Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia

Karen A.G. Takazaki, Thiago Junqueira R. Rezende, Alberto R.M. Martinez, Carelis González, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. França, Sudomotor dysfunction is frequent and correlates with disability in Friedreich ataxia, Clinical Neurophysiology, 2018, doi:10.1016/j.clinph.2018.08.017.

We found abnormal sudomotor but normal heart rate variability in FRDA. Small cholinergic post-ganglionic fibers are affected in the disease.

Friedreich’s Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases

Vamshi K. Rao, Christine J. DiDonato and Paul D. Larsen; Case Reports in Neurological Medicine Volume 2018, Article ID 8587203, 5 pages doi:10.1155/2018/8587203

In conclusion, if the index of suspicion is high for Friedrich’s ataxia then frataxin sequencing should be performed if there is a repeat expansion detected only on one allele. Secondly, for the most part, compound heterozygous patients have an earlier age of onset that directly correlates with the trinucleotide expansion size. Finally, whether there is a unique phenotype to the nonsense mutations requires further study before counseling families regarding natural history of disease.

Magnetic susceptibility of the dentate in a longitudinal study of Friedreich ataxia

Phillip G D Ward, Ian H Harding, Parnesh Raniga, Tom G Close, Louise A Corben, Martin B Delatycki, Monique R Stagnitti, Elsdon Storey, Nellie Georgiou-Karistianis, and Gary F Egan; International Society for Magnetic Resonance in Medicine, (Abstract #3731) 16-21 June 2018 Paris (France)

We performed in-vivo measurements of the magnetic susceptibility in the dentate nucleus in individuals with Friedreich ataxia and healthy controls over a two-year longitudinal study using quantitative susceptibility mapping. The results show a significant susceptibility difference between individuals with Friedreich ataxia and control subjects, and a strong correlation with disease severity in the Friedreich ataxia cohort. These findings may lead to the development of a sensitive biomarker of disease severity and progression in Friedreich ataxia.

Regional cortical folding morphometry in Friedreich ataxia using Laplace Beltrami based gyrification index

Rosita Shishegar, Imis Dogan, Martin B. Delatycki, Gary F. Egan, Elsdon Storey, Louise A. Corben, and Nellie Georgiou-Karistianis; International Society for Magnetic Resonance in Medicine, (Abstract #3616) 16-21 June 2018 Paris (France)

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder mainly affecting the spinal cord and dentate nuclei of the cerebellum. Although there is growing evidence of cerebral atrophy and cortical thinning in FRDA, no research has investigated the pattern of cortical folding (gyrification) in the disorder. We have proposed a new MRI analysis technique, Laplace Beltrami based gyrification index (LB-GI), and validated its use in individuals with FRDA. Preliminary results reveal significantly increased regional gyrification in the motor cortex in individuals with FRDA, compared to healthy controls. Overall, our results demonstrate that LB-GI is a sensitive technique which requires further investigation as a potential neuroimaging marker of disease progression in FRDA.

BRAIN FUNCTIONAL CHANGES CORRELATE WITH COGNITIVE DYSFUNCTION IN FRIEDREICH'S ATAXIA: AN RS-fMRI STUDY

Sirio Cocozza, Teresa Costabile, Enrico Tedeschi, Filomena Abate, Camilla Russo, Agnese Liguori, Walter Del Vecchio, Francesca Paciello, Mario Quarantelli, Alessandro Filla, Francesco Saccà, and Arturo Brunetti; International Society for Magnetic Resonance in Medicine, (Abstract #4670) 16-21 June 2018 Paris (France)

We performed a seed-based Resting-State fMRI analysis in Friedreich’s Ataxia (FRDA) patients to assess possible brain functional connectivity (FC) changes in these patients, which are know to be charactherized by an impairment of neuropsychological functions. We found an increased FC in FRDA patients compared to controls in different brain regions, including the medial frontal gryrus, the angular gyri and cingulate gyrus, with a decreased cerebellar FC. Our findings of diffuse alterations of FC in FRDA patients compared to controls may shed new light on the pattern of supratentorial and infratentorial involvement and on dynamics of brain plasticity in this condition.

Child Neurology: Friedreich ataxia with upper motor neuron findings

Elizabeth A. Harvey, Kimberly S. Jones; Neurology Aug 2018, 91 (9) 426-428; DOI: 10.1212/WNL.0000000000006086

A 16-year-old boy with hypertrophic cardiomyopathy, gait abnormalities, and balance problems was found to have Friedreich ataxia. Though Friedreich ataxia typically renders patients areflexic, this child had upper motor neuron findings of spasticity in both lower extremities, with crossed adductors, and 4+ deep tendon reflexes at the patella and Achilles bilaterally. This unusual presentation of an uncommon genetic disorder led to uncertainty of the patient's true diagnosis until genetic testing confirmed that he had 2 alleles with the Friedreich ataxia mutation.

DNA repair in trinucleotide repeat ataxias

Yau, W. Y., O'Connor, E. , Sullivan, R. , Akijian, L. and Wood, N. W. (2018), FEBS J. Accepted Author Manuscript. doi:10.1111/febs.14644

In this review, we discuss the mechanisms in which DNA repair pathways, epigenetics and other genetic factors may act as modifiers in cerebellar ataxias due to trinucleotide repeat expansions.

Novel Epigenetic Techniques Provided by the CRISPR/Cas9 System.

Nina Xie, Yafang Zhou, Qiying Sun, and Beisha Tang, Stem Cells International, vol. 2018, Article ID 7834175, 12 pages, 2018. doi:10.1155/2018/7834175.

Other representative candidates may include the Rett syndrome, Huntington’s disease, and Friedreich ataxia, where dCas9-epieffector complex may be harnessed to restore or repress the responsible gene to cure the disease.

In conclusion, all of the studies described above indicated that CRISPR/Cas9-mediated epigenome editing holds a great promise for epigenetic studies and therapeutics. However, there are still some limitations to be scrutinized. First of all, in terms of basic science studies, although most studies claimed high specificity in their experiments, however, the high specificity usually is the result of repeated optimization. A precise model that could predict deleterious off-target effects during the experiment design stage is still lacking. In addition, although transactivation or repression effects on multiple genes were well documented in publications, mechanisms underlying the phenomenon were not clear. Epigenetic mark profiling on epigenome scale was not sufficient. Local CHIP-seq data usually only focused on the characterization of one or few histone marks. Theoretically, we hope that epigenome editing could achieve targeted gene regulation by changing epigenetic marks specifically and freely according to our wills. To achieve this goal, high specificity and clarified mechanisms are the prerequisite. Therefore, more thorough off-target event assessments and more studies focusing on mechanisms underlying epigenome editing are needed.

Moreover, in terms of clinical applications, several issues need to be addressed prior to successful clinical translation. Firstly, the endurance of gene activation or a repression effect mediated by CRISPR/Cas9 remains to be undetermined. It has been thought that epigenome-editing-induced gene activation or repression is short-term. On the contrary, there was also evidence showing that a gene silencing effect mediated by the hit-and-run epigenome editing strategy could also be long-term and inheritable. A short-term effect is more suitable for antagonizing acute pathogenic factor exposure and the transdifferentiation process. However, for treating chronic diseases, a long-term effect is expected. Additionally, a safer and efficient delivery method should be developed [92]. Adeno-associated virus (AAV) vectors have been the prevailing delivery method for some time. By tagging a synthetic surface peptide, splitting the Cas9 protein or using its smaller orthologues, and choosing a suitable administration route, researchers significantly improved the packaging capacity and delivery efficiency of AAV vectors. However, for clinical applications, more optimization is required. The immunogenicity of AAV vectors, dCas9 proteins, and guide RNAs should be determined precisely. The off-target effects of AAV vectors or dCas9-epieffector complex should be minimized as much as possible to ensure clinical safety.

Company hopes to speed up payments for clinical trial patients

(Action News) KING OF PRUSSIA, Pa. Wednesday, August 22, 2018
Clinical trials help drive medical advances. However, some patients hedge at taking part because reimbursement for their expenses take time.

Two years ago, Kyle took part in a test of ClinCard, a reloadable debit card. Once a patient's ClinCard is established, money is loaded after each research visit... no check, no cash. It's instant money for the patient, and instant documentation for the trial site.

PTC Therapeutics Successfully Completes Acquisition of Agilis Biotherapeutics

SOUTH PLAINFIELD, N.J., Aug. 23, 2018 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT), today announced that it has successfully completed the acquisition of Agilis Biotherapeutics, Inc., a private biotechnology company focused on the advancement of innovative gene therapy programs for rare genetic disorders that affect the central nervous system (CNS).
The acquisition also includes gene therapy programs in development, GT-FA, GT-AS, and GT-RLN, for Friedreich Ataxia, Angelman Syndrome and Cognitive Disorders associated with several neurodevelopmental and neurodegenerative disorders, respectively.

Longitudinal Diffusion Tensor Imaging in the brain in Friedreich’s Ataxia: follow-up at 12 and 24 months

Pierre-Gilles Henry, James Joers, Dinesh Deelchand, Diane Hutter, and Christophe Lenglet; International Society for Magnetic Resonance in Medicine, (Abstract #3730) 16-21 June 2018

We report 12-month and 24-month longitudinal diffusion tensor imaging (DTI) data in the brain of subjects with Friedreich’s ataxia (FRDA). Significant longitudinal changes were observed in several brain areas (including the corpus callosum, internal capsule and superior corona radiata) in a group of 13 patients over 24 months. Our data suggest that diffusion MRI of the brain could be useful to better understand the impact of FRDA on brain microstructure and connectivity, and to assess the effect of potential treatments on neurodegeneration in upcoming clinical trials in FRDA.

Noninvasive brain stimulation may help treat symptoms of rare movement disorders

August 22, 2018, American Academy of Neurology.
Electrical stimulation of the brain and spinal cord may help treat the symptoms of rare movement disorders called neurodegenerative ataxias, according to a study published in the August 22, 2018, online issue of Neurology, the medical journal of the American Academy of Neurology. There are several types of these disorders, which can be hereditary or occur randomly, including spinocerebellar ataxia, multiple system atrophy and Friedreich's ataxia.

Public summary of opinion on orphan designation: Omaveloxolone for treatment of Friedreich's ataxia

EMA/395368/2018, 16 August 2018

On 27 June 2018, orphan designation (EU/3/18/2037) was granted by the European Commission to Dr Stefan Blesse, Germany, for omaveloxolone (also known as RTA 408) for the treatment of Friedreich’s ataxia.
In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 24 May 2018 recommending the granting of this designation.

Jupiter Orphan Therapeutics Announces Favorable Data Which Expands JOTROL's Applications to the Estimated $5 Billion Mitochondrial Rare Disease Market

JUPITER, Fla., Aug. 22, 2018 /PRNewswire/ -- Jupiter Orphan Therapeutics, Inc. ("JOT"), Jupiter, FL, today announced that it has received new data regarding an increase in mitochondrial biogenesis in liver and brain from a recently performed study in a frequently studied Alzheimer's disease animal model, the triple transgenic (APPsw / PS1M146V / TauP301L) mouse.

Murdoch Children's Research Institute, a JOT partner, has conducted an open label study showing that high dose of resveratrol (not JOTROL), with associated GI-side effects, had significant positive impact in 4 vital endpoints. Target, for this indication, is to reproduce this study with JOTROL and reproduce the same positive results without side effects.

Test-retest reliability of an instrumented electronic walkway system (GAITRite) for the measurement of spatio-temporal gait parameters in young patients with Friedreich’s ataxia

Bastien Roche, Anne-Laure Simon, Sophie Guilmin-Crépon, Priscilla Boizeau, Béatrice Andriss, Corinne Alberti, Ana Presedo, Brice Ilharreborde, Isabelle Husson, Gait & Posture, 2018, doi:10.1016/j.gaitpost.2018.08.017.

The GAITRite system allows feasible and reliable measurements of gait parameters in young patients with FRDA. Lower reliability found for the weakest parameters was attributed to the software automatic errors and the ankle laxity noted in every patient.

Investigating Molecular Mechanisms Underlying Mild Phenotype in Friedreich Ataxia Patients with G130V Missense Mutation

Clark, Elisia. University of Pennsylvania, ProQuest Dissertations Publishing, 2018. 10748306. A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Ful fillment of the Requirements for the Degree of Doctor of Philosophy.

Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase

Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, et al. (2018) Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase. PLoS ONE 13(8): e0201369. https://doi.org/10.1371/journal.pone.0201369

Genetic basis of hypertrophic cardiomyopathy in children

tefan Rupp, Moataz Felimban, Anne Schänzer, Dietmar Schranz, Christoph Marschall, Martin Zenker, Thushiha Logeswaran, Christoph Neuhäuser, Josef Thul, Christian Jux, Andreas Hahn; Clin Res Cardiol (2018). doi:10.1007/s00392-018-1354-8

42 patients with the diagnoses of HCM made before age 18 years were treated in our center from 2000 to 2016. Genetic analysis was performed in 36 subjects, a genetic defect was detected in 29 (78%) patients. 15 individuals (42%) had pathogenic variants in genes encoding sarcomere proteins, and 5 (14%) in genes coding for components of the RAS/MAPK signaling pathway. 4 subjects (11%) had mutations in the GAA gene (Pompe disease), and 3 (8%) had Frataxin repeat expansions (Friedreich’s ataxia). One patient each showed a mutation in BAG3 and LMNA. Discussion of unsolved HCM cases after performing next-generation sequencing (28 genes) in an interdisciplinary board unraveled the genetic cause in 9 subjects (25%).
A definite genetic diagnosis can be reached in nearly 80% with HCM of childhood onset. Next-generation sequencing in conjunction with a multidisciplinary cooperation can enhance the diagnostic yield substantially. This may be important for risk stratification, treatment planning and genetic counseling.

Nonataxia symptoms in Friedreich Ataxia. Report from the Registry of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS)

Kathrin Reetz, Imis Dogan, Christian Hohenfeld, Claire Didszun, Paola Giunti, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Ilaria Giordano, Katrin Bürk, Massimo Pandolfo, Jörg B. Schulz, the EFACTS Study Group, Neurology Aug 2018, DOI: 10.1212/WNL.0000000000006121

The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems.

Gene therapy for neurological disorders: progress and prospects

Benjamin E. Deverman, Bernard M. Ravina, Krystof S. Bankiewicz, Steven M. Paul & Dinah W. Y. Sah; Nature Reviews Drug Discovery, Published: 10 August 2018 doi:10.1038/nrd.2018.110

Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Longitudinal analysis of contrast acuity in Friedreich ataxia

Ali G. Hamedani, Lauren A. Hauser, Susan Perlman, Katherine Mathews, George R. Wilmot, Theresa Zesiewicz, S.H. Subramony, Tetsuo Ashizawa, Martin B. Delatycki, Alicia Brocht, David R. Lynch; Neurol Genet. 2018 Jul 23;4(4):e250. doi: 10.1212/NXG.0000000000000250. eCollection 2018 Aug.

Low-contrast visual acuity decreases linearly over time in Friedreich ataxia, and the rate of decrease is greater at higher GAA repeat lengths. Contrast sensitivity has the potential to serve as a biomarker and surrogate outcome in future studies of Friedreich ataxia.

Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration

Abdalkader M, Lampinen R, Kanninen KM, Malm TM, Liddell JR. Front Neurosci. 2018;12 . PMCID: PMC6048292.

Ferroptosis is a newly described form of regulated cell death, distinct from apoptosis, necroptosis and other forms of cell death. Ferroptosis is induced by disruption of glutathione synthesis or inhibition of glutathione peroxidase 4, exacerbated by iron, and prevented by radical scavengers such as ferrostatin-1, liproxstatin-1, and endogenous vitamin E. Ferroptosis terminates with mitochondrial dysfunction and toxic lipid peroxidation. Although conclusive identification of ferroptosis in vivo is challenging, several salient and very well established features of neurodegenerative diseases are consistent with ferroptosis, including lipid peroxidation, mitochondrial disruption and iron dysregulation. Accordingly, interest in the role of ferroptosis in neurodegeneration is escalating and specific evidence is rapidly emerging. One aspect that has thus far received little attention is the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). This transcription factor regulates hundreds of genes, of which many are either directly or indirectly involved in modulating ferroptosis, including metabolism of glutathione, iron and lipids, and mitochondrial function. This potentially positions Nrf2 as a key deterministic component modulating the onset and outcomes of ferroptotic stress. The minimal direct evidence currently available is consistent with this and indicates that Nrf2 may be critical for protection against ferroptosis. In contrast, abundant evidence demonstrates that enhancing Nrf2 signaling is potently neuroprotective in models of neurodegeneration, although the exact mechanism by which this is achieved is unclear. Further studies are required to determine to extent to which the neuroprotective effects of Nrf2 activation involve the prevention of ferroptosis

Novoheart, Pfizer develop 3-D model of Friedreich ataxia

VANCOUVER, British Columbia – June 25, 2018 (GLOBE NEWSWIRE) – Novoheart (“Novoheart” or the “Company”) (TSXV: NVH; FWB: 3NH) is pleased to announce a presentation was delivered on June 22nd, 2018, entitled “Modeling Cardiac Dysfunction of Friedreich’s Ataxia Using Ventricular Sheets, Tissues and Chambers Engineered from Human Pluripotent Stem Cells,” at the Annual Meeting of the International Society for Stem Cell Research in Melbourne, Australia. The presentation includes data from research conducted with Pfizer Inc. on a 3D engineered human cardiac tissue disease model of Friedreich’s ataxia (FRDA), a neurodegenerative disease in which patients most often die of heart complications. The new disease model helps capture both electrical and mechanical defects of the heart observed in patients with FRDA.
“We are very excited by the outcome of this study, and hope this will accelerate the development of safe and effective new therapies for FRDA patients. Also, by demonstrating the biomimetic capabilities of our MyHeartTM Platform for modeling diseased hearts, we are hoping to establish new standards for creating a proprietary library of disease models and expand our presence in drug discovery and precision medicine.” said Novoheart CSO, Dr. Kevin Costa.

The Effects of Game Based Exercise Training on Balance and Postural Control in Patients With Ataxia

ClinicalTrials.gov Identifier: NCT03607058

Patients who meet the inclusion criteria will be divided into two groups randomly: 'Kinect and exercise training' and 'exercise training'. The assessments will be made by a blind investigator four times, before and after the implementation of both protocols. The evaluations will take approximately 1 hour. The demographic information of the cases will be recorded. Designed as cross over study, two treatment protocols will be used in this study. The first protocol will be Xbox Kinect application plus exercise program, the second protocol will be only exercise program. At the beginning of the study, 2 groups will be allocated (Group A and Group B) randomly. For group A, the Xbox Kinect application plus exercise program will be applied for the first 8 weeks. For group B, only exercise program will be applied therapy first 8 weeks. All assessments will be repeated before and after each therapy period. Exercise program will consist of selected balance, coordination and walking exercises according to the individual needs of patients. . After 1 week washout period, patients will be included in the other group. All patients will take the treatment 1-hour, 3 days in a week for 8 weeks.

Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 13 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Ataksik Hastalarda Oyun Temelli Egzersiz Eğitiminin Denge ve Postural Kontrol Üzerine Etkisi
Actual Study Start Date : October 18, 2017
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : September 2018
Locations: Turkey, Hacettepe University, Faculty of Health Sciences, Department of Physiotherapy and Rehabilitation