Plasma idebenone monitoring in Friedreich's ataxia patients during a long-term follow-up.

INTRODUCTION AND OBJECTIVES: Despite the growing interest and the potential benefits of idebenone as a repurposed drug for different orphan conditions, data regarding its monitoring are scarce. Our main goal was to report plasma idebenone values in a cohort of Friedreich's ataxia (FRDA) patients during a long-term follow-up. Taking advantage of this, we also assessed cardiological and neurological status together with idebenone values and genetic background. METHODS: Long-term follow-up retrospective study in 27 FRDA patients with a disease onset at the paediatric age treated with idebenone by compassionate use. Plasma idebenone was measured by HPLC with electrochemical detection. RESULTS: Median plasma idebenone values increased when doses were increased, but apparently linearity was lost in the highest dose group. Marked intraindividual and interindividual differences were observed among patients. We did not find a consistent positive effect after analysis of paired data at the beginning and the end of the study. We only found a correlation between some cardiological measures and the duration of idebenone therapy at high doses, but with uncertain significance. CONCLUSIONS: The large variations observed among the different individuals involved in this study should be considered for optimization of individual dosage regimens.

NfL and pNfH are increased in Friedreich's ataxia.

OBJECTIVE: To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich's ataxia. METHODS: Single molecule array measurements of neurofilament light (NfL) and heavy chain (pNfH) in 99 patients with genetically confirmed Friedreich's ataxia. Correlation of NfL/pNfH serum levels with disease severity, disease duration, age, age at onset, and GAA repeat length. RESULTS: Median serum levels of NfL were 21.2 pg/ml (range 3.6-49.3) in controls and 26.1 pg/ml (0-78.1) in Friedreich's ataxia (p = 0.002). pNfH levels were 23.5 pg/ml (13.3-43.3) in controls and 92 pg/ml (3.1-303) in Friedreich's ataxia (p = 0.0004). NfL levels were significantly increased in younger patients (age 16-31 years, p < 0.001) and patients aged 32-47 years (p = 0.008), but not in patients of age 48 years and older (p = 0.41). In a longitudinal assessment, there was no difference in NfL levels in 14 patients with repeated sampling 2 years after baseline measurement. Levels of NfL correlated inversely with GAA1 repeat length (r = - 0.24, p = 0.02) but not with disease severity (r = - 0.13, p = 0.22), disease duration (r = - 0.06, p = 0.53), or age at onset (r = 0.05, p = 0.62). CONCLUSION: Serum levels of NfL and pNfH are elevated in Friedreich's ataxia, but differences to healthy controls decrease with increasing age. Long-term longitudinal data are required to explore whether this reflects a selection bias from early death of more severely affected individuals or a slowing down of the neurodegenerative process with age. In a pilot study over 2 years of follow-up-a period relevant for biomarkers indicating treatment effects-we found NfL levels to be stable.

Potential biomarker identification for Friedreich's ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion.

Friedreich's ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.

Dimethyl fumarate dosing in humans increases frataxin expression: A potential therapy for Friedreich's Ataxia.

Friedreich's Ataxia (FA) is an inherited neurodegenerative disorder resulting from decreased expression of the mitochondrial protein frataxin, for which there is no approved therapy. High throughput screening of clinically used drugs identified Dimethyl fumarate (DMF) as protective in FA patient cells. Here we demonstrate that DMF significantly increases frataxin gene (FXN) expression in FA cell model, FA mouse model and in DMF treated humans. DMF also rescues mitochondrial biogenesis deficiency in FA-patient derived cell model. We further examined the mechanism of DMF's frataxin induction in FA patient cells. It has been shown that transcription-inhibitory R-loops form at GAA expansion mutations, thus decreasing FXN expression. In FA patient cells, we demonstrate that DMF significantly increases transcription initiation. As a potential consequence, we observe significant reduction in both R-loop formation and transcriptional pausing thereby significantly increasing FXN expression. Lastly, DMF dosed Multiple Sclerosis (MS) patients showed significant increase in FXN expression by ~85%. Since inherited deficiency in FXN is the primary cause of FA, and DMF is demonstrated to increase FXN expression in humans, DMF could be considered for Friedreich's therapy.

Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich Ataxia.

Objective: In vitro, in vivo, and open-label studies suggest that interferon gamma (IFN-γ 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN-γ 1b in the treatment of Friedreich Ataxia through a double-blind, multicenter, placebo-controlled trial. Methods: Ninety-two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN-γ 1b or placebo for 6 months. The primary outcome measure was the modified Friedreich Ataxia Rating Scale (mFARS). Results: No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open-label extension period, subjects had a more stable course than expected based on natural history data. Conclusions: This study provides no direct evidence for a beneficial effect of IFN-γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

Assessment of cell-free levels of iron and copper in patients with Friedreich's ataxia.

Friedreich's ataxia (FRDA), a progressive neurodegenerative disorder caused by trinucleotide (GAA) repeat expansion in frataxin (fxn) gene which results in decreased levels of frataxin protein. Insufficient frataxin levels leads to iron and copper deposits in the brain and cardiac cells. A total of hundred and twenty patients, suspected of FRDA were screened for the (GAA) repeats in the fxn gene and only confirmed patients (n = 25) were recruited in the study. The total Iron and total copper concentrations were measured in blood plasma using Nitro PAPS and Dibrom PAESA method, respectively both in patients and age, sex matched healthy controls. The iron levels mean ± SD (6.2 ± 3.8) in plasma of FRDA patients were found to be significantly decreased as compared to healthy controls mean ± SD (15.2 ± 4.2). A similar trend was observed in case of plasma copper levels in FRDA patient (8.15 ± 4.6) as compared to controls (17.5 ± 3.40). Present results clearly prove abnormal distribution of extra-cellular iron in FRDA patients, which is in accordance with the well established fact of intracellular iron overload, which is the key feature of the pathogenesis of this disease. This can be of importance in understanding the pathophysiology of the disease in association with frataxin/iron. It appears that intracellular sequestration of trace metals in FRDA patients (due to low frataxin) results in their sub-optimal levels in blood plasma (extra-cellular) an observation that can find prognostic application in clinical trials.

Double-blind, randomized and controlled trial of EPI-743 in Friedreich's ataxia.

AIM: To evaluate the safety and clinical effects of EPI-743 in Friedreich's ataxia patients. EPI-743 is a compound that targets oxidoreductase enzymes essential for redox control of metabolism. METHODS: We conducted a multicenter trial that evaluated EPI-743 during a 6-month placebo-controlled phase, followed by an 18-month open-label phase. End points included low-contrast visual acuity and the Friedreich's Ataxia Rating Scale. RESULTS/CONCLUSION: EPI-743 was demonstrated to be safe and well tolerated. There were no significant improvements in key end points during the placebo phase. However, at 24 months, EPI-743 treatment was associated with a statistically significant improvement in neurological function and disease progression relative to a natural history cohort (p < 0.001).

Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients.

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues-such as dorsal root ganglia, sensory neurons and cerebellum-in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared with both heterozygous expansion carriers (n = 228) and controls (n = 93 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.

Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia.

BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk. RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject with a low body mass index experienced steatorrhea taking a high dose and discontinued the study. Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to be present in plasma on day 28. There was an improvement in peak workload in the drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116), and in stride speed (P = 0.15). CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted. © 2018 International Parkinson and Movement Disorder Society.

Serum uric acid in Friedreich Ataxia.

Serum uric acid (UA) is a circulating antioxidant whose levels are typically lower in patients with idiopathic neurodegenerative diseases than healthy controls, reflecting a higher oxidative stress. Here we provided the first assessment of serum UA in Friedreich Ataxia (FRDA), an inherited neurodegenerative disorder, aimed at exploring novel disease biomarkers. Serum UA was measured in 19 FRDA patients and compared to 26 healthy controls (CTL). Multivariate analysis was conducted to eliminate main confounding factors (age, gender and BMI). Diagnostic accuracy was tested with ROC curve analysis and cut-off point calculation. Clinical predictive value was quantified by means Spearman's correlation with SARA score and other clinical parameters. Serum UA levels resulted significantly higher in FRDA than CTL (p = .016), independently from age, gender and BMI. At the cut-off value of 4.45 mg/dl, serum UA discriminates FRDA from CTL with >70% of sensitivity and >60% of specificity. No correlations emerged with clinical data. Contrarily to other neurodegenerative diseases, in FRDA, we observed an independent increase of serum UA content. Taking in account previous experimental findings, we hypothesize that such a finding may result from biochemical impairment induced by the genetic defect, acting as a sort of compensatory antioxidant defense although proper dedicated studies are mandatory. This preliminary report focuses UA as a potential biomarker for FRDA and encourages further studies on novel therapeutic strategies.

Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy.

Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.

Differentially Regulated Cell-Free MicroRNAs in the Plasma of Friedreich's Ataxia Patients and Their Association with Disease Pathology.

Friedreich's ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223-3p, hsa-24-3p, and hsa-miR-21-5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.

No changes in heme synthesis in human Friedreich´s ataxia erythroid progenitor cells.

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the protein frataxin. Frataxin is thought to play a role in iron-sulfur cluster biogenesis and heme synthesis. In this study, we used erythroid progenitor stem cells obtained from FRDA patients and healthy donors to investigate the putative role, if any, of frataxin deficiency in heme synthesis. We used electrochemiluminescence and qRT-PCR for frataxin protein and mRNA quantification. We used atomic absorption spectrophotometry for iron levels and a photometric assay for hemoglobin levels. Protoporphyrin IX and Ferrochelatase were analyzed using auto-fluorescence. An "IronChip" microarray analysis followed by a protein-protein interaction analysis was performed. FRDA patient cells showed no significant changes in iron levels, hemoglobin synthesis, protoporphyrin IX levels, and ferrochelatase activity. Microarray analysis presented 11 genes that were significantly changed in all patients compared to controls. The genes are especially involved in oxidative stress, iron homeostasis and angiogenesis. The mystery about the involvement of frataxin on iron metabolism raises the question why frataxin deficiency in primary FRDA cells did not lead to changes in biochemical parameters of heme synthesis. It seems that alternative pathways can circumvent the impact of frataxin deficiency on heme synthesis. We show for the first time in primary FRDA patient cells that reduced frataxin levels are still sufficient for heme synthesis and possibly other mechanisms can overcome reduced frataxin levels in this process. Our data strongly support the fact that so far no anemia in FRDA patients was reported.

Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is one of the most devastating childhood onset neurodegenerative disease affecting multiple organs in the course of progression. FRDA is associated with mitochondrial dysfunction due to deficit in a nuclear encoded mitochondrial protein, frataxin. Identification of disease-specific biomarker for monitoring the severity remains to be a challenging topic. This study was aimed to identify whether circulating cell-free nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in blood plasma can be a potential biomarker for FRDA. Clinical information was assessed using International Cooperative Ataxia Rating Scale and the disease was confirmed using Long-range PCR for GAA repeat expansion within the gene encoding frataxin. The frataxin expression was measured using Western blot. Plasma nDNA and mtDNA levels were quantified by Multiplex real-time PCR. The major observation is that the levels of nDNA found to be increased, whereas mtDNA levels were reduced significantly in the plasma of FRDA patients (n=21) as compared to healthy controls (n=21). Further, plasma mtDNA levels showed high sensitivity (90%) and specificity (76%) in distinguishing from healthy controls with optimal cutoff indicated at 4.1×10(5)GE/mL. Interestingly, a small group of follow-up patients (n=9) on intervention with, a nutrient supplement, omega-3 fatty acid (a known enhancer of mitochondrial metabolism) displayed a significant improvement in the levels of plasma mtDNA, supporting our hypothesis that plasma mtDNA can be a potential monitoring or prognosis biomarker for FRDA.

GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients.

Friedreich's ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNγ) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNγ in Friedreich's patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21-38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 µg) of IFNγ (human recombinant interferon 1 b gamma, trade name IMUKIN(®)), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNγ by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNγ in Friedreich's ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich's ataxia.

Delayed-onset Friedreich's ataxia revisited.

BACKGROUND: Friedreich's ataxia usually occurs before the age of 25. Rare variants have been described, such as late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, occurring after 25 and 40 years, respectively. We describe the clinical, functional, and molecular findings from a large series of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia and compare them with typical-onset Friedreich's ataxia. METHODS: Phenotypic and genotypic comparison of 44 late-onset Friedreich's ataxia, 30 very late-onset Friedreich's ataxia, and 180 typical Friedreich's ataxia was undertaken. RESULTS: Delayed-onset Friedreich's ataxia (late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia) had less frequently dysarthria, abolished tendon reflexes, extensor plantar reflexes, weakness, amyotrophy, ganglionopathy, cerebellar atrophy, scoliosis, and cardiomyopathy than typical-onset Friedreich's ataxia, along with less severe functional disability and shorter GAA expansion on the smaller allele (P < 0.001). Delayed-onset Friedreich's ataxia had lower scale for the assessment and rating of ataxia and spinocerebellar degeneration functional scores and longer disease duration before wheelchair confinement (P < 0.001). Both GAA expansions were negatively correlated to age at disease onset (P < 0.001), but the smaller GAA expansion accounted for 62.9% of age at onset variation and the larger GAA expansion for 15.6%. In this comparative study of late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia, no differences between these phenotypes were demonstrated. CONCLUSION: Typical- and delayed-onset Friedreich's ataxia are different and Friedreich's ataxia is heterogeneous. Late-onset Friedreich's ataxia and very-late-onset Friedreich's ataxia appear to belong to the same clinical and molecular continuum and should be considered together as "delayed-onset Friedreich's ataxia." As the most frequently inherited ataxia, Friedreich's ataxia should be considered facing compatible pictures, including atypical phenotypes (spastic ataxia, retained reflexes, lack of dysarthria, and lack of extraneurological signs), delayed disease onset (even after 60 years of age), and/or slow disease progression.

Gene Expression Profile in Peripheral Blood Cells of Friedreich Ataxia Patients.

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia characterized by a combination of neurological involvement, cardiomyopathy, and skeletal and glucose metabolism disturbances. FRDA is caused by mutations in FXN gene that results in reduction of mRNA and protein levels of frataxin. Previous microarray and real-time quantitative PCR (qPCR) studies showed that the downregulation of FXN is associated with a complex gene expression profile. However, these studies showed a wide variability in the subset of genes with altered expression among tissues and models. Genes differentially expressed in peripheral blood cells (PBC) could potentially help in the understanding of FRDA pathophysiology and also function as reliable disease biomarkers obtained from an easily accessible tissue, which could have implications in clinical practice. This study aimed to validate by qPCR the expression of 26 genes, revealed as differentially expressed by other studies, using peripheral blood cells (PBC) of 11 FRDA patients compared to 11 healthy controls. We found a robust downregulation of FXN, but no statistically significant differences were found between FRDA and controls for the remaining genes. Except for FXN, our study did not find a differential gene expression profile in PBC of FRDA patients and a reliable gene expression profile biomarker in a clinical relevant and noninvasive tissue remains unclear.

The cardiomyopathy in Friedreich's ataxia - New biomarker for staging cardiac involvement.

BACKGROUND: Patients with autosomal-recessively inherited Friedreich's ataxia (FA) may develop a hypertrophic cardiomyopathy (CM), which potentially progresses towards a life-limiting problem. The typical features of this CM and the sequence of progression are widely unknown. METHODS: Thirty-two consecutive patients with genetically confirmed FA were included. All patients received resting electrocardiogram (ECG), 24-hour Holter-ECG, echocardiography with speckle tracking imaging, cardiac magnetic resonance imaging (cMRI) with late enhancement imaging (for replacement fibrosis), and measurement of high-sensitive troponin-T (hsTNT). In addition, morphological parameters were retrospectively compared to data obtained five years before. RESULTS: Based on criteria comprising ejection fraction (<55%), left ventricular end-diastolic posterior wall thickness (LVPWT ≥ 11 mm), fibrosis on cMRI, hsTNT ≥ 14 ng/ml, or T-wave-inversion, in all but two patients a CM could be detected (94%). Using these criteria we propose the following staging: a) mild CM (n=5, 16%; T-wave-inversion only); b) intermediate CM (n=4, 13%; T-wave-inversion with hypertrophy but no fibrosis); c) severe CM (n=13, 41%; fibrosis with raised hsTNT); and d) end-stage CM (n=8; 25%; ejection-fraction<55%). All patients with end-stage CM also showed fibrosis on cMRI, T-wave-inversion, marked elevation in hsTNT, and a decrease in LVPWT during the last five years (from 10.7 ± 1.2mm to 9.5 ± 1.3mm, p=0.025). In addition, 38% suffered from supraventricular tachycardia on Holter-ECG. CONCLUSIONS: A comprehensive cardiac assessment will unravel established CM in almost all patients with FA with electrocardiographic abnormalities as earliest signs. Advanced stages can be characterized by elevated hsTNT and replacement fibrosis leading to recession of hypertrophy, reduction of global myocardial function, and electrical instability.

Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial.

OBJECTIVE: We conducted a 6-month, randomized, double-blind, placebo-controlled study to assess safety, tolerability, and efficacy of deferiprone in Friedreich ataxia (FRDA). METHODS: Seventy-two patients were treated with deferiprone 20, 40, or 60mg/kg/day or placebo, divided into 2 daily doses. Safety was the primary objective; secondary objectives included standardized neurological assessments (Friedreich Ataxia Rating Scale [FARS], International Cooperative Ataxia Rating Scale [ICARS], 9-Hole Peg Test [9HPT], Timed 25-Foot Walk, Low-Contrast Letter Acuity), general functional status (Activities of Daily Living), and cardiac assessments. RESULTS: Deferiprone was well tolerated at 20mg/kg/day, whereas more adverse events occurred in the 40mg/kg/day than in the placebo group. The 60mg/kg/day dose was discontinued due to worsening of ataxia in 2 patients. One patient on deferiprone 20mg/kg/day experienced reversible neutropenia, but none developed agranulocytosis. Deferiprone-treated patients receiving 20 or 40mg/kg/day showed a decline in the left ventricular mass index, compared to an increase in the placebo-treated patients. Patients receiving 20mg/kg/day of deferiprone had no significant change in FARS, similar to the placebo-treated patients, whereas those receiving 40mg/kg/day had worsening in FARS and ICARS scores. The lack of deterioration in the placebo arm impaired the ability to detect any potential protective effect of deferiprone. However, subgroup analyses in patients with less severe disease suggested a benefit of deferiprone 20mg/kg/day on ICARS, FARS, kinetic function, and 9HPT. INTERPRETATION: This study demonstrated an acceptable safety profile of deferiprone at 20mg/kg/day for the treatment of patients with FRDA. Subgroup analyses raise the possibility that, in patients with less severe disease, deferiprone 20mg/kg/day may reduce disease progression, whereas higher doses appear to worsen ataxia.

Cross-sectional analysis of glucose metabolism in Friedreich ataxia.

OBJECTIVES: To evaluate the relationship between disease features in Friedreich ataxia and aberrant glucose metabolism. METHODS: Fasting glucose, fasting insulin and random HbA1C were obtained in 158 patients with Friedreich ataxia. Regression analysis evaluated glucose, insulin, and homeostatic model assessment (HOMA) of insulin resistance (IR) and beta-cell function (ß) in relation to age, BMI, sex, and genetic severity. Categorical glucose values were analyzed in relation to other FRDA-associated disease characteristics. RESULTS: In the FRDA cohort, age and GAA repeat length predicted fasting glucose and HbA1c levels (accounting for sex and BMI), while insulin and HOMA-IR were not predicted by these parameters. Within the cohort, average BMI was consistently lower than the national average by age and was marginally associated with insulin levels and HOMA-IR. Within juvenile subjects, insulin and HOMA-IR were predicted by age. Controlling for age and genetic severity, diabetes-related measures were not independent predictors of any quantitative measure of disease severity in FRDA. Glucose handling properties were also predicted by the presence of a point mutation, with 40% of individuals heterozygous for point mutations having diabetes, compared to 4.3% of subjects who carried two expanded GAA repeats. INTERPRETATION: In FRDA, aberrant glucose metabolism is linked to increasing age, longer GAA repeat length on the shorter allele, frataxin point mutations, and increasing BMI. The effect of age to some degree may be mediated through changes in BMI, with increasing age associated with increases in BMI, and with HOMA-IR and insulin increases in children.