Of 4,282 records surveyed, the diagnosis of ataxia appeared in 95. After eliminating repeated or incomplete records, 63 were reviewed. Results: Ataxia was sporadic, genetic and acquired in 27, 22 and 14 patients, respectively. The mean age at presentation for genetic, acquired and sporadic ataxia was 24, 46 and 53 years respectively. All autosomal dominant ataxias were type 3 spinocerebellar ataxia (SCA). Friedrich's ataxia was the most common recessive form. Most sporadic forms of ataxia were multiple system atrophy with predominant cerebellar ataxia (MSA-C) subtype. Conclusions: Considering the heterogeneity of patients with ataxia, we propose a method to approach them.

The importance of central auditory evaluation in Friedreich's ataxia / A importância da avaliação auditiva central na ataxia de Friedreich

ABSTRACT Objective To assess central auditory function in Friedreich's ataxia. Methods A cross-sectional, retrospective study was carried out. Thirty patients underwent the anamnesis, otorhinolaryngology examination, pure tone audiometry, acoustic immittance measures and brainstem auditory evoked potential (BAEP) assessments. Results The observed alterations were: 43.3% in the pure tone audiometry, bilateral in 36.7%; 56.6% in the BAEP test, bilateral in 50%; and 46.6% in the acoustic immittance test. There was a significant difference (p < 0.05) in the comparison between the tests performed. Conclusion In the audiological screening, there was a prevalence of the descending audiometric configuration at the frequency of 4kHz, and absence of the acoustic reflex at the same frequency. In the BAEP test, there was a prevalence of an increase of the latencies in waves I, III and V, and in the intervals of interpeaks I-III, I-V and III-V. In 13.3% of the patients, wave V was absent, and all waves were absent in 3.3% of patients.

RESUMO Objetivo Avaliar a função auditiva central na ataxia de Friedreich (AFRD). Métodos Foi realizado um estudo retrospectivo de corte transversal. 30 pacientes realizaram anamnese, avaliações otorrinolaringológica, audiológica, imitanciométrica e do potencial evocado auditivo de tronco encefálico (PEATE). Resultados As alterações observadas foram: 43,3% no exame audiométrico sendo 36,7% dos casos, bilateralmente; 56,6% na avaliação do PEATE com 50% dos casos, bilateralmente e 46,6% no exame imitanciométrico. Houve diferença significativa (p < 0,05) na comparação entre os exames realizados. Conclusão No exame audiológico, ocorreu uma preponderância maior da configuração audiométrica descendente a partir da freqüência de 4kHz e ausência do reflexo acústico na mesma frequência. No exame do PEATE, houve prevalência do aumento das latências nas ondas I, III e V, e nos intervalos dos interpicos I-III, I-V e III-V. Em 13,3% dos casos, a onda V estava ausente, e em 3,3% dos casos, todas as ondas estavam ausentes.

Friedreich's Ataxia: dance and somatic education a case report

This research aims to determine the effects of a dance program in dialogue with somatic education in psychomotor aspects in a subject with Friedreich ataxia. We used the research method intra-subject BAB design, were phase "B" comprises the treatment phase through interventions with stimuli, and "A" the stimuli are removed. We performed a dance program with 24 interventions on a subject with Friedreich Ataxia, and assessed pre- and post-program through the Monitoring Instrument Learning in Educational Dance. The results showed that the dance program with somatic education can improve the analyzed skills: getting up, sitting, shifting feet, shifting the ground, sitting position, body image, movement rhythm, and fluency movement.(AU)

The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population

BACKGROUND AND PURPOSE: The etiologies and frequencies of cerebellar ataxias vary between countries. Our primary aim was to determine the frequency of each diagnostic group of cerebellar ataxia patients in a Korean population. METHODS: We reviewed the medical records of patients who were being followed up between November 1994 and February 2016. We divided patients with cerebellar ataxias into familial and non-familial groups and analyzed the frequency of each etiology. Finally, we categorized patients into genetic, sporadic, secondary, and suspected genetic, but undetermined ataxia. RESULTS: A total of 820 patients were included in the study, among whom 136 (16.6%) familial patients and 684 (83.4%) non-familial cases were identified. Genetic diagnoses confirmed 98/136 (72%) familial and 72/684 (11%) nonfamilial patients. The overall etiologies of progressive ataxias comprised 170 (20.7%) genetic, 516 (62.9%) sporadic, 43 (5.2%) secondary, and 91 (11.1%) undetermined ataxia. The most common cause of ataxia was multiple-system atrophy (57.3%). In the genetic group, the most common etiology was spinocerebellar ataxia (152/170, 89.4%) and the most common subtype was spinocerebellar ataxia-3.38 of 136 familial and 53 of 684 sporadic cases (91/820, 11.1%) were undetermined ataxia. CONCLUSIONS: This is the largest epidemiological study to analyze the frequencies of various cerebellar ataxias in a Korean population based on the large database of a tertiary hospital movement-disorders clinic in South Korea. These data would be helpful for clinicians in constructing diagnostic strategies and counseling for patients with cerebellar ataxias.

Urinary Symptoms and Urodynamics Findings in Patients with Friedreich's Ataxia

Purpose To assess the prevalence of LUTS, urinary tract and urodynamics changes in patients with Friedreich's Ataxia (FA), the most common form of hereditary ataxia. Materials and Methods This study evaluated 258 patients with genetically confirmed diagnoses of FA. Of the patients, 158 responded to a questionnaire which assessed their urinary symptoms. Patients with clinical changes underwent renal function examinations, ultrasound, and urodynamic studies (UDS). Results The sample analyzed showed that 82% of the patients complained of LUTS, although only 22% related the symptoms with quality of life impairment. Twenty eight (18%) of them agreed to undergo urodynamic evaluation. Urgency was the most common symptom. The exam was normal in 4 (14%) and detrusor underactivity was the most common finding. 14% (4 patients) presented with dilatation of the upper urinary tract at ultrasound scans. None of them had creatinine alterations. Conclusions LUTS was found in a large percentage of patients with FA, but only a few related it to their quality of life impairment. Although creatinine levels was normal in this sample, some patients may show upper urinary tract abnormalities, with deserves close observation and proper care. .

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.

DNA triplex structures in neurodegenerative disorder, Friedreich’s ataxia.

It is now established that a small fraction of genomic DNA does adopt the non-canonical B-DNA structure or ‘unusual’ DNA structure. The unusual DNA structures like DNA-hairpin, cruciform, Z-DNA, triplex and tetraplex are represented as hotspots of chromosomal breaks, homologous recombination and gross chromosomal rearrangements since they are prone to the structural alterations. Friedreich’s ataxia (FRDA), the autosomal recessive degenerative disorder of nervous and muscles tissue, is caused by the massive expansion of (GAA) repeats that occur in the first intron of Frataxin gene X25 on chromosome 9q13-q21.1. The purine strand of the DNA in the expanded (GAA) repeat region folds back to form the (R∙R*Y) type of triplex, which further inhibits the frataxin gene expression, and this clearly suggests that the shape of DNA is the determining factor in the cellular function. FRDA is the only disease known so far to be associated with DNA triplex. Structural characterization of GAA-containing DNA triplexes using some simple biophysical methods like UV melting, UV absorption, circular dichroic spectroscopy and electrophoretic mobility shift assay are discussed. Further, the clinical aspects and genetic analysis of FRDA patients who carry (GAA) repeat expansions are presented. The potential of some small molecules that do not favour the DNA triplex formation as therapeutics for FRDA are also briefly discussed.

Cardiopatía dilatada en ataxia de Friedreich: el punto sin retorno / Dilated cardiomyopathy in Friedreich's ataxia: point of no return

Las cardiopatías infiltrativas se caracterizan por el depósito de sustancias en el miocardio que causan un impacto negativo en la arquitectura de la pared ventricular. La ataxia espino-cerebelosa de Friedreich es una enfermedad degenerativa, heredada, con carácter autosómico recesivo. Clínicamente se caracteriza por ataxia de extremidades y tronco, hiporreflexia, neuropatía periférica, retinopatía y cardiopatía, entre otros. La afectación cardíaca es muy frecuente y se detectan alteraciones en estudios pos-mortem en 95% a 100% de los pacientes. La tasa de mortalidad es elevada y se considera una enfermedad incurable, a pesar de la existencia actual de múltiples medicamentos en estudio basados en los fundamentos fisiopatológicos de esta afección.

Infiltrative heart diseases are characterized by deposit of substances in the myocardium that cause a negative impact on the architecture of the ventricular wall. Friedreich's spino-cerebellar ataxia is a degenerative disease, inherited in an autosomal recessive pattern. Clinically it is characterized by limb and trunk ataxia, hyporeflexia, peripheral neuropathy, retinopathy and heart disease among others. Cardiac involvement is common and on post-mortem studies cardiac abnormalities are found in 95% to 100% of patients. The mortality rate is high and it is considered an incurable disease, despite the current existence of multiple medications being studied, based on the pathophysiological basis of this condition.

The role of idehenone in the treatment of nervous system diseases New knowledge and new findings / 国际脑血管病杂志

Idebenone is a synthetic analogue of coenzyme Q10. As a potent antioxidant,idebenone operates under low oxygen tension situations, protects cell membranes and mitochondria from oxidative damage through inhibiting lipid peroxidation, thereby protects against cerebral ischemia and nervous system damage. Idebenone also interacts with the mitochondrial electron transport chain and maintains the formation of ATP under ischemic conditions. Because idebenone has a good tolerability and safety, it is expected as a neuroprotective agent for the treatment of acute ischernic stroke. Studies in recent years have showed that idebenone has a certain therapeutic effect in a variety of nervous system diseases involving mitochondrial dysfunction and oxidative stress damage, such as mitochodrial encephalomyopathy, lactic acidosis, stroke-like episodes syndrome, Friedreich's ataxia, Alzheimer's diseases, Leber's hereditary optic neuropathy, and Duchenne muscular dystrophy. At present, some clinical trials in the mitochondria-related diseases and neuromuscular diseases are underway, and their results are expected to further expand the indications of idebenone.

Ataxia de friedreich: relato de um caso com manifestação tardia / Friedreich?s ataxia: a case report with late manifestation

A Ataxia de Friedreich é uma doença neurodegenerativa progressiva, de herança autossômica recessiva, que foi descrita pela primeira vez por Nicholaus Friedreich, em 1863. A mutação responsável por essa doença se encontra no cromossomo nove, onde ocorre uma expansão de trinucleotídios GAA. O gene afetado tem a função de codificar a proteína mitocondrial frataxina, que está envolvida no metabolismo do ferro. O principal sintoma é a ataxia (coordenação prejudicada), que, no início, é mais evidente nos membros inferiores e, posteriormente, atinge os membros superiores. Este estudo teve por objetivo relatar um caso de Ataxia de Friedreich, uma doença genética rara de caráter degenerativo que, ao contrário do prognóstico esperado, se manifestou mais tardiamente no indivíduo afetado. Este trabalho também descreve a evolução clínica, enfocando os sintomas e deficiências que o paciente apresentou antes e após o diagnóstico, bem como, discute as bases moleculares que podem ter contribuído para a manifestação tardia da doença, além dos tratamentos emergentes.

The Friedreich?s ataxia is a progressive neurodegenerative disease with autosomal recessive inheritance, which was first described by Nicholaus Friedreich in 1863. The mutation responsible for this disease is located on chromosome nine, where there is a GAA trinucleotide expansion repeats. The affected gene function is to encode the mitochondrial protein frataxin, which is involved in the iron metabolism. The main symptom is ataxia (impaired coordination), which at first is more evident in the lower limbs and eventually reaches the upper limbs. This study aimed to report a case of Friedreich?s Ataxia, a rare genetic disease with degenerative characteristic that manifested itself later in the affected individual unlike the expected outcome. This paper also describes the clinical course, focusing on the symptoms and disabilities that the patient presented before and after diagnosis, and also discusses the molecular basis that may have contributed to the late-onset of the disease besides the emerging treatments.

Autosomal recessive ataxias: 20 types, and counting / Ataxias autossômicas recessivas: 20 tipos e muito mais

More than 140 years after the first description of Friedreich ataxia, autosomal recessive ataxias have become one of the more complex fields in Neurogenetics. Currently this group of diseases contains more than 20 clinical entities and an even larger number of associated genes. Some disorders are very rare, restricted to isolated populations, and others are found worldwide. An expressive number of recessive ataxias are treatable, and responsibility for an accurate diagnosis is high. The purpose of this review is to update the practitioner on clinical and pathophysiological aspects of these disorders and to present an algorithm to guide the diagnosis.

Mais de 140 anos após a primeira descrição da ataxia de Friedreich, as ataxias autossômicas recessivas se transformaram em um dos mais complexos campos da Neurogenética. Atualmente, este grupo de doenças é composto por mais de 20 entidades clínicas e possui um número ainda maior de genes associados. Algumas doenças são muito raras, tendo sido observadas apenas em populações isoladas, enquanto que outras são encontradas no mundo todo. Um número expressivo de ataxias é tratável, e a responsabilidade em se fazer um diagnóstico correto é alta. A finalidade desta revisão é a de atualizar o neurologista a respeito dos principais aspectos clínicos e fisiopatológicos destas doenças e de apresentar um algoritmo para auxiliar a sua investigação e o seu diagnóstico.

Fenotipo y genotipo de once pacientes con Ataxia de Friedreich / Friedreic's Ataxia: Phenotype and Genotype in Eleven Patients

Introducción: La ataxia de Friedreich (FRDA) es una enfermedad autosómica recesiva debida a una mutación en el gen X25. Dicho gen está localizado en el cromosoma 9 y codifica para la proteína frataxina. La enfermedad es causada por la repetición del trinucleótido GAA. En individuos normales la secuencia GAA se encuentra repetida entre siete y veintidós veces, mientras que, en pacientes con ataxia de Friedreich GAA puede estar repetida cientos o miles de veces. Objetivos: Evaluar si existe correlación entre el tamaño de la expansión, la edad de inicio de FRDA y su severidad en la muestra seleccionada. Métodos: - Se estudiaron once pacientes con fenotipo típico de ataxia de Friedreich. El análisis molecular por PCR determinó la expansión del trinucleótido GAA. Se analizó la correlación entre la edad de inicio de FRDA y su progresión con el número de repeticiones GAA. Resultados y conclusiones: - El análisis molecular por PCR mostró ocho pacientes homocigotos para la expansión, y tres negativos. El promedio del tamaño de las expansiones en los alelos es 622±5 con un promedio correspondiente de la edad inicio de FRDA 13±8. Para el tamaño de la muestra no se observó una correlación estadística significativa entre la edad de inicio de la enfermedad y el número de repeticiones, pero sí una tendencia a correlacionarse de forma inversa (p<0.11). El diagnóstico molecular de FRDA sumado a la comprensión de su fisiología y a la utilización de los criterios de inclusión de Harding, constituye un paso importante en el logro de un tratamiento óptimo de la enfermedad.

Introduction: - Friedreich's ataxia is an autosomal recessive disease due to a mutation in gene X25. This gene codes for frataxin and it is located on chromosome 9. The disease is caused by a triplet particular sequence of bases (GAA). Normally, the GAA sequence is repeated 7 to 22 times, but in people with Friedreich's ataxia, it can be repeated hundreds or even over thousand times. Objectives: To determine if there is a correlation between clinical and molecular findings in our FRDA patients. Methods: Eleven patients with the typical Friedreich´s ataxia phenotype were studied by PCR we determined the size of the GAA expansions, and analyzed the correlation of age at onset and rate of disease progression with the number of GAA repetitions. Results and conclusions: Molecular analysis by PCR showed eight homozygous patients for the expansion and three negative. The average of the size of the expansions in the allele was of 622±5 with an average in the age of beginning of 13±8. For the sample size, there was no significant statistical correlation between the age of beginning of the disease and the number of repetitions, although there was like an inverse correlation. Besides understanding of FRDA physiology and the Harding clinical inclusion criteria, molecular diagnosis is an important step in the achievement of an optimal therapeutic treatment.

Early Onset Cerebellar Ataxia with Retained Tendon Reflexes Developed in Brothers: Report of two cases

Early onset cerebellar ataxia with retained tendon reflexes is distinctive clinical syndrome characterized by progressive cerebellar ataxia of unknown etiology with an onset within the first two decades. This disorder was distinguished from Friedreich's ataxia by the preservation of the deep tendon reflexes. There is 22-year-old male with 13 year history of slowly progressive cerebellar ataxia and dysarthria. His elder brother, also, has milder clinical manifestations, electrophysiological and radiological abnormalities. We experienced two cases of early onset cerebellar ataxia with retained tendon reflexes developed in brothers which was diagnosed by clinical manifestations, electrophysiologic, radiologic studies and report with brief review of related literatures.

A Case of Early Onset Cerebellar Ataxia with Retained Tendon Reflexes

Early onset cerebellar ataxia with retained tendon reflexes is clinical syndrome characterized by progressive cerebelar ataxia of unknown etiology with an onset within the first two decades. This disorder was distinguished from Friedreich's ataxia by the preservation of the tendon reflexes. We have experienced a case of early onset cerebellar ataxia with retained tendon reflexes which was diagnosed by clinical features, eletrophysiologic studies, and MRI scan. This 8 year-old male patient had suffered from gait ataxia with delayed growth and development since 3 years of age. A brief review of the related literatures was also made.

A Case of Early Onset Cerebellar Ataxia with Retained Tendon Reflexes

Early onset cerebellar ataxia with retained tendon reflexes is clinical syndrome characterized by progressive cerebelar ataxia of unknown etiology with an onset within the first two decades. This disorder was distinguished from Friedreich's ataxia by the preservation of the tendon reflexes. We have experienced a case of early onset cerebellar ataxia with retained tendon reflexes which was diagnosed by clinical features, eletrophysiologic studies, and MRI scan. This 8 year-old male patient had suffered from gait ataxia with delayed growth and development since 3 years of age. A brief review of the related literatures was also made.