Lisa S. Friedman

Measuring the rate of progression in Friedreich ataxia: Implications for clinical trial design

Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria, and arreflexia. A variety of measures are currently used to quantify disease progression, including the Friedreich Ataxia Rating Scale, examiner‐rated functional disability scales, self‐reported activities of daily living and performance measures such as the timed 25‐foot walk, 9‐hole pegboard test, PATA speech test, and low‐contrast letter acuity vision charts. This study examines the rate of disease progression over one and two years in a cohort of 236 Friedreich ataxia patients using these scales and performance measure composites. The Friedreich Ataxia Rating Scale and performance‐measure composites captured disease progression, with a greater sensitivity to change over 2 years than over 1 year. The measures differed in their sensitivity to change and in possible bias. These results help to establish norms for progression in FRDA that can be useful in measuring the long‐term success of therapeutic agents and defining sample‐size calculations for double‐blind clinical trials.

Analysis of Echocardiograms in a Large Heterogeneous Cohort of Patients With Friedreich Ataxia

Although Friedreich ataxia (FA) is associated with cardiomyopathy, the severity and evolution of cardiac disease is poorly understood. To identify factors predicting cardiomyopathy in FA, we assessed echocardiograms from a large heterogenous cohort and their relation to disease traits. The most recent echocardiograms from 173 subjects with FA were analyzed in a core laboratory to determine their relation to disease duration, subject age, age of onset, functional disability score, and GAA repeat length. Mean age of the cohort was 19.7 years, mean age of disease onset was 10.6 years, and mean shorter GAA length was 681 repeats. Echocardiograms collectively illustrated systolic dysfunction, diastolic dysfunction, and hypertrophy. Measurements of hypertrophy correlated moderately with each other (r = 0.39 to 0.79) but not with measurements of diastolic dysfunction (r <0.35). Diastolic measurements correlated poorly with each other, although 26% of the cohort had multiple diastolic abnormalities. The most common diastolic dysfunction classification was pseudonormalization. Classification of diastolic dysfunction was predicted by GAA repeat length but not by age or gender. Ejection fraction was below normal in 20% of the cohort. In linear regression analysis, increasing age predicted decreasing ejection fraction. Functional disability score, a measurement of neurologic ability, did not predict any echocardiographic measurements. In conclusion, hypertrophy and diastolic and systolic dysfunctions occur in FA and are substantially independent; diastolic dysfunction is the most common abnormality with most patients having an assigned diastolic dysfunction class of pseudonormalization.

Pharmacotherapy for Friedreich ataxia.

Friedreich ataxia (FA) is a progressive genetic neurological disorder associated with degeneration of the dorsal columns, spinocerebellar tracts and other regions of the nervous system. The disorder results from mutations in the gene referred to as FXN. Almost all mutations are expansions of an intronic GAA repeat in this gene, which gives rise to decreased transcription of the gene product (called frataxin). Following these discoveries, drug discovery has moved at a rapid pace. Therapeutic trials in the next 5 years are expected to address amelioration of the effects of frataxin deficiency and methods for increasing frataxin expression. These therapies are directed at all levels of biochemical dysfunction in FA. Agents such as idebenone potentially improve mitochondrial function and decrease production of reactive oxygen species. Idebenone is presently in a phase III trial in the US and in Europe, with the primary outcome measure being neurological function. Deferiprone, an atypical iron chelator, may decrease build-up of toxic iron in the mitochondria in patients. It has entered a phase II trial in Europe, Australia and Canada directed toward improvement of neurological abilities. Finally, targeted histone deacetylase (HDAC) inhibitors and erythropoietin increase levels of frataxin when used in vitro, suggesting that they may provide methods for increasing frataxin levels in patients. Erythropoietin has been tested in a small phase II trial in Austria, while HDAC inhibitors are still at a preclinical stage. Symptomatic therapies are also in use for specific symptoms such as spasticity (baclofen). Thus, there is substantial optimism for development of new therapies for FA in the near future, and we suggest that one or several may be available over the next few years. However, continued development of new therapies will require creation of new, more sensitive measures for neurological dysfunction in FA, and clinically relevant measures of cardiac dysfunction.

Friedreich ataxia clinical outcome measures: natural history evaluation in 410 participants.

Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia, dysarthria, and areflexia. The authors report the progress of a large international noninterventional cohort (n = 410), tracking the natural history of disease progression using the neurologic examination-based Friedreich Ataxia Rating Scale. The authors analyzed the rate of progression with cross-sectional analysis and longitudinal analysis over a 2-year period. The Friedreich Ataxia Rating Scale captured disease progression when used at 1 and 2 years following initial evaluation, with a lower ratio of standard deviation of change to mean change over 2 years of evaluation. However, modeling of disease progression identified substantial ceiling effects in the Friedreich Ataxia Rating Scale, suggesting this measure is most useful in subjects before maximal deficit is approached.

Antioxidant use in Friedreich ataxia

Many antioxidants have been suggested as potential treatments for Friedreich ataxia, but have not been tested in clinical trials. We found that a majority of patients in our cohort already use such antioxidants, including idebenone, which is not available at a pharmaceutical grade in the United States. Younger age, cardiomyopathy and shorter GAA repeat length were independent predictors of idebenone use, but no factors predicted use of other antioxidants. This confirms that non-prescription antioxidant use represents a major confounder to formal trials of existing and novel agents for Friedreich ataxia.

Clinical data and characterization of the liver conditional mouse model exclude neoplasia as a non-neurological manifestation associated with Friedreich's ataxia.

SUMMARY Friedreich’s ataxia (FRDA) is the most common hereditary ataxia in the caucasian population and is characterized by a mixed spinocerebellar and sensory ataxia, hypertrophic cardiomyopathy and increased incidence of diabetes. FRDA is caused by impaired expression of the FXN gene coding for the mitochondrial protein frataxin. During the past ten years, the development of mouse models of FRDA has allowed better understanding of the pathophysiology of the disease. Among the mouse models of FRDA, the liver conditional mouse model pointed to a tumor suppressor activity of frataxin leading to the hypothesis that individuals with FRDA might be predisposed to cancer. In the present work, we investigated the presence and the incidence of neoplasia in the largest FRDA patient cohorts from the USA, Australia and Europe. As no predisposition to cancer could be observed in both cohorts, we revisited the phenotype of the liver conditional mouse model. Our results show that frataxin-deficient livers developed early mitochondriopathy, iron-sulfur cluster deficits and intramitochondrial dense deposits, classical hallmarks observed in frataxin-deficient tissues and cells. With age, a minority of mice developed structures similar to the ones previously associated with tumor formation. However, these peripheral structures contained dying, frataxin-deficient hepatocytes, whereas the inner liver structure was composed of a pool of frataxin-positive cells, due to inefficient Cre-mediated recombination of the Fxn gene, that contributed to regeneration of a functional liver. Together, our data demonstrate that frataxin deficiency and tumorigenesis are not associated.

Health-Related Quality of Life in Children With Friedreich Ataxia

The use of health-related quality of life scales as outcome measures in clinical trials is increasing. Although such measures have been validated in adults with Friedreich ataxia, they have not been studied in children with this disorder. The health-related quality of life of children with Friedreich ataxia was assessed using the PedsQL 4.0 Generic Core Module and Multidimensional Fatigue Scale. The scores from the Friedreich ataxia cohort were compared to those of control groups (children without a chronic disease). Minimal missing responses support the feasibility of using the PedsQL 4.0 in the Friedreich ataxia population. The scales demonstrated internal consistency, and concordance was observed between child and proxy scores. Children with Friedreich ataxia and their proxies reported lower health-related quality of life than did controls in the Core and Fatigue scales. A modest relationship was seen between markers of disease status and health-related quality of life, providing support for the idea that children with Friedreich ataxia have a lower health-related quality of life than those without a chronic disease. Additional studies are needed to examine the relationship between health-related quality of life and disease markers and to further establish the validity of the PedsQL 4.0 in this population.

Urinary isoprostanes in Friedreich ataxia: Lack of correlation with disease features

To assess the utility of urinary isoprostanes as markers of oxidative injury in Friedreich ataxia (FA), we compared levels of urinary F2‐isoprostanes in patients with FA and healthy control subjects. Levels of urinary F2‐isoprostanes in FA patients were not different from controls and were not significantly associated with age, GAA repeat length, disability level, or the use of antioxidants. Thus, urinary F2‐isoprostanes are not a useful biomarker in FA.

Cross-Sectional Analysis of Electrocardiograms in a Large Heterogeneous Cohort of Friedreich Ataxia Subjects

Electrocardiographic (ECG) findings in Friedreich ataxia and their relation to disease characteristics have not been well described. In this retrospective cross-sectional study, the authors reviewed baseline ECGs from 239 children and adults with Friedreich ataxia. ECG abnormalities—assessed in relation to participant age, sex, shorter guanine-adenine-adenine triplet repeat length, age of disease onset, and functional disability score—were found in 90% of subjects, including nonspecific ST-T wave changes (53%), right axis deviation (32%), left ventricular hypertrophy (19%), and right ventricular hypertrophy (13%). Female sex and shorter guanine-adenine-adenine repeat lengths were associated with a normal ECG (P = .004 and P = .003). Males and those of younger age were more likely to show ventricular hypertrophy (P = .006 and P = .026 for left ventricular hypertrophy and P < .001 and P = .001 for right). Neurologic status as measured by the functional disability score did not predict ECG abnormalities.

Management and therapy for cardiomyopathy in Friedreich's ataxia.

The autosomal-recessive disorder Friedreich’s ataxia is characterized by progressive ataxia, often in association with cardiomyopathy. The most frequent cause of death is cardiac dysfunction, reflecting congestive heart failure, ventricular arrhythmias and cardio–embolic stroke. With the discovery of the underlying genetic mutation, a variety of novel therapies are now progressing into clinical trials. Consequently, it is crucial to understand the features of cardiomyopathy in this disease and how new treatments may improve cardiac function. The present artcle reviews the molecular basis of the disease, the clinical features of cardiomyopathy in Friedreich’s ataxia and the upcoming therapies.