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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.


Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle

Neurological and cardiac comorbidities are prominent in FRDA and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Here, the authors show that lean mass is lower, whereas body mass index is unaltered, in separate cohorts of adults and children with FRDA. In adults, lower lean mass correlated with disease severity. To further investigate FXN loss in skeletal muscle, a transgenic mouse model of whole-body inducible and progressive FXN depletion was used. There was little impact of FXN loss when FXN was approximately 20% of control levels. When residual FXN was approximately 5% of control levels, muscle mass was lower along with absolute grip strength. When we examined mechanisms that can affect muscle mass, only global protein translation was lower, accompanied by integrated stress response (ISR) activation. Also in mice, aerobic exercise training, initiated prior to the muscle mass difference, improved running capacity, yet, muscle mass and the ISR remained as in untrained mice. Thus, FXN loss can lead to lower lean mass, with ISR activation, both of which are insensitive to exercise training.

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2022 HRS expert consensus statement on evaluation and management of arrhythmic risk in neuromuscular disorders

This international multidisciplinary document is intended to guide electrophysiologists, cardiologists, other clinicians, and health care professionals in caring for patients with arrhythmic complications of neuromuscular disorders (NMDs). The document presents an overview of arrhythmias in NMDs followed by detailed sections on specific disorders: Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy type 2; myotonic dystrophy type 1 and type 2; Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B; facioscapulohumeral muscular dystrophy; and mitochondrial myopathies, including Friedreich ataxia and Kearns-Sayre syndrome, with an emphasis on managing arrhythmic cardiac manifestations. End-of-life management of arrhythmias in patients with NMDs is also covered. The document sections were drafted by the writing committee members according to their area of expertise. The recommendations represent the consensus opinion of the expert writing group, graded by class of recommendation and level of evidence utilizing defined criteria. The recommendations were made available for public comment; the document underwent review by Heart Rhythm Society Scientific and Clinical Documents Committee and external review and endorsement by the partner and collaborating societies. Changes were incorporated based on these reviews. By using a breadth of accumulated available evidence, the document is designed to provide practical and actionable clinical information and recommendations for the diagnosis and management of arrhythmias and thus improve the care of patients with NMDs.

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Increased brain tissue sodium concentration in Friedreich ataxia: A multimodal MR imaging study

In patients with Friedreich ataxia, structural MRI is typically used to detect abnormalities primarily in the brainstem, cerebellum, and spinal cord. The aim of the present study was to additionally investigate possible metabolic changes in Friedreich ataxia using in vivo sodium MRI that may precede macroanatomical alterations, and to explore potential associations with clinical parameters of disease progression. Tissue sodium concentration across the whole brain was estimated from sodium MRI maps acquired at 3 T and compared between 24 patients with Friedreich ataxia (21-57 years old, 13 females) and 23 controls (21-60 years old, 12 females). Compared to controls, patients showed reduced brain volume in the right cerebellar lobules I-V (difference in means: -0.039% of total intracranial volume [TICV]; Cohen's d = 0.83), cerebellar white matter (WM) (-0.105%TICV; d = 1.16), and brainstem (-0.167%TICV; d = 1.22), including pons (-0.102%TICV; d = 1.00), medulla (-0.036%TICV; d = 1.72), and midbrain (-0.028%TICV; d = 1.05). Increased sodium concentration was additionally detected in the total cerebellum (difference in means: 2.865 mmol; d = 0.68), and in several subregions with highest effect sizes in left (5.284 mmol; d = 1.01) and right cerebellar lobules I-V (5.456 mmol; d = 1.00), followed by increases in the vermis (4.261 mmol; d = 0.72), and in left (2.988 mmol; d = 0.67) and right lobules VI-VII (2.816 mmol; d = 0.68). In addition, sodium increases were also detected in all brainstem areas (3.807 mmol; d = 0.71 to 5.42 mmol; d = 1.19). After controlling for age, elevated total sodium concentrations in right cerebellar lobules IV were associated with younger age at onset (r = -0.43) and accordingly with longer disease duration in patients (r = 0.43). These findings support the potential of in vivo sodium MRI to detect metabolic changes of increased total sodium concentration in the cerebellum and brainstem, the key regions in Friedreich ataxia.

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Inherited Ataxias in Children

The purpose of this review is to describe the current diagnostic approach to inherited ataxias during childhood. With the expanding use and availability of gene testing technologies including large sequencing panels, the ability to arrive at a precise genetic diagnosis in this group of disorders has been improving. The authors have reviewed all the gene sequencing studies of ataxias available by a comprehensive literature search and summarize their results. A logical algorithm for a diagnostic approach in the context of this evolving information is provided. The authors stress the fact that both autosomal recessive and autosomal dominant mutations can occur in children with ataxias and the need for keeping in mind nucleotide repeat expansions, which cannot be detected by sequencing technologies, as a possible cause of progressive ataxias in children. The traditional phenotype-based diagnostic approach in the context of gene testing technologies is discusses. Finally, this review summarizes those disorders in which a specific therapy may be indicated.

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Posttranslational Regulation of Mitochondrial Frataxin and Identification of Compounds that Increase Frataxin Levels in Friedreich's Ataxia

This study shows that conditions that result in increased mitochondrial reactive oxygen species (ROS) in yeast or mammalian cell culture give rise to increased turnover of frataxin, but not of other iron-sulfur cluster (ISC) synthesis proteins. The authors demonstrate that the mitochondrial Lon protease is involved in frataxin degradation and that iron export through the mitochondrial metal transporter Mmt1 protects yeast frataxin from degradation. When FRDA fibroblasts were grown in media containing elevated iron, mitochondrial ROS increased and frataxin decreased compared to WT fibroblasts. Furthermore, a library of FDA-approved compounds was screened and 38 compounds that increased yeast frataxin levels identified, including the azole Bifonazole, antiparasitic Fipronil, anti-tumor compound Dibenzoylmethane (DBM), antihypertensive 4-hydroxychalcone (4'-OHC), and a non-specific anion channel inhibitor 4,4-diisothiocyanostilbene-2,2-sulfonic acid (DIDS). The authors show that top hits 4'-OHC and DBM increased mRNA levels of transcription factor Nrf2 in FRDA patient-derived fibroblasts, as well as downstream antioxidant targets thioredoxin (TXN), glutathione reductase (GSR), and superoxide dismutase 2 (SOD2). Taken together, these findings reveal that FRDA progression may be in part due to oxidant-mediated decreases in frataxin, and that some approved compounds may be effective in increasing mitochondrial frataxin in FRDA, delaying disease progression.

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