Lynch DR, McCormick A, Schadt K, Kichula E.; Semin Pediatr Neurol. 2018 Apr;25:54-64. doi: 10.1016/j.spen.2018.01.001.
FRDA is the most common ataxia, and its phenotype is readily recognized. In children of typical age, it is frequently possible to diagnose FRDA by examination and genetic testing without the need for adjunctive tests (MRI and EMG). Genetic confirmation is required for diagnosis. In addition, one must remember that all patients with FRDA identified have at least one expanded GAA repeat. Thus GAA repeat expansion testing should occur before sequencing for point mutations. (This is a common mistake in genetic testing). Currently, genetic panels and exome sequencing does not include the ability to test for repeats, so this testing must be requested separately.
Thursday, May 17, 2018
DNA triplex structure, thermodynamics, and destabilisation: insight from molecular simulations
Belinda J. Boehm, Charles Whidborne, Alexander L. Button, Tara L. Pukala and David M. Huang; Phys Chem Chem Phys. 2018 May 10. doi: 10.1039/c8cp02385a
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
A structural analysis of the DNA triplexes that can form with the FRDA-related duplex sequence indicates that the triplex with a parallel homopyrimidine TFO is likely to be more stable than the antiparallel homopurine-TFO triplex, which may have implications for disease onset and treatment.
Cardiovascular and sudomotor autonomic assessment in Friedreich’s Ataxia
Karen A. Girotto Takazaki, Alberto Martinez, Thiago Junqueira Rezende, Carelis González-Salazar, Anamarli Nucci, Iscia Lopes-Cendes, Marcondes C. Franca; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e86
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
doi:10.1016/j.clinph.2018.04.216
Sudomotor, but not cardiovascular autonomic dysfunction is frequent in FDRA. Small cholinergic post-ganglionic nerve fibers are affected in the disease.
Peripheral nerve ultrasound in Friedreich’s ataxia
Eoin Mulroy, Luciana Pelosi, Ruth Leadbetter, Purwa Joshi, Miriam Rodrigues, Stuart Mossman, Dean Kilfoyle, Richard Roxburgh; Clinical Neurophysiology, Volume 129, Supplement 1, May 2018, Pages e167-e168 doi:10.1016/j.clinph.2018.04.429
Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.
Our findings add further weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are likely to also play a role.
The dys-regulation of anti-oxidant defense via an impairment of Nrf2 response in the pathology of Friedreich’s ataxia
Shannon Chiang, Amy Anzovino, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang; Free Radical Biology and Medicine, Volume 120, Supplement 1, 20 May 2018, Pages S35 doi:10.1016/j.freeradbiomed.2018.04.120
The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.
The transcription factor, nuclear factor-erythroid 2-related factor-2 (Nrf2), is the master regulator of antioxidant response. Decreased Nrf2 expression was previously reported in studies with models of the neuro-and cardio-degenerative disease, Friedreich’s ataxia (FA), where oxidative stress is a key contributor to its pathology. Using a mouse conditional frataxin knockout (KO) model, we examined the Nrf2 pathway in the frataxin-deficient heart and skeletal muscle. In the KO heart, our studies have demonstrated increased protein and GSH oxidation, decreased total and nuclear Nrf2 levels, and increased expression of its inhibitor, Keap1. However, the opposite was found in skeletal muscle. The activation of nuclear Nrf2 export/degradation machinery via Gsk3f3-signaling was demonstrated in the KO heart through the process of: (i) increased Gsk3f3 activation; (ii) f3-TrCP nuclear accumulation; and (iii) Fyn phosphorylation. This corresponded with decreased Nrf2-DNA-binding activity and a general decrease in Nrf2-target mRNA in KO hearts. Overall, increased levels of cytosolic Keap1, and activation of Gsk3f3-signaling are potential mechanisms for the decreased Nrf2 levels in the frataxin-deficient Heart, in contrast to skeletal muscle, where Nrf2 was not decreased.
A CRISPR/TALEN-mediated gene editing approach for the Frataxin gene
Silvia Zaccagnino. Edizioni Accademiche Italiane, ISBN: 978-3-330-77664-7
Development and characterization of a new Friedreich Ataxia cellular model
Development and characterization of a new Friedreich Ataxia cellular model
Rapid and complete reversal of sensory ataxia by gene therapy in a novel model of Friedreich ataxia
Françoise Piguet, Charline de Montigny, Nadège Vaucamps, Laurence Reutenauer, Aurélie Eisenmann, Hélène Puccio, Molecular Therapy , Volume 0 , Issue 0 , DOI: 10.1016/j.ymthe.2018.05.006
Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin positive cells which recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, proprioceptive neurons can survive for many weeks without frataxin, although fully dysfunctional. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue the sensory neuropathy associated with frataxin deficiency, thus establishing the preclinical proof of concept for the potential of gene therapy in treating FA neuropathy.
Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin positive cells which recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, proprioceptive neurons can survive for many weeks without frataxin, although fully dysfunctional. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue the sensory neuropathy associated with frataxin deficiency, thus establishing the preclinical proof of concept for the potential of gene therapy in treating FA neuropathy.
Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry
Angeliki Pappa, Martin G. Häusler, Andreas Veigel, Konstantina Tzamouranis, Martin W. Pfeifer, Andreas Schmidt, Martin Bökamp, Holger Haberland, Siegfried Wagner, Joachim Brückel, Gideon de Sousa, Lukas Hackl, Esther Bollow, Reinhard W Holl, Diabetes Res Clin Pract. 2018 May 12. pii: S0168-8227(17)32029-6 DOI: 10.1016/j.diabres.2018.05.008
Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ±165 and 384± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups.
FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ±165 and 384± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups.
FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
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