Tuesday, September 26, 2017

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Brian Feingold, William T. Mahle, Scott Auerbach, Paula Clemens, Andrea A. Domenighetti, John L. Jefferies, Daniel P. Judge, Ashwin K. Lal, Larry W. Markham, W. James Parks, Takeshi Tsuda, Paul J. Wang, Shi-Joon Yoo
and On behalf of the American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council; Circulation. 2017;136:e200-e231 doi:10.1161/CIR.0000000000000526

For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions.
Cardiac manifestations consist of LV hypertrophy with fibrosis and scarring, arrhythmias, and progressive HF. Cardiac dysfunction is the most frequent cause of death in FA.
Because no relationship between severity of cardiac involvement and neurological status has been identified, regular cardiac evaluation regardless of neurological status is likely warranted.

Sunday, September 24, 2017

Diabetes mellitus as the presenting feature of Friedreich's ataxia

Garg M, Kulkarni SD, Shah KN, Hegde AU. J Neurosci Rural Pract 2017;8, Suppl S1:117-9 DOI: 10.4103/jnrp.jnrp_112_17

This is an unusual report of diabetes as the initial presentation in a patient with FA. This patient has also shown accelerated course of disease. However, the genetic mechanisms accounting for phenotypic variations in FA remain to be fully elucidated. In patients with diabetes who present with early sensory neuropathy or ataxia, FA should be a consideration even in the pediatric age group. A better understanding of molecular mechanisms will certainly pave the way for improved therapeutic strategies in the near future.

Saturday, September 23, 2017

Lipophilic methylene violet analogues as modulators of mitochondrial function and dysfunction

Sandipan Roy Chowdhury, Omar M. Khdour, Indrajit Bandyopadhyay, Sidney M. Hecht. In Bioorganic & Medicinal Chemistry, 2017,ISSN 0968-0896, doi:10.1016/j.bmc.2017.08.021.

The methylene violet analogues were evaluated for their ability to preserve mitochondrial function in Friedreich’s ataxia (FRDA) lymphocytes. The analogues were shown to be efficient ROS scavengers, and able to protect cultured FRDA lymphocytes from oxidative stress resulting from inhibition of complex I. The analogues also preserved mitochondrial membrane potential and augmented ATP production. The analogues were found to be better antioxidants than the parent compounds methylene blue and methylene violet.

Keywords: Methylene blue; Methylene violet; Mitochondria; Reactive oxygen species; Friedreich’s ataxia; Cytoprotection

Friday, September 22, 2017

Manuela Corti, assistant professor in the department of pediatrics at the University of Florida in Gainesville, was awarded an MDA research grant totaling $298,954 over three years to study gene therapy in Friedreich’s ataxia (FA).

Source: MDA.org, 09/21/2017.

Our objective is to develop a treatment strategy for FA, one of the most common forms of ataxia. Specifically, our research plan focuses on the correction of both the cardiac and neurological degeneration found in the disease. These changes are due to harmful changes in the frataxin gene.
This work will specifically answer important mechanistic questions in a new FA mouse model, which has many of the symptoms of the human patients. First, we will identify the best route of delivery for the frataxin gene in the nervous system by comparing three different strategies for injecting the vector (delivery vehicle). Second, we will test the safety of repeated delivery of the frataxin gene vector in combination with medications that will prevent reactions against the frataxin protein and the vector components. Completion of this project will be an important milestone in the development of a treatment strategy that will dramatically improve quality of life for FA patients.

Bioavailability of resveratrol: Possibilities for enhancement

Konrad de Vries, Morné Strydom, Vanessa Steenkamp, Journal of Herbal Medicine, Available online 12 September 2017, ISSN 2210-8033, doi:10.1016/j.hermed.2017.09.002.

Resveratrol is a naturally occurring polyphenol that has been shown to elicit a variety of beneficial effects in vitro. Translating these gains to in vivo and clinical settings has proven to be a major challenge, because of its poor oral bioavailability. This caveat was confirmed after reviewing clinical trials conducted on this investigational product over the past two years. This review provides alternative methods of administration of resveratrol which may enhance its bioavailability. However, these methods: remain to be validated.
From current literature, it is clear that orally administered resveratrol has low bioavailability in vivo. A variety of methods that could overcome the inherent issues with resveratrol bioavailability have been proposed, however these need to be further validated in order to determine which are safe, effective and superior to traditional oral administration of resveratrol before clinical evaluation can take place.

Thursday, September 21, 2017

Friedreich Ataxia: Treatment with Genetic Approach

Martin L. Nelwan, Journal of Advances in Biology & Biotechnology, 2394-1081,Vol.: 14, Issue.: 4

Adequate treatments are unavailable for this disorder at present. However, to treat FA, genetic approach can be used. The approach may comprise genetic counseling and use of advanced therapy, gene therapy for instance. 

Wednesday, September 20, 2017

Molecular Alterations in a Mouse Cardiac Model of Friedreich’s Ataxia: An Impaired Nrf2 Response Mediated via Up-Regulation of Keap1 and Activation of the Gsk3β Axis

Amy Anzovino, Shannon Chiang, Bronwyn E. Brown, Clare L. Hawkins, Des R. Richardson, Michael L.-H. Huang, The American Journal of Pathology, Available online 19 September 2017, ISSN 0002-9440,  doi:10.1016/j.ajpath.2017.08.021.

Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich’s ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms.
Collectively, cardiac frataxin-deficiency reduces Nrf2 levels via two potential mechanisms: increased levels of cytosolic Keap1, and activation of Gsk3β-signaling that decreases nuclear Nrf2. These findings are in contrast to the frataxin-deficient skeletal muscle, where Nrf2 was not decreased.

Tuesday, September 19, 2017

Movement disorders hidden in the neuromuscular clinic

J. Reimann, S. Paus, Neuromuscular Disorders, Volume 27, Supplement 2, October 2017, Page S243, ISSN 0960-8966, doi:10.1016/j.nmd.2017.06.531.

We present these exemplary cases to increase awareness of these disorders and the differential diagnosis for those working in neuromuscular clinics, as well as an incentive for more interaction with the movement disorder field, in particular when struggling to define a diagnosis. We also observe a number of referrals that turn out to be movement disorders. In some, this is caused by known neuromuscular manifestations while missing the CNS signs. Examples are our cases of Huntington’s disease presenting with weakness, pain and atrophy of the calves and of Friedreich ataxia send for work-up of sensory axonal neuropathy and scoliosis, where “restlessness” and “nasal speech”, respectively, were ignored as symptoms. In others, the attribution of the pathophysiology to muscle is simply wrong.

Monday, September 18, 2017

Relationship Between Neurological Disability and Visual Impairment in Patients With ALS or Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT03285204, First received: March 8, 2017
Principal Investigator: Jose L Urcelay, PhD HGU Gregorio Marañón.
Location: Madrid, Spain,

The aim of this study is to obtain an early biomarker of amyotrophic lateral sclerosis and Friedreich's Ataxia which allows to diagnose the disease in an initial stage and to follow up the patient with optic coherence tomography, a fast, non-invasive and comfortable method.

Saturday, September 16, 2017

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots

Shao-Hua Yang, Wenjun Li, Nathalie Sumien, Michael Forster, James W. Simpkins, Ran Liu, In Progress in Neurobiology, Volume 157, 2017, Pages 273-291, ISSN 0301-0082, doi:10.1016/j.pneurobio.2015.10.005.

Reprogramming energetic metabolism is a common feature for neurodegenerative diseases and cancers.
Methylene blue functions as an alternative mitochondrial electron transfer carrier, enhancing bioenergetics and inhibiting biosynthetics.
Methylene blue provides protective effect in rodent models of Parkinson disease, Alzheimer's disease, Huntington's disease, and Friedreich's ataxia.
Methylene blue reverses Warburg's effect and inhibits cancers proliferation.
Alternative mitochondrial electron transfer may provide a common novel therapeutic mechanism for cancers and neurodegenerative diseases.