The Classification of Autosomal Recessive Cerebellar Ataxias: a Consensus Statement from the Society for Research on the Cerebellum and Ataxias Task Force

Marie Beaudin, Antoni Matilla-Dueñas, Bing-Weng Soong, Jose Luiz Pedroso, Orlando G. Barsottini, Hiroshi Mitoma, Shoji Tsuji, Jeremy D. Schmahmann, Mario Manto, Guy A Rouleau, Christopher Klein, Nicolas Dupre. Cerebellum (2019). doi:10.1007/s12311-019-01052-2

There is currently no accepted classification of autosomal recessive cerebellar ataxias, a group of disorders characterized by important genetic heterogeneity and complex phenotypes. The objective of this task force was to build a consensus on the classification of autosomal recessive ataxias in order to develop a general approach to a patient presenting with ataxia, organize disorders according to clinical presentation, and define this field of research by identifying common pathogenic molecular mechanisms in these disorders.

Seelos Therapeutics Receives Notice of Allowance for a US Patent for SLS-005 in New Indication of Friedreich Ataxia

July 02, 2019, Source: Seelos Therapeutics, Inc.

NEW YORK, July 02, 2019 (GLOBE NEWSWIRE) -- Seelos Therapeutics, Inc. (NASDAQ: SEEL), a clinical-stage biopharmaceutical company, announced today that they have received a Notice of Allowance from the United States Patent and Trademark Office (USPTO) for Seelos’ U.S. Patent Application for SLS-005 (trehalose) for treating Friedreich Ataxia (FA).

Friedreich Ataxia (FA) is a rare inherited neuromuscular disease affecting the nervous system resulting in issues with balance and coordination, spinal deformity, cardiovascular issues and in some patients can lead to the onset of diabetes. It is among the group of neurological conditions related by the commonality of protein aggregations, such as Sanfilippo syndrome, Oculopharyngeal Muscular Dystrophy (OPMD) and Huntington's disease. FA affects about one in 50,000 people worldwide, making it the most common in a group of related disorders called hereditary ataxias. More information about FA can be found at: https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/friedreichs-ataxia-fact-sheet

SLS-005 already has orphan indication for Spinocerebellar Ataxia (SCA3) and Seelos is currently developing SLS-005 for Sanfilippo syndrome followed by the OPMD indication.

Related:
Bioblast Pharma Announces Sale of its Trehalose Clinical Development Programs to Seelos Therapeutics.
Tel Aviv, Israel, Feb. 19, 2019 (GLOBE NEWSWIRE) -- Bioblast Pharma Ltd. ( Nasdaq: ORPN), a clinical-stage, orphan disease-focused biotechnology company, today announced the sale of its Trehalose clinical development programs (including its advanced phase 2 clinical program of Trehalose to treat Oculoharyngeal Muscular Dystrophy (OPMD) to Seelos Therapeutics, Inc. (Nasdaq: SEEL), a clinical-stage biopharmaceutical company.

Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut)

Laura Guarga, Xavier Badia, Mercè Obach, Manel Fontanet, Alba Prat, Atonio Vallano, Josep Torrent and Caridad Pontes; Orphanet Journal of Rare Diseases 2019 14:157 doi:10.1186/s13023-019-1121-6

Orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut.

Frequency and Genetic Profile of Compound Heterozygous Friedreich’s Ataxia Patients—the Brazilian Experience

Thiago Mazzo Peluzzo, Luciana Cardoso Bonadia, Amanda Donatti, Miriam Coelho Molck, Laura Bannach Jardim, Wilson Marques Jr, Iscia Teresinha Lopes-Cendes, Marcondes C. França Jr. Cerebellum (2019). doi:10.1007/s12311-019-01055-z

There were 143 unrelated patients (128 families), five of which had a single expanded allele. We identified point mutations in three out of these five (3/128 = 2.34%). Two patients had the c.157delC variant, whereas one individual had the novel variant c.482+1G>T. These results indicate that FXN point mutations are rare, but exist in Brazilian patients with FRDA. This has obvious implications for diagnostic testing and genetic counseling.

Keeping heart homeostasis in check through the balance of iron metabolism

Driton Vela; Acta Physiol. Accepted Author Manuscript. doi:10.1111/apha.13324

This review is a synthesis of our current knowledge concerning the regulation of cardiac iron metabolism. In addition, different models of cardiac iron dysmetabolism will be discussed through the examples of heart failure (cardiomyocyte iron deficiency), myocardial infarction (acute changes in cardiac iron turnover), doxorubicin induced cardiotoxicity (cardiomyocyte iron overload in mitochondria), thalassemia (cardiomyocyte cytosolic and mitochondrial iron overload), friedreich ataxia (assymetric cytosolic/mitochondrial cardiac iron dysmetabolism). Finally, future perspectives will be discussed in order to resolve actual gaps in knowledge, which should be helpful in finding new treatment possibilities in different cardiac diseases.

Open label Pilot Study of Oral Methylprednisolone for the Treatment of Patients with Friedreich Ataxia

Patel, M. , Schadt, K. , McCormick, A. , Isaacs, C. , Dong, Y. N. and Lynch, D. R. (2019), Muscle & Nerve. Accepted Author Manuscript. doi:10.1002/mus.26610

Results
In comparisons of participants’ baseline and week 26 visits, only the pediatric cohort's 1MW score showed change (p<0 .05="" br="" change="" did="" measure="" not="" outcome="" primary="" significantly.="" t25fw="" the="">
Discussion
Pediatric participants improved in gait distance in the 1MW, but not significantly in other measures in this overall negative study. Methylprednisolone was generally well tolerated, suggesting that it may be useful for ambulatory children with FRDA if benefit is found with further study.

Neuromuscular disorders: a guide for the orthopaedic surgeon

Catriona Heaver, Simon Hill, Tracey Willis; Neuromuscular disorders: a guide for the orthopaedic surgeon, Orthopaedics and Trauma, doi:10.1016/j.mporth.2019.05.008

Patients with neuromuscular conditions are frequently seen in final professional clinical examinations as they have good clinical signs, which often point towards the underlying diagnosis. This paper outlines some of the most common neuromuscular disorders that you are likely to come across in orthopaedic practise.
Keywords: arthrogryposis, Charcot-Marie-Tooth, Friedreich's ataxia, hereditary sensory motor neuropathy, muscular dystrophy, neuromuscular conditions, poliomyelitis, spinal muscular atrophy

MON-LB030 Muscle Mitochondrial Oxidative Phosphorylation Capacity and Whole Body Glucose Metabolism in Friedreich's Ataxia

Sara Nguyen, Neil Wilson, Darko Stefanovski, G. Maria Gur, Anna Dedio, Kristin Wade, David Lynch, Ravinder Reddy, Andrea Kelly, Michael Rickels, Shana McCormack; Journal of the Endocrine Society, Volume 3, Issue Supplement_1, April-May 2019, MON–LB030, doi:10.1210/js.2019-MON-LB030

Individuals with a genetic mitochondrial disorder conferring increased diabetes risk have decreased whole body insulin sensitivity that may be mediated by decreased skeletal muscle OXPHOS capacity. Studies in rare disorders may provide insights into the role of skeletal muscle metabolism in the pathogenesis of Type 2 diabetes.

Evidence for genetically determined degeneration of proprioceptive tracts in Friedreich ataxia

Brice Marty, Gilles Naeije, Mathieu Bourguignon, Vincent Wens, Veikko Jousmäki, David R. Lynch, William Gaetz, Serge Goldman, Riitta Hari, Massimo Pandolfo, Xavier De Tiège; Neurology Jun 2019, 10.1212/WNL.0000000000007750; DOI: 10.1212/WNL.0000000000007750

This study provides electrophysiologic evidence demonstrating that proprioceptive impairment in FRDA is mostly genetically determined and scarcely progressive after symptom onset. It also positions CKC as a reliable, robust, specific marker of proprioceptive impairment in FRDA.

Deuterated Polyunsaturated Fatty Acids Reduce Oxidative Stress and Extend the Lifespan of C. elegans

Beaudoin-Chabot C, Wang L, Smarun AV, Vidović D, Shchepinov MS and Thibault G (2019). Front. Physiol. 10:641. doi: 10.3389/fphys.2019.00641

Chemically reinforced essential fatty acids (FAs) promise to fight numerous age-related diseases including Alzheimer's, Friedreich's ataxia and other neurological conditions. The reinforcement is achieved by substituting the atoms of hydrogen at the bis-allylic methylene of these essential FAs with the isotope deuterium. This substitution leads to a significantly slower oxidation due to the kinetic isotope effect, inhibiting membrane damage. The approach has the advantage of preventing the harmful accumulation of reactive oxygen species (ROS) by inhibiting the propagation of lipid peroxidation while antioxidants potentially neutralize beneficial oxidative species. Here, we developed a model system to mimic the human dietary requirement of omega-3 in Caenorhabditis elegans to study the role of deuterated polyunsaturated fatty acids (D-PUFAs). Deuterated trilinolenin [D-TG(54:9)] was sufficient to prevent the accumulation of lipid peroxides and to reduce the accumulation or ROS. Moreover, D-TG(54:9) significantly extended the lifespan of worms under normal and oxidative stress conditions. These findings demonstrate that D-PUFAs can be used as a food supplement to decelerate the aging process, resulting in extended lifespan.