Friedreich’s ataxia associated with marfanoid features & alopecia areata-rare disease manifestations or chance association?

Chandramohan Sharma, Banshilal Kumawat, Maulik Panchal, Kaushik Rana, Indian Journal of Medical Specialities, Available online 19 June 2017, ISSN 0976-2884, doi:10.1016/j.injms.2017.06.005.

Apart from neurological features it has cardiac, skeletal and endocrine manifestations but its association with marfanoid features and/or alopecia areata have not been described in literature.

Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients´ experiences

Berntsson SG, Landtblom A-M, Flensner G; PLoS ONE 12(6): e0180054. https://doi.org/10.1371/journal.pone.0180054

Elucidating patients´ experiences of living with chronic progressive hereditary ataxia and the symptomatic treatment with intrathecal baclofen (ITB) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants’ experiences through semi-structured interviews. The transcribed text was analyzed according to content analysis guidelines. Overall we identified living in the present/ taking one day at a time as the main theme covering the following categories: 1) Uncertainty about the future as a consequence of living with a hereditary disease; The disease; 2) Impact on life as a whole, 3) Influence on personal life in terms of feeling forced to terminate employment, 4) Limiting daily activities, and 5) ITB therapy, advantages, and disadvantages. Uncertainty about the future was the category that affected participants’ personal life, employment, and daily activities. The participants’ experience of receiving ITB therapy was expressed in terms of improved quality of life due to better body position and movement as well as better sleep and pain relief.

Reata Pharmaceuticals, Inc. Receives Orphan Drug Designation For Omaveloxolone For The Treatment Of Friedreich’s Ataxia

RVING, Texas, June 22, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to omaveloxolone for the treatment of Friedreich’s ataxia.
"Orphan drug designation serves as an important milestone for our company as it recognizes the promise of omaveloxolone as a potential new treatment for FA. In light of the recent, encouraging clinical data, we are hopeful that omaveloxolone will be the first therapy approved for patients with FA," said Warren Huff, Chief Executive Officer of Reata.

Muscle ultrasound comparison between patients with early and delayed onset Friedreich's ataxia – Preliminary data

R.J. Verbeek, A.J.E. Waalkens, M.J. Kuiper, C.C. Verschuuren-Bemelmans, J.H. van der Hoeven, J.J. de Vries, J. van Gaalen, M.A.A.P. Willemsen, H.P.H. Kremer, D.A. Sival, European Journal of Paediatric Neurology, Volume 21, Supplement 1, June 2017, Page e234, ISSN 1090-3798, doi:10.1016/j.ejpn.2017.04.1259.

Muscle ultrasound density leg-muscle parameters are substantially higher in d-FA than healthy subjects, but do not reveal a discriminative pattern between d-FA and p-FA phenotypes. This could be attributed to the large proportion of d-FA patients with an intermediate (mildly-delayed) age of onset (17-25 years, n=7/8 (88%)) and to the cross-sectional nature of the study. These findings implicate that p-FA and “intermediate-d-FA” muscle ultrasound outcomes refer to a similar neuro-muscular spectrum rather than distinctly different neuromuscular phenotypes.

Genotype-phenotype correlation in Friedreich's ataxia

G. Kovacevic, S. Todorovic, I. Novakovic, D. Pavicevic Savic, V. Milic Rasic, M. Svetel, V. Dobricic; European Journal of Paediatric Neurology Volume 21, Supplement 1, June 2017, Pages e205–e206, doi:10.1016/j.ejpn.2017.04.1083


Contrary to other published studies we didn’t find any significant correlation between the age of onset and the GAA1 size. Two possible explanation could be the relative small number of patients in our study as well as the small differences in alleles size and age of onset between the patients. We found a correlation between the size of the smaller allele and extensor plantar response and between the size of the larger allele (GAA2) and impaired vibration sense. The duration of the disease is correlated european journal of paediatric neurology 21 (2017) e197 ee213 e205 with presence of nystagmus, foot deformities, upper limb areflexia, dysarthria and ECG abnormality.

Lower medulla hypoplasia in Friedreich ataxia: MR Imaging confirmation 140 years later

Mario Mascalchi, Andrea Bianchi, Stefano Ciulli, Andrea Ginestroni, Marco Aiello, Maria Teresa Dotti, Fabrizio Salvi, Emanuele Nicolai, Andrea Soricelli, Stefano Diciotti; Neurol (2017). doi:10.1007/s00415-017-8542-8 DOI: 10.1007/s00415-017-8542-8

Hence ataxia in the disease described by Friedreich may be due to two components: a mal-developmental one affecting spinal cord and medulla and a superimposed degenerative one affecting the cerebellar dentate.

DNA trinucleotide (GAA) repeats in human genome: hint for disease pathogenesis?

Himanshu Narayan Singh, Barbara Scheiber-Mojdehkar, and Moganty R. Rajeswari, Journal of Biomolecular Structure and Dynamics Vol. 0 , Iss. ja,0 (posted online: 12 Jun 2017) doi:10.1080/07391102.2017.1341336

Short DNA triplet repeats are generally considered to ‘benign’ in nature, however, it can lead to abnormal genetic features by inducing hyper expansion including mutational hotspots, unusual DNA structure etc. Thus, the expanded DNA base triplets in human genome are expected to play crucial role in disease pathogenesis. One such triplet repeat expansion of (GAA) is observed in FXN gene which is well established to cause neurological disease “Friedreich’s ataxia”. Network analyses on disease associated genes were involved with signaling cascade which could be potential target in order to combat disease conditions. Therefore, the genes identified in the present study can throw light on the understanding of role of (GAA) repeats in various disease phenotypes. However, they are required to be further investigated in the in-vitro conditions.

Neurodegenerative disease mechanism and potential drug identified: Offers hope for patients with Friedreich's Ataxia and related diseases

University of California - Davis. ScienceDaily, 6 June 2017.

Two new studies of neurodegenerative diseases linked to mitochondrial defects offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases.
One of the new studies shows that a loss of the frataxin protein causes a decrease in mitochondrial number in blood and skin cells from patients with Friedreich's ataxia. Mice with a deficiency in the protein also have fewer mitochondria.
In the second study, Cortopassi and colleagues focused on the drug dimethyl fumarate, or DMF, already approved by the FDA for treating adult patients with a relapsing form of multiple sclerosis as well as psoriasis, an autoimmune skin disease.

Tert-butylhydroquinone protects PC12 cells against ferrous sulfate-induced oxidative and inflammatory injury via the Nrf2/ARE pathway

Wenzhe Xu, Feng Li, Zhenkuan Xu, Bin Sun, Jingwei Cao, Yuguang Liu, Chemico-Biological Interactions, Available online 2 June 2017, ISSN 0009-2797, doi:10.1016/j.cbi.2017.05.021

Increasing evidence had proved the critical role of iron in the pathogenesis of numerous neurodegenerative diseases because of its capacity to promote the formation of reactive oxygen species (ROS). Tert-butylhydroquinone (tBHQ) was a metabolite of butylated hydroxyanisole, a widely used food antioxidant. tBHQ could change the conformation of the Keap1-Nrf2 complex and helps Nrf2 escape from Keap1-mediated degradation, which can lead to Nrf2 stabilization. tBHQ has been proven to exert neuroprotective effects in different models of CNS injury and has been approved for human use

Free iron exhibits cytotoxicity because of its ability to promote the generation of reactive oxygen species (ROS), which could lead to lipid peroxidation, DNA strand breaks, degradation of biomolecules, and induce inflammatory response. Brain iron content tends to increase during healthy aging, while excessive iron deposits are found in neuritic plaques in brains with Alzheimer’s disease, substantia nigra in Parkinson’s disease, basal ganglia in Huntington’s disease and dorsal root ganglia in Friedreich’s ataxia (FRDA). This study proved the beneficial effects of tBHQ on the attenuation of iron-induced neurotoxicity, suggesting the therapeutic potential of tBHQ for neurodegenerative diseases.

Is Reata's Friedreich's Ataxia Study a Failure?

Rare Disease ReportData from a Phase 2 Friedreich’s ataxia (FA) study by Reata Pharmaceuticals is making its rounds on social media today. The data, according to Reata, is exceptional. However, according to many on Twitter, the trial is a failure.

In spite of what the critics think, the company and the advocacy group Friedreich’s Ataxia Research Alliance (FARA) are cautiously optimistic.

About: Rare Disease Report is a website and weekly e-newsletter that offers an independent voice for the Rare Disease Community. It strives to bring together medical, scientific, investment, regulatory, and advocate professionals interested in rare diseases and orphan drugs.


NOTE: This is a news published on the web, from a news source that is usually rigorous. I usually try to publish here all the scientific news around the FA, without censorship. This means that I do not always necessary should agree with the opinions.

Reata Pharmaceuticals, Inc. Announces Positive Data From Part One of Moxie Trial of Omaveloxolone for Friedreich’s Ataxia

IRVING, Texas, June 01, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced positive data from Part 1 of the Company’s Phase 2 trial (MOXIe) of omaveloxolone for the treatment of Friedreich’s ataxia (FA). The trial demonstrated that in FA patients, omaveloxolone induced Nrf2, which is suppressed in FA patients, and this was associated with improvements in mitochondrial and neurological function. Dose-dependent and time-dependent effects on the modified Friedreich’s Ataxia Rating Scale (mFARS) were observed at the pharmacodynamically active doses, and the maximum effect on mFARS was observed at the 160 mg dose level. The Company is planning to initiate Part 2 of MOXIe during the second half of 2017.

Friedreich’s ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency

Duncan E. Crombie, Claire L. Curl, Antonia JA Raaijmakers, Priyadharshini Sivakumaran, Tejal Kulkarni, Raymond CB Wong, Itsunari Minami, Marguerite V. Evans-Galea, Shiang Y. Lim, Lea Delbridge, Louise A. Corben, Mirella Dottori, Norio Nakatsuji, Ian A. Trounce, Alex W. Hewitt, Martin B. Delatycki, Martin F. Pera, Alice Pébay; Aging (Albany NY). 2017; 9:1440-1452. doi: 10.18632/aging.101247.

FRDA- cardiomyocytes display a significant increase in beat rate variability, demonstrating a potential for cardiac dysfunction, compared to the control cardiomyocytes. These data also suggest that impairment in Ca2+ handling is responsible for the observed electrophysiological phenotype. This was confirmed by assessing Ca2+ transients. In the FRDA-cardiomyocytes significantly lower diastolic and systolic Ca2+ levels and reduced transient amplitude signals were observed compared with control cardiomyocytes. Collectively, our data demonstrates a Ca2+ handling impairment in the FRDA cardiomyocytes.

Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders

Inder Singh, Vishnu Swarup, Sunil Shakya, Vinay Goyal, Mohammed Faruq, Achal Kumar Srivastava, Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders, Journal of the Neurological Sciences, Available online 22 May 2017, ISSN 0022-510X, doi:10.1016/j.jns.2017.05.042.

The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4–5 h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders.