Kimberly Schadt

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.

Therapeutic approaches for the treatment of Friedreich’s ataxia

Friedreich ataxia (FRDA) is an inherited, progressive, neurodegenerative disease for which there is presently no cure or effective therapeutic intervention. While physiologically complex, FRDA is caused by deficits in production and expression of frataxin (FXN), a mitochondrial protein important for regulation of iron-sulfur cluster containing enzymes in the cell. Depletion of FXN is associated with dysfunction of ATP synthesis, mitochondrial iron accumulation, potentially an increase in oxidative stress, and cellular dysfunction. Therapeutic development presently focuses on improving mitochondrial function and increasing FXN expression. Gene therapy, a field which has undergone significant advances in recent years, may offer a promising treatment for FRDA in the future. This collection of approaches provides many possible opportunities for treating this multisystem disorder.

Open‐label pilot study of interferon gamma‐1b in Friedreich ataxia

This is an open‐label trial of the safety of interferon gamma‐1b (IFN‐γ) and its effect on frataxin levels and neurologic measures in 12 children with Friedreich ataxia.

Progression of Friedreich ataxia: quantitative characterization over 5 years

Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder of adults and children. This study analyzed neurological outcomes and changes to identify predictors of progression and generate power calculations for clinical trials.

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.

Pharmacological therapeutics in Friedreich ataxia: the present state

ABSTRACT Introduction: Friedreich ataxia (FRDA) is a progressive, inherited, neurodegenerative disease for which there is currently no cure or approved treatment. FRDA is caused by deficits in the production and expression of frataxin, a protein found in the mitochondria that is most likely responsible for regulating iron-sulfur cluster enzymes within the cell. A decrease in frataxin causes dysfunction of adenosine triphosphate synthesis, accumulation of mitochondrial iron, and other events leading to downstream cellular dysfunction. Areas covered: Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. Expert commentary: The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.

Friedreich Ataxia and nephrotic syndrome: a series of two patients

BackgroundFriedreich Ataxia (FRDA) is a neurodegenerative disorder characterized by gait and balance abnormalities, sensory loss, weakness, loss of reflexes, and ataxia. Previously, two cases of FRDA and Nephrotic Syndrome (NS) have been reported. Here we report two additional individuals with NS and FRDA, providing further evidence for a possible connection between the two diseases and focusing on the neuromuscular responsiveness of one individual to corticosteroid treatment, an effect not previously described in FRDA.Case presentationsWe describe two patients with FRDA also presenting with NS. The first patient was diagnosed with FRDA at age 5 and NS at age 7 following the development of periorbital edema, abdominal swelling, problems with urination, and weight gain. The second patient was diagnosed with NS at age 2 after presenting with periorbital edema, lethargy, and abdominal swelling. He was diagnosed with FRDA at age 10. Nephrotic syndrome was confirmed by laboratory testing in both cases and both individuals were treated with corticosteroids.ConclusionsNephrotic syndrome may occur in individuals with FRDA, but was not associated with myoclonic epilepsy in our patients as previously described. It is unlikely that this association is coincidental given the rarity of both conditions and the association of NS with mitochondrial disease in model systems, though coincidental coexistence is possible. One patient showed neurological improvement following steroid treatment. Although neurological improvement could be attributed to the treatment of NS, we also identified some degree of steroid responsiveness in a series of patients with FRDA but without NS.

Elevation of serum cardiac troponin I in a cross-sectional cohort of asymptomatic subjects with Friedreich ataxia

BACKGROUND Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia of all four limbs, dysarthria, areflexia, and cardiomyopathy. At present, baseline values of cardiac troponin I are unknown among Friedreich ataxia subjects. METHODS In this study, we evaluated baseline plasma cardiac troponin I levels among a cross-sectional cohort of 49 pediatric and adult Friedreich ataxia subjects without active arrhythmia, chest pain or features of acute coronary syndrome at the time of sampling. We also reviewed baseline electrocardiograms from 45 of these subjects. RESULTS Troponin I values were elevated above the 99th percentile population cutoff in 46.9% of all subjects, with 16.3% of asymptomatic subjects having levels typically seen during an acute myocardial infarction. In logistic regression models, younger age and an earlier disease onset predicted higher serum cardiac troponin I values. Only weak correlations were seen between cardiac troponin I values and echocardiogram parameters, including ejection fraction. Additionally, 82.2% of subjects also had abnormal baseline electrocardiograms. CONCLUSION The present study demonstrates that both abnormal electrocardiograms and elevated serum cardiac troponin I values may be common baseline characteristics seen in Friedreich ataxia subjects. Further longitudinal studies will allow for a better understanding of the cause and prognostic implications of elevated levels, as well as the clinical utility of serum cardiac troponin I testing in Friedreich ataxia.

IFN-γ for Friedreich ataxia: present evidence

IFN-γ-1b is currently US FDA approved as an orphan drug for the treatment of chronic granulomatous disease and severe malignant osteopetrosis. It is administered via subcutaneous injection and is a potential therapy for Friedreich ataxia (FRDA), a rare degenerative neurological condition. Ongoing Phase II and III trials in both adults and children with FRDA were preceded by a small Phase I, open-label trial in children that showed that IFN-γ-1b was reasonably well-tolerated and improved overall neurological function as measured by the Friedreich Ataxia Rating Scale after 12 weeks of treatment, though the primary outcome measure of frataxin level showed no improvement. Although there is an established dose of IFN-γ-1b prescribed for the current indications, the efficacy and tolerability of these dose levels in the FRDA population remains the subject of ongoing investigation.