Friedreich's ataxia: clinical features, pathogenesis and management.

INTRODUCTION: Friedreich's ataxia is the most common inherited ataxia. SOURCES OF DATA: Literature search using PubMed with keywords Friedreich's ataxia together with published papers known to the authors. AREAS OF AGREEMENT: The last decade has seen important advances in our understanding of the pathogenesis of disease. In particular, the genetic and epigenetic mechanisms underlying the disease now offer promising novel therapeutic targets. AREAS OF CONTROVERSY: The search for effective disease-modifying agents continues. It remains to be determined whether the most effective approach to treatment lies with increasing frataxin protein levels or addressing the metabolic consequences of the disease, for example with antioxidants. AREAS TIMELY FOR DEVELOPING RESEARCH: Management of Freidreich's ataxia is currently focussed on symptomatic management, delivered by the multidisciplinary team. Phase II clinical trials in agents that address the abberrant silencing of the frataxin gene need to be translated into large placebo-controlled Phase III trials to help establish their therapeutic potential.

A 22-Year Follow-up Study of Long-term Cardiac Outcome and Predictors of Survival in Friedreich Ataxia.

IMPORTANCE: Friedreich ataxia (FRDA) is the most common genetic sensory ataxia, and myocardial involvement is a major determinant of survival. OBJECTIVE: To assess FRDA survival and cardiac outcome to adapt future therapeutic trials. DESIGN, SETTING, AND PARTICIPANTS: In a longitudinal follow-up study, all patients with genetically confirmed FRDA seen in the reference center and referred for cardiac evaluation (standard 12-lead electrocardiogram and transthoracic echocardiography) to the cardiology department were enrolled and followed up from April 27, 1990, to July 31, 2013. The setting was the French National Reference Center for Rare Diseases and the Department of Cardiology, Salpêtrière University Hospital, Paris, France. In total, 138 patients with FRDA were followed up. Among 133 patients homozygous for expanded GAA repeats, the mean (SD) age was 31 (10) years (age range, 11-62 years), with a mean (SD) age at disease onset of 16 (8) years (age range, 3-50 years) and a mean (SD) age at first wheelchair use of 26 (9) years (age range, 11-64 years). Cardiac hypertrophy was present in 57.9% (77 of 133), and electrocardiography was normal in 6.8% (9 of 133). MAIN OUTCOMES AND MEASURES: Long-term cardiac outcome and predictors of survival in FRDA. RESULTS: After a mean (SD) follow-up of 10.5 (5.5) years (range, 0.6-23.0 years), the 10-year survival rate was 88.5%. In 80.0% of patients (12 of 15), death was due to cardiac causes. Predictors of survival were a shorter GAA repeat length on the smaller allele of the frataxin gene (hazard ratio [HR], 1.85; 95% CI, 1.28-2.69), left ventricular ejection fraction (HR, 0.42; 95% CI, 0.20-0.89), and left ventricular mass index (HR, 1.19; 95% CI, 1.04-1.36). Two cardiac evolutions were distinguished with a group-based trajectory model, including a low-risk cardiac group (78.6% [81 of 103] with normal ejection fraction at baseline that declined slightly over time but remained within the normal range) and a high-risk cardiac group (21.4% [22 of 103] in which the ejection fraction progressively declined during follow-up). The patients with the worse cardiac evolution had longer GAA repeats. Neurological impairment was not predictive of cardiac change over time. CONCLUSIONS AND RELEVANCE: Survival in FRDA is determined by cardiac complications, which are dependent on the mutation (ie, the size of the expanded GAA repeat). Patients with progressive decline of the left ventricular ejection fraction had a worse prognosis. This finding demonstrates that cardiac follow-up is important in FRDA to identify individuals at risk for further cardiac complications.

Clinical features of Friedreich's ataxia: classical and atypical phenotypes.

One hundred and fifty years since Nikolaus Friedreich's first description of the degenerative ataxic syndrome which bears his name, his description remains at the core of the classical clinical phenotype of gait and limb ataxia, poor balance and coordination, leg weakness, sensory loss, areflexia, impaired walking, dysarthria, dysphagia, eye movement abnormalities, scoliosis, foot deformities, cardiomyopathy and diabetes. Onset is typically around puberty with slow progression and shortened life-span often related to cardiac complications. Inheritance is autosomal recessive with the vast majority of cases showing an unstable intronic GAA expansion in both alleles of the frataxin gene on chromosome 9q13. A small number of cases are caused by a compound heterozygous expansion with a point mutation or deletion. Understanding of the underlying molecular biology has enabled identification of atypical phenotypes with late onset, or atypical features such as retained reflexes. Late-onset cases tend to have slower progression and are associated with smaller GAA expansions. Early-onset cases tend to have more rapid progression and a higher frequency of non-neurological features such as diabetes, cardiomyopathy, scoliosis and pes cavus. Compound heterozygotes, including those with large deletions, often have atypical features. In this paper, we review the classical and atypical clinical phenotypes of Friedreich's ataxia.

A TAT-frataxin fusion protein increases lifespan and cardiac function in a conditional Friedreich's ataxia mouse model.

Friedreich's ataxia (FRDA) is the most common inherited human ataxia and results from a deficiency of the mitochondrial protein, frataxin (FXN), which is encoded in the nucleus. This deficiency is associated with an iron-sulfur (Fe-S) cluster enzyme deficit leading to progressive ataxia and a frequently fatal cardiomyopathy. There is no cure. To determine whether exogenous replacement of the missing FXN protein in mitochondria would repair the defect, we used the transactivator of transcription (TAT) protein transduction domain to deliver human FXN protein to mitochondria in both cultured patient cells and a severe mouse model of FRDA. A TAT-FXN fusion protein bound iron in vitro, transduced into mitochondria of FRDA deficient fibroblasts and reduced caspase-3 activation in response to an exogenous iron-oxidant stress. Injection of TAT-FXN protein into mice with a conditional loss of FXN increased their growth velocity and mean lifespan by 53% increased their mean heart rate and cardiac output, increased activity of aconitase and reversed abnormal mitochondrial proliferation and ultrastructure in heart. These results show that a cell-penetrant peptide is capable of delivering a functional mitochondrial protein in vivo to rescue a very severe disease phenotype, and present the possibility of TAT-FXN as a protein replacement therapy.

Mortality in Friedreich ataxia.

BACKGROUND: Although cardiac dysfunction is widely accepted as the most common cause of mortality in Friedreich ataxia (FRDA), no studies have evaluated this since the advent of specific clinical and genetic diagnostic criteria. METHODS: We performed a retrospective study of FRDA patients to determine cause of death followed by a case-control analysis comparing characteristics of deceased patients with living, age- and sex-matched FRDA controls. RESULTS: Causes of death were cardiac dysfunction (59%), probable cardiac dysfunction (3.3%), non-cardiac (27.9%) or unknown (9.8%). Compared to non-cardiac deaths, cardiac deaths occurred earlier in the disease course (median 29 vs. 17years respectively). Congestive heart failure and arrhythmia were common causes of cardiac-related death. Compared to living, matched FRDA controls, deceased patients had longer triplet repeat lengths and higher rates of arrhythmia and dilated cardiomyopathy. The presence of hypertrophic cardiomyopathy did not differ between deceased and living patients. CONCLUSION: Cardiac dysfunction was the most frequent cause of death (59%), most commonly from congestive heart failure or arrhythmia. Arrhythmia and dilated cardiomyopathy were significantly more common in deceased patients compared to matched FRDA controls, while in contrast, the presence of cardiac hypertrophy did not differ. More research is needed to establish the clinical significance of hypertrophy in FRDA.

The natural history of degenerative ataxia: a retrospective study in 466 patients.

The aim of the present study was (i) to compare disease progression and survival in different types of degenerative ataxia, and (ii) to identify variables that may modify the rate of disease progression. We included patients suffering from Friedreich's ataxia (FRDA, n = 83), early onset cerebellar ataxia (EOCA, n = 30), autosomal dominant cerebellar ataxia (ADCA) type I (ADCA-I, n = 273), ADCA-III (n = 13) and multiple system atrophy (MSA, n = 67). Molecular genetic testing allowed us to assign 202 ADCA-I patients to one of the following subgroups: spinocerebellar ataxia type I (SCAI, n = 36), SCA2 (n = 56) and SCA3 (n = 110). To assess disease progression we defined the following disease stages: stage 0 = no gait difficulties; stage 1 = disease onset, as defined by onset of gait difficulties; stage 2 = loss of independent gait; stage 3 = confinement to wheelchair; stage 4 = death. Disease progression was most rapid in MSA, intermediate in FRDA, ADCA-I and ADCA-III and slowest in EOCA. The rate of progression was similar in SCA1, SCA2 and SCA3. The CAG repeat length was a significant risk factor for faster progression in SCA2 and SCA3, but not in SCA1. In FRDA, the time until confinement to wheelchair was shorter in patients with earlier disease onset, suggesting that patients with long GAA repeats and early disease onset have a poor prognosis. Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA. In SCA2, female gender was associated with shortened survival. In MSA, later age of onset increased the risk of rapid progression and death.

Hereditary ataxias: epidemiological aspects.

Hereditary ataxias, hereditary spastic paraplegia and Charcot-Marie-Tooth syndrome (HA) are chronic progressive neurological diseases. Epidemiologic studies of these disorders are few. In a geographically well-defined Danish population, we present incidence rates, cumulated incidence rates and prevalence for patients with HA based on modern continuous-time survival analysis techniques. From these, prevalence has been estimated to be 6.06 per 10(5) in the 10 to 50-year-old population. Combined risk of HA was found to be 0.16% for women and 0.20% for men up to their 51st birthday.

Friedreich's disease: survival analysis in an Italian population.

This investigation is the first population-based study of survival in Friedreich's disease (FD). All cases of FD diagnosed between 1945 through 1984 among residents of a defined area of northwestern Italy were ascertained (N = 58). These patients were followed to death or to December 31, 1984 (whichever came first) to determine the patterns of survival. The 10-, 20-, and 30-year survival rates were respectively 96%, 80%, and 61%, suggesting a better prognosis than previously reported. Survival of FD patients was poorer than expected from the general population. Survival for males was poorer than for females even after adjustment for expected survival. Age of onset was not a significant prognostic factor. Survival for patients diagnosed in 1960 or later was better than for those diagnosed before 1960; however, the difference was not statistically significant.

Genetic and family studies in Friedreich's ataxia.

This study consists of two parts: 1. A detailed genetic analysis of 35 sibships in which 58 individuals were affected with Friedreich's ataxia; and 2. Clinical and laboratory examinations of parents and siblings, in an attempt at carrier detection and diagnosis of the pre-clinical state. The increased parental consanguinity, the lack of affected individuals in other generations, and the lack of significance of extrinsic etiological variables, all suggested an autosomal recessive mode of inheritance, and this was confirmed by formal genetic analyses, employing several different methods. Associated abnormalities in our series of 58 patients included cardiomyopathy (51.7%), diabetes mellitus (19.0%), optic atrophy (5.2%), nerve deafness (5.2%) and congenital malformations (6.9%). The incidence of diabetes mellitus, congenital malformations, and epilepsy and/or febrile convulsions was elevated in first degree relatives of patients with Friedreich's ataxia.

Study of fatal cases of Friedreich's ataxia.

A study of 82 fatal cases of Friedreich's ataxia showed that over half the patients died of heart failure while nearly three-quarters had evidence of cardiac dysfunction during life. A high incidence of diabetes mellitus (23%) was another finding, and four patients developed diabetic ketosis terminally.