FXN gene methylation determines carrier status in Friedreich ataxia.

BACKGROUND: Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat (GAA-TRE) in intron 1 of the FXN gene. Some patients are compound heterozygous for the GAA-TRE and another FXN pathogenic variant. Detection of the GAA-TRE in the heterozygous state, occasionally technically challenging, is essential for diagnosing compound heterozygotes and asymptomatic carriers. OBJECTIVE: We explored if the FRDA differentially methylated region (FRDA-DMR) in intron 1, which is hypermethylated in cis with the GAA-TRE, effectively detects heterozygous GAA-TRE. METHODS: FXN DNA methylation was assayed by targeted bisulfite deep sequencing using the Illumina platform. RESULTS: FRDA-DMR methylation effectively identified a cohort of known heterozygous carriers of the GAA-TRE. In an individual with clinical features of FRDA, commercial testing showed a paternally inherited pathogenic FXN initiation codon variant but no GAA-TRE. Methylation in the FRDA-DMR effectively identified the proband, his mother and various maternal relatives as heterozygous carriers of the GAA-TRE, thus confirming the diagnosis of FRDA. CONCLUSION: FXN DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE.

Open-label pilot study of oral methylprednisolone for the treatment of patients with friedreich ataxia.

INTRODUCTION: In this study we assessed the effect of methylprednisolone on safety, tolerability, and ability in Friedreich ataxia (FRDA). METHODS: The study was an open-label trial of pulse methylprednisolone on 11 participants with FRDA. All participants followed a 28-day treatment cycle, repeated 7 times. Patients were assessed with the timed 25-foot walk (T25FW), 1-minute walk (1MW), the Friedreich Ataxia Rating Scale (FARS), and the 9-hole peg test (9HPT). Efficacy was tested by comparing baseline and week 26 visits, separated into adult and pediatric groups. RESULTS: In comparisons of participants' baseline and week 26 visits, only the pediatric cohort's 1MW score showed change (P < 0.05). The T25FW, the primary outcome measure, did not change significantly. DISCUSSION: Pediatric participants improved their gait distance in the 1MW, but did not significantly improve in other measures in this overall negative study. Methylprednisolone was generally well tolerated, suggesting that it may be useful for ambulatory children with FRDA if benefit is found with further study.

Friedreich Ataxia and nephrotic syndrome: a series of two patients.

BACKGROUND: Friedreich 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 PRESENTATIONS: We 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. CONCLUSIONS: Nephrotic 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.

Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia.

Friedreich ataxia is a progressive autosomal recessive neurodegenerative disorder characterized by ataxia, dyscoordination, and cardiomyopathy. A subset of patients with Friedreich ataxia have elevated levels of serum cardiac troponin I, but associations with disease outcomes and features of cardiomyopathy remain unclear. In this study, we characterized clinically obtained serum cardiac biomarker levels including troponin I, troponin T, and B-type natriuretic peptide in subjects with Friedreich ataxia and evaluated their association with markers of disease. While unprovoked troponin I levels were elevated in 36% of the cohort, cTnI levels associated with a cardiac event (provoked) were higher than unprovoked levels. In multivariate linear regression models, younger age predicted increased troponin I values, and in logistic regression models younger age, female sex, and marginally longer GAA repeat length predicted abnormal troponin I levels. In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.

Frataxin controls ketone body metabolism through regulation of OXCT1.

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of mitochondrial protein frataxin, which plays a crucial role in iron-sulphur cluster formation and ATP production. The cellular function of frataxin is not entirely known. Here, we demonstrate that frataxin controls ketone body metabolism through regulation of 3-Oxoacid CoA-Transferase 1 (OXCT1), a rate limiting enzyme catalyzing the conversion of ketone bodies to acetoacetyl-CoA that is then fed into the Krebs cycle. Biochemical studies show a physical interaction between frataxin and OXCT1 both in vivo and in vitro. Frataxin overexpression also increases OXCT1 protein levels in human skin fibroblasts while frataxin deficiency decreases OXCT1 in multiple cell types including cerebellum and skeletal muscle both acutely and chronically, suggesting that frataxin directly regulates OXCT1. This regulation is mediated by frataxin-dependent suppression of ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. Concomitantly, plasma ketone bodies are significantly elevated in frataxin deficient knock-in/knockout (KIKO) mice with no change in the levels of other enzymes involved in ketone body production. In addition, ketone bodies fail to be metabolized to acetyl-CoA accompanied by increased succinyl-CoA in vitro in frataxin deficient cells, suggesting that ketone body elevation is caused by frataxin-dependent reduction of OXCT1 leading to deficits in tissue utilization of ketone bodies. Considering the potential role of metabolic abnormalities and deficiency of ATP production in FRDA, our results suggest a new role for frataxin in ketone body metabolism and also suggest modulation of OXCT1 may be a potential therapeutic approach for FRDA.

Pregnancy with Friedreich ataxia: a retrospective review of medical risks and psychosocial implications.

OBJECTIVE: Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease. Recent medical advances have improved the average life expectancy, and as such, many female patients are contemplating pregnancy. However, little research exists exploring the medical or psychosocial complications that arise from pregnancy with this disease. STUDY DESIGN: In this study, we retrospectively examined 31 women with FRDA who had 65 pregnancies, resulting in 56 live offspring. RESULTS: FRDA did not appear to increase the risk of spontaneous abortion, preeclampsia, or preterm birth. Despite the sensory and proprioceptive loss that occurs in FRDA, nearly four fifths of births were vaginal. Of babies, 94.4% were discharged home with their mothers. Equal numbers of women reported that pregnancy made their disease symptoms worse, better, or unchanged. CONCLUSION: This study demonstrates that women with FRDA can have uncomplicated pregnancies that do not uniformly complicate disease symptomatology.

Identification of a novel missense mutation in Friedreich's ataxia -FXNW 168R.

Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, we find that frataxinW168R, a novel disease-causing missense mutation, is expressed predominantly as the intermediate frataxin42-210 form, with very little expression of mature frataxin81-210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxinW168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease-modifying manner.

Pediatric Ataxia: Focus on Chronic Disorders.

Evaluation of a pediatric patient presenting with ataxia can be expensive and time consuming. Acute causes tend to have a clear developmental paradigm, but chronic presentations are more likely to be secondary to a genetic disorder, either one that primarily causes ataxia or that presents ataxia as one of a multitude of symptoms. Evaluation should focus on a quick diagnosis for those that have treatment options and for those that require other systemic monitoring. Friedreich ataxia is the most common, and genetic testing can easily confirm the suspicion. Testing for vitamin E (for ataxia with isolated vitamin E deficiency) and alpha fetoprotein (for Ataxia Telangiectasia or AT) are important, as is empiric treatment with coenzyme Q10 for those genetic abnormalities that can lead to coenzyme Q deficiency. Clear family history, disease progression, physical examination focusing on type of ataxia and other associated neurologic features, and investigation of systemic involvement can help in focusing clinical assessment.

Pharmacological therapeutics in Friedreich ataxia: the present state.

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.

Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis.

OBJECTIVE: To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients. METHODS: Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer. RESULTS: Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced. CONCLUSIONS: Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial.

Comorbid Medical Conditions in Friedreich Ataxia: Association With Inflammatory Bowel Disease and Growth Hormone Deficiency.

Friedreich ataxia is a progressive degenerative disease with neurologic and cardiac involvement. This study characterizes comorbid medical conditions in a large cohort of patients with Friedreich ataxia. Patient diagnoses were collected in a large natural history study of 641 subjects. Prevalence of diagnoses in the cohort with Friedreich ataxia was compared with prevalence in the population without Friedreich ataxia. Ten patients (1.6%) had inflammatory bowel disease, 3.5 times more common in this cohort of individuals with Friedreich ataxia than in the general population. Four subjects were growth hormone deficient, reflecting a prevalence in Friedreich ataxia that is 28 times greater than the general population. The present study identifies specific diagnoses not traditionally associated with Friedreich ataxia that are found at higher frequency in this disease. These associations could represent coincidence, shared genetic background, or potentially interactive disease mechanisms with Friedreich ataxia.

Progression of Friedreich ataxia: quantitative characterization over 5 years.

OBJECTIVE: 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. METHODS: Eight hundred and twelve subjects in a natural history study were evaluated annually across 12 sites using the Friedreich Ataxia Rating Scale (FARS), 9-Hole Peg Test, Timed 25-Foot Walk, visual acuity tests, self-reported surveys and disability scales. Cross-sectional outcomes were assessed from recent visits, and longitudinal changes were gaged over 5 years from baseline. RESULTS: Cross-sectional outcomes correlated with measures of disease severity. Age, genetic severity (guanine-adenine-adenine [GAA] repeat length), and testing site predicted performance. Serial progression was relatively linear using FARS and composite measures of performance, while individual performance outcomes were nonlinear over time. Age strongly predicted change from baseline until removing the effects of baseline FARS scores, when GAA becomes a more important factor. Progression is fastest in younger subjects and subjects with longer GAA repeats. Improved coefficients of variation show that progression results are more reproducible over longer assessment durations. INTERPRETATION: While age predicted progression speed in simple analyses and may provide an effective way to stratify cohorts, separating the effects of age and genetic severity is difficult. Controlling for baseline severity, GAA is the major determinant of progression rate in FRDA. Clinical trials will benefit from enrollment of younger subjects, and sample size requirements will shrink with longer assessment periods. These findings should prove useful in devising gene therapy trials in the near future.

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.

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.

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.

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.

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.