Angela D. Bhalla, Alireza Khodadadi-Jamayran, Yanjie Li, David R. Lynch and Marek Napierala. Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.322
Open access Creative Commons Attribution-NonCommercial-NoDerivs License
Next-generation sequencing of FRDA mitochondrial genomes revealed a widespread increase in mutation load in patient fibroblasts. Although mtDNA damage alone can have profound consequences within the cell, low expression of FXN may also affect the nuclear genome as recent studies have demonstrated shortening of telomeres in cells derived from FRDA patients.
Friday, June 17, 2016
Thursday, June 16, 2016
Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders
R. Brian Sommerville, Margherita Guzzi Vincenti, Kathleen Winborn, Anne Casey, Nathan O. Stitziel, Anne M. Connolly, Douglas L. Mann, Trends in Cardiovascular Medicine, Available online 14 June 2016, ISSN 1050-1738, Doi:10.1016/j.tcm.2016.06.005.
We advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients.
Friedreich Ataxia: Although progressive debilitating ataxia is the most prominent clinical finding in FRDA and generally precedes the onset of cardiac symptoms, heart failure and arrhythmias account for at least 60% of the mortality in FRDA. Importantly, in patients with advanced neurological disease, a subclinical hypertrophic cardiomyopathy may be present despite the absence of overt cardiac symptoms.
We advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients.
Friedreich Ataxia: Although progressive debilitating ataxia is the most prominent clinical finding in FRDA and generally precedes the onset of cardiac symptoms, heart failure and arrhythmias account for at least 60% of the mortality in FRDA. Importantly, in patients with advanced neurological disease, a subclinical hypertrophic cardiomyopathy may be present despite the absence of overt cardiac symptoms.
Wednesday, June 15, 2016
Obstructive Form of Hypertrophic Cardiomyopathy-Left Ventricular Outflow Tract Gradient: Novel Methods of Provocation, Monitoring of Biomarkers, and Recent Advances in the Treatment.
Pawel Petkow Dimitrow and Renata Rajtar-Salwa. Biomed Res Int. 2016; 2016: 1575130. Published online 2016 May 10. doi: 10.1155/2016/1575130
Open access article distributed under the Creative Commons Attribution License
From a practical point of view, the effective monitoring, including biochemical biomarkers indicating reduction of LVOT gradient, is important because this parameter has become a risk factor for sudden death in the 2014 ESC guideline. In this context, the maximized physiological LVOT gradient provocation stimulus seems to be an important diagnostic element. Novel invasive therapeutic techniques have been recently dynamically developed, providing attractive treatment opportunities.
Septal myectomy may be a viable option to relieve symptoms and interrupt progression of heart disease also in selected Friedreich's ataxia patients.
Open access article distributed under the Creative Commons Attribution License
From a practical point of view, the effective monitoring, including biochemical biomarkers indicating reduction of LVOT gradient, is important because this parameter has become a risk factor for sudden death in the 2014 ESC guideline. In this context, the maximized physiological LVOT gradient provocation stimulus seems to be an important diagnostic element. Novel invasive therapeutic techniques have been recently dynamically developed, providing attractive treatment opportunities.
Septal myectomy may be a viable option to relieve symptoms and interrupt progression of heart disease also in selected Friedreich's ataxia patients.
Tuesday, June 14, 2016
STEADFAST Long-Term Safety Extension
ClinicalTrials.gov. First received: June 2, 2016. ClinicalTrials.gov Identifier: NCT02797080. Sponsor: Horizon Pharma Ireland, Ltd., Dublin Ireland.
Official Title: Long-Term Safety Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich's Ataxia
Phase 3
ACTIMMUNE® will be administered three times per week by subcutaneous injection. The initial dose will be individualized for each participant and will be determined by the investigator, provided that the initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302 (NCT02593773). The investigator may subsequently adjust the dose for any participant if deemed clinically appropriate, provided that the dose does not exceed 100 μg/m2.
Official Title: Long-Term Safety Extension Study of ACTIMMUNE® (Interferon γ-1b) in Children and Young Adults With Friedreich's Ataxia
Phase 3
ACTIMMUNE® will be administered three times per week by subcutaneous injection. The initial dose will be individualized for each participant and will be determined by the investigator, provided that the initial dose does not exceed the maximum tolerated dose in HZNP-ACT-302 (NCT02593773). The investigator may subsequently adjust the dose for any participant if deemed clinically appropriate, provided that the dose does not exceed 100 μg/m2.
Monday, June 13, 2016
Oxidative Stress and altered lipid metabolism in Friedreich ataxia
Jordi Tamarit, Èlia Obis, Joaquim Ros, Free Radical Biology and Medicine, Available online 11 June 2016, ISSN 0891-5849, doi: 10.1016/j.freeradbiomed.2016.06.007.
Lipid metabolism is compromised in FA and therefore is emerging as a new potential therapeutic target. Current approaches are also meant to restore mitochondrial function, improve energy metabolism and decrease oxidative stress. Ongoing clinical trials will reveal the potential of these therapeutic strategies to attenuate disease progression.
Lipid metabolism is compromised in FA and therefore is emerging as a new potential therapeutic target. Current approaches are also meant to restore mitochondrial function, improve energy metabolism and decrease oxidative stress. Ongoing clinical trials will reveal the potential of these therapeutic strategies to attenuate disease progression.
Saturday, June 11, 2016
Classifications of neurogenetic diseases: An increasingly complex problem
J.-M. Vallat, C. Goizet, M. Tazir, P. Couratier, L. Magy, S. Mathis. Revue Neurologique, Available online 27 May 2016, ISSN 0035-3787, doi:org/10.1016/j.neurol.2016.04.005.
Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases.
The nomenclature used in each case also requires the name of the mutated gene: for example Friedreich’s ataxia becomes ‘‘AR-CA-FXN’’. Nevertheless, these designations could allow some exceptions to be retained, such as names that are very well known, such as Friedreich’s ataxia and ataxia–telangiectasia.
Neurodegenerative disorders represent a wide group of diseases affecting the central and/or peripheral nervous system. Many of these disorders were described in the 19th century, but our genetic knowledge of them is recent (over the past 25 years). However, the continual discovery of disease-causing gene mutations has led to difficulties in the classification of these diseases.
The nomenclature used in each case also requires the name of the mutated gene: for example Friedreich’s ataxia becomes ‘‘AR-CA-FXN’’. Nevertheless, these designations could allow some exceptions to be retained, such as names that are very well known, such as Friedreich’s ataxia and ataxia–telangiectasia.
Friday, June 10, 2016
NRF2 activators: how do they work and how advanced is their clinical use?
Antonio Cuadrado, Free Radical Biology and Medicine, Volume 96, Supplement 1, July 2016, Pages S6-S7, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.04.043
The transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of cell homeostasis that regulates the expression of antioxidant and cytoprotective genes. The synthetic triterpenoid CDDO-methyl ester (also known as bardoxolone methyl) is being studied for therapy of diabetic nephropathy, pulmonary arterial hypertension, melanoma and Friedreich ataxia.
The transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of cell homeostasis that regulates the expression of antioxidant and cytoprotective genes. The synthetic triterpenoid CDDO-methyl ester (also known as bardoxolone methyl) is being studied for therapy of diabetic nephropathy, pulmonary arterial hypertension, melanoma and Friedreich ataxia.
Thursday, June 9, 2016
Responsible implementation of expanded carrier screening
Lidewij Henneman, Pascal Borry, Davit Chokoshvili, Martina C Cornel, Carla G van El, Francesca Forzano, Alison Hall, Heidi C Howard, Sandra Janssens, Hülya Kayserili, Phillis Lakeman, Anneke Lucassen, Sylvia A Metcalfe, Lovro Vidmar, Guido de Wert, Wybo J Dondorp and Borut Peterlin on behalf of the European Society of Human Genetics (ESHG).European Journal of Human Genetics (2016) 24, e1–e12; doi:10.1038/ejhg.2015.271; published online 16 March 2016
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
There are currently 1300 known recessive (autosomal and X-linked) diseases and about 100 of these have a prevalence of >1/100 000. Several important conditions, for example, Duchenne/Becker muscular dystrophy and Friedreich ataxia are not included in any of the commercial panels, presumably due to technological limitations of the microarray-based testing approach (eg, trinucleotide repeat mutations). We propose that, pending convincing evidence to the contrary, retaining a ‘serious congenital and childhood onset disorders’ scope is important in panel design.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
There are currently 1300 known recessive (autosomal and X-linked) diseases and about 100 of these have a prevalence of >1/100 000. Several important conditions, for example, Duchenne/Becker muscular dystrophy and Friedreich ataxia are not included in any of the commercial panels, presumably due to technological limitations of the microarray-based testing approach (eg, trinucleotide repeat mutations). We propose that, pending convincing evidence to the contrary, retaining a ‘serious congenital and childhood onset disorders’ scope is important in panel design.
Wednesday, June 8, 2016
Histone deacetylase inhibitors modulating non-epigenetic players: The novel molecular targets for therapeutic intervention
Shabir Ahmad Ganai. Current Drug Targets, Volume 17 DOI: 10.2174/1389450117666160527143257
Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-кB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer.
Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-кB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer.
Tuesday, June 7, 2016
Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers
T. Morel, S. Aymé, D. Cassiman, S. Simoens, M. Morgan and M. Vandebroek. Orphanet Journal of Rare Diseases 2016 DOI: 10.1186/s13023-016-0444-9
This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.
Our study data confirmed that patients and their caregivers were willing to accept greater risk or side effects associated with a new medicine, for instance, in the hope for some extra chance in drug response or greater health improvement potential. Attitudes about benefit-risk may change over time with disease progression or context of care.
In that context, we believe that patients and caregivers should be increasingly involved as active research partners in the development of clinical outcomes assessments – including patient-reported outcomes (PRO) measures – that directly evaluate how the patient feels, functions or survives. If a treatment effect is not meaningful to the patient, it is not a benefit to the patient.
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.
Our study data confirmed that patients and their caregivers were willing to accept greater risk or side effects associated with a new medicine, for instance, in the hope for some extra chance in drug response or greater health improvement potential. Attitudes about benefit-risk may change over time with disease progression or context of care.
In that context, we believe that patients and caregivers should be increasingly involved as active research partners in the development of clinical outcomes assessments – including patient-reported outcomes (PRO) measures – that directly evaluate how the patient feels, functions or survives. If a treatment effect is not meaningful to the patient, it is not a benefit to the patient.
Open Access
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/)
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