Mitochondria and Iron: current questions

Bibbin T. Paul, David H. Manz, Frank M. Torti, and Suzy V. Torti; Expert Review of Hematology Vol. 0 , Iss. 0,0 doi:10.1080/17474086.2016.1268047

Several genetic diseases can result in disrupted iron-sulfur cluster biogenesis and severe mitochondrial iron overload. For example, point mutations or homozygous unstable GAA trinucleotide expansion in the FXN gene can result in Friedreich's ataxia (FRDA), an autosomal recessive disease characterized by severe neurodegeneration and cardiomyopathy. These manifestations of FRDA are caused by an accumulation of intra-mitochondrial iron, which decreases mitochondrial function and increases sensitivity to oxidative stress.
Mitochondria serve a key role in the synthesis and assembly of heme and Fe-S clusters, and are therefore essential for the delivery of iron to client proteins. Appropriate levels of iron, however, are also important for the proper function of the mitochondria. Conditions of iron deficiency or excess disrupt a myriad of mitochondrial functions. This interdependence between iron and mitochondria is best demonstrated by diseases that simultaneously disrupt mitochondrial iron and mitochondrial function, such as Frederich’s Ataxia, infantile mitochondrial complex II/III deficiency, neonatal oxidative phosphorylation deficiency, and sideroblastic anemia.
To develop effective treatment for pathologies leading to localized mitochondrial iron overload or deficiency, we will first need to develop a more detailed understanding of mitochondrial iron regulation. We anticipate substantial progress towards this goal in the next five years.

Amélioration des paramètres spatiotemporels de la marche par des chaussures orthopédiques dans l’ataxie de Friedreich

Bastien Roche, Isabelle Husson, Neurophysiologie Clinique/Clinical Neurophysiology, Volume 46, Issues 4–5, November 2016, Pages 276-277, ISSN 0987-7053, doi:10.1016/j.neucli.2016.09.098

Alors que l’évolution de l’ataxie s’oriente vers une instabilité plus importante, puis une perte de la marche, l’utilisation des chaussures orthopédiques permet d’améliorer, comparativement à la marche pieds nus, la stabilité et la fonctionnalité de la marche.

Paediatric spinal conditions

Tomlinson JE, Gummerson NW, Surgery (2016), doi:10.1016/j.mpsur.2016.10.013

Achieving an upright posture, and balancing the 24 mobile segments of the spine in a vertical column, is clearly no easy task. The neuromuscular control of the spine involves brain, nerve and muscle (including feedback pathways). Problems anywhere in this pathway may lead to a neuromuscular scoliosis. Causes include cerebral palsy, Friedreich’s ataxia, syringomyelia, tumour, trauma, myelodysplasia, spinal muscular atrophy, poliomyelitis, Duchenne muscular dystrophy and arthrogryposis.
The treatment goals in this group of patients are to prevention of significant cardiorespiratory compromise, and maintain function. Function may often be maintenance of sitting balance, use of the upper limbs, the use of a wheelchair, or ease of hygiene and pressure area care rather than walking. Scoliosis surgery in neuromuscular conditions is a significant undertaking and other adaptations such as moulded seating should be considered, with surgery playing a role when other options have been exhausted. Surgery is usually a long posterior instrumented fusion, but unlike idiopathic curves, fixation is often to the pelvis.

Gradually Progressive Spastic Ataxia in a Young Man: Steadily Unsteady

Divyanshu Dubey, MD; Pravin Khemani, MD; Eric Remster, MD; Jeffrey L. Elliott, MD; JAMA Neurol. Published online December 12, 2016. doi:10.1001/jamaneurol.2016.1581

The final diagnosis was adult-onset FA. An atypical presentation of a more common condition such as FA, should always be considered as more likely than a common presentation of an extraordinarily rare disorder. It is now recognized that up to 25%of patients with FA may be considered atypical according to classical diagnostic criteria.
Patients with atypical FA may present with retained reflexes, spasticity, mild or absent limb ataxia, lack of dysarthria, and no cardiomyopathy. Among them, spastic ataxia with almost no sensory neuropathy has been associated with a limited GAA expansion. It is thought that GAA expansion size significantly affects the degree of involvement of the central somatosensory pathway and peripheral sensory axons, along with the overall severity of disease, as the clinical course of disease and neuropathology can be variable based on the degree of repeat expansion or heterozygosity of GAA mutation.

Automatic classification of gait in children with Early-Onset Ataxia or Developmental Coordination Disorder and controls using inertial sensors

Andrea Mannini, Octavio Martinez-Manzanera, Tjitske F. Lawerman, Diana Trojaniello, Ugo Della Croce, Deborah A. Sival, Natasha M. Maurits, Angelo Maria Sabatini; Gait & Posture, Available online 2 December 2016, ISSN 0966-6362, doi:10.1016/j.gaitpost.2016.12.002.

Early-Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) are two conditions that affect coordination in children. Phenotypic identification of impaired coordination plays an important role in their diagnosis. Gait is one of the tests included in rating scales that can be used to assess motor coordination. A practical problem is that the resemblance between EOA and DCD symptoms can hamper their diagnosis. In this study we employed inertial sensors and a supervised classifier to obtain an automatic classification of the condition of participants.
In absence of reliable distinctive biomarkers, the Scale for Assessment and Rating of Ataxia (SARA), is often used as an additional, supportive biomarker to indicate ataxia severity. Despite the high reliability of the scale, we have shown that pediatric SARA is confounded by other factors than ataxia, as well. Nevertheless, we have shown that the relative SARA gait subscore can support the recognition of an indisputable EOA phenotype in mildly affected participants. Presently available quantitative gait parameters [14] are still not ubiquitously implemented as a clinical tool. Based on the remarks reported above, we reasoned that clinically simple and reproducible quantitative gait analysis could be worthwhile for reliable EOA and DCD recognition.
In the present paper, we evaluate a method for the automatic and objective assessment of pediatric gait as compared to a clinical diagnosis in a similar way to what was previously done for other pathological conditions. Additionally, the accuracy of phenotypic assessments is estimated. Both methods classify patients into three groups (EOA, DCD and CTRL). To be effective, the automatic assessment is expected to guarantee both a limited increase of the complexity of the evaluation and a minimal impact on the gait patterns under evaluation. Hopefully, this study provides a first step towards incorporating a clinically objective and viable biomarker for uniform identification of EOA and DCD.

Vestibular findings in autosomal recessive ataxia

Bianca Simone Zeigelboim, Helio Afonso Ghizoni, Teive Hugo Amilton Santos de Carvalho, Edna Marcia da Silva Abdulmassih, Jair Mendes Marques and Rafaella Cristyne Cardoso. International Tinnitus Journal. 2013;18(2):156-162.

The most evident neurotological symptoms were dizziness, lack of coordination of movement, and imbalance when walking. Alterations in vestibular examinations occurred in 89.5% of patients, mostly in the caloric test, with a predominance of deficient central vestibular system dysfunction. This underscores the importance of the contribution of topodiagnostic labyrinthine evaluations for neurodegenerative diseases.

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice

Calatrava-Ferreras, L.; Gonzalo-Gobernado, R.; Reimers, D.; Herranz, A.S.; Casarejos, M.J.; Jiménez-Escrig, A.; Regadera, J.; Velasco-Martín, J.; Vallejo-Muñoz, M.; Díaz-Gil, J.J.; Bazán. Int. J. Mol. Sci. 2016, 17, 2066. doi:10.3390/ijms17122066 (registering DOI)

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We intend to determine if liver growth factor (LGF), which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 μg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA.

Horizon slumps after phase 3 Friedreich's ataxia trial flops

FierceBiotech. by Nick Paul Taylor | Dec 8, 2016 9:40am. Horizon Pharma’s Actimmune has missed the primary endpoint in a phase 3 trial, sparking a 20% drop in its stock price. The study set out to show that interferon gamma-1b could improve outcomes in patients with the rare neurodegenerative movement disorder Friedreich's ataxia, but the drug failed to move the needle.

RareDR (Rare Disease Report).Andrew Black Published Online: Thursday, Dec 08, 2016
Horizon Pharma’s Phase 3 study assessing actimmune for the treatment of Friedreich’s ataxia did not meet its primary endpoint of displaying significant change in the modified Friedreich's Ataxia Rating Scale (FARS‐mNeuro) during a 26-week time period.

Globe Newswire. 8th December 2016. Today announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich’s Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich’s ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich’s Ataxia Rating Scale (FARS‐mNeuro) at 26 weeks versus treatment with placebo. FARS‐mNeuro is an exam-based rating scale that measures disease progression based on functional parameters such as speech, ability to swallow, upper and lower limb coordination, gait and posture. In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications.

REUTERS. Dec 8 Horizon Pharma Plc.
* Horizon Pharma Plc announces topline results from phase 3 study of ACTIMMUNE (interferon gamma-1b) in Friedreich's Ataxia
* Horizon Pharma Plc says ACTIMMUNE for treatment of Friedreich's Ataxia (FA) did not meet its primary endpoint
* Horizon Pharma Plc says secondary endpoints did not meet statistical significance
* Horizon Pharma Plc says company believes it is well-positioned for growth in 2017 and beyond based on its existing portfolio of medicines
* Horizon Pharma Plc says announcement does not impact Horizon Pharma's full-year 2016 adjusted net sales or adjusted EBITDA guidance Source text for Eikon: Further company coverage.

UNITED STATES, SECURITIES AND EXCHANGE COMMISSION, WASHINGTON, D.C. 20549. CURRENT REPORT: Pursuant to Section 13 or 15(d) of the Securities Exchange Act of 1934. Date of Report (Date of earliest event reported): December 8, 2016.
On December 8, 2016, Horizon Pharma announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich’s Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich’s ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich’s Ataxia Rating Scale (FARS-mNeuro) at 26 weeks versus treatment with placebo. In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications. The Company, in conjunction with the independent Data Safety Monitoring Board, the principal investigator and the Friedreich’s Ataxia Research Alliance (FARA) Collaborative Clinical Research Network (CCRN) in FA, has determined that, based on the trial results, the FA development program will be discontinued, including the 26-week extension study and the long-term safety study.

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Horizon Pharma plc Announces Topline Results from Phase 3 Study of ACTIMMUNE® (interferon gamma-1b) in Friedreich's Ataxia

DUBLIN, Ireland, Dec. 08, 2016 (GLOBE NEWSWIRE) -- Horizon Pharma plc (NASDAQ:HZNP), today announced that the Phase 3 trial, STEADFAST (Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich's Ataxia study), evaluating ACTIMMUNE® (interferon gamma-1b) for the treatment of Friedreich's ataxia (FA) did not meet its primary endpoint of a statistically significant change from baseline in the modified Friedreich's Ataxia Rating Scale (FARS‐mNeuro) at 26 weeks versus treatment with placebo. FARS‐mNeuro is an exam-based rating scale that measures disease progression based on functional parameters such as speech, ability to swallow, upper and lower limb coordination, gait and posture.
In addition, the secondary endpoints did not meet statistical significance. No new safety findings were identified on initial review of data other than those already noted in the ACTIMMUNE prescribing information for approved indications. The Company, in conjunction with the independent Data Safety Monitoring Board, the principal investigator and the Friedreich's Ataxia Research Alliance (FARA) Collaborative Clinical Research Network (CCRN) in FA, has determined that, based on the trial results, the FA development program will be discontinued, including the 26-week extension study and the long-term safety study.

Researchers uncover possible source of genetic error causing multiple diseases

Phys.org, Tufts University, December 5, 2016.

Tufts University researchers have discovered a possible explanation for the occurrence of a genetic error that causes over a dozen neuromuscular and neurodegenerative disorders, including Huntington's disease, myotonic dystrophy and forms of spinocerebellar ataxia.

More information: The role of break-induced replication in large-scale expansions of (CAG)n∙(CTG)n repeats, Jane C Kim, Samantha T Harris, Teresa Dinter, Kartik A Shah & Sergei M Mirkin, Nature Structural & Molecular Biology, Published online 05 December 2016 doi:10.1038/nsmb.3334