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.
Saturday, June 29, 2019
Friday, June 28, 2019
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.
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.
Thursday, June 27, 2019
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.
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.
Wednesday, June 19, 2019
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.
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.
Tuesday, June 18, 2019
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
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
Monday, June 17, 2019
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.
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.
Sunday, June 16, 2019
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.
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.
Saturday, June 15, 2019
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.
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.
Friday, June 14, 2019
DNA repair deficiency in neuropathogenesis: when all roads lead to mitochondria
Luis Bermúdez-Guzmán and Alejandro Leal; Translational Neurodegeneration 20198:14 doi:10.1186/s40035-019-0156-x
Diseases such as Friedreich’s ataxia and MIRAS (caused by POLG mutations) present an extended phenotype, maybe derived from the equal vulnerability that these variants confer to the mitochondria in the whole organism. Even though the clinical difference is evident, still more research is needed to understand the molecular basis of this systemic damage compared with the diseases that tend to present a pathological tropism.
Diseases such as Friedreich’s ataxia and MIRAS (caused by POLG mutations) present an extended phenotype, maybe derived from the equal vulnerability that these variants confer to the mitochondria in the whole organism. Even though the clinical difference is evident, still more research is needed to understand the molecular basis of this systemic damage compared with the diseases that tend to present a pathological tropism.
Thursday, June 13, 2019
Prominent Spasticity and Hyperreflexia of the Legs in a Nepalese Patient with Friedreich At
Hiroya Naruse, Yuji Takahashi, Hiroyuki Ishiura, Takashi Matsukawa, Jun Mitsui, Yaeko Ichikawa, Masashi Hamada, Jun Shimizu, Jun Goto, Tatsushi Toda, Shoji Tsuji, axia, Internal Medicine, Article ID 2953-19, [Advance publication] Released June 07, 2019, Online ISSN 1349-7235, Print ISSN 0918-2918, doi:10.2169/internalmedicine.2953-19,
Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.
Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.
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