Julianna E. Shinnick, Kimberly Schadt, Cassandra Strawser, Nicholas Wilcox, Susan L. Perlman, George R. Wilmot, Christopher M. Gomez, Katherine D. Mathews, Grace Yoon, Theresa Zesiewicz, Chad Hoyle, S. H. Subramony, Eppie M. Yiu, Martin B. Delatycki, Alicia F. Brocht, Jennifer M. Farmer, and David R. Lynch; J Child Neurol 0883073816643408, first published on April 12, 2016 as doi:10.1177/0883073816643408
Diagnoses with more than twice the prevalence in this Friedreich ataxia cohort than the general population were growth hormone deficiency, ulcerative colitis, Crohn’s disease, and inflammatory bowel disease. However, patients with Friedreich ataxia did not have a higher incidence of other neurological disorders such as epilepsy or migraine; other sleep disorders besides sleep apnea; other cardiovascular disorders such as coronary artery disease, hypercholesterolemia, or hypertension; or psychiatric disorders such as anxiety
Friday, April 15, 2016
Thursday, April 14, 2016
Researchers from Mount Sinai and Sage Bionetworks Report Analysis of Nearly 600,000 Genomes for Resilience Project
Icahn School of Medicine at Mount Sinai, New York, NY – April 11, 2016 /Press Release/ ––
As part of a global collaboration, scientists from the Icahn School of Medicine at Mount Sinai and Sage Bionetworks conducted the largest genome study to date and reported the first systematic search across hundreds of Mendelian disorders in hundreds of thousands of individuals apparently not afflicted with any of these disorders to identify those carrying disease protective factors. Genome analysis of these resilient people could uncover naturally occurring, protective mechanisms that would serve as novel treatments for people affected by these diseases.
In this study, researchers analyzed DNA from 12 previously collected data sets, using a newly developed targeted sequencing panel to screen 874 genes for 584 distinct genetic diseases. The diseases, which were mostly metabolic conditions, neurological diseases, or developmental disorders, present in childhood with severe symptoms. All genomes analyzed were from adults who had never been diagnosed with any of these diseases. A sophisticated, in-depth analysis process identified 13 healthy people with genetic variants associated with eight diseases.
As part of a global collaboration, scientists from the Icahn School of Medicine at Mount Sinai and Sage Bionetworks conducted the largest genome study to date and reported the first systematic search across hundreds of Mendelian disorders in hundreds of thousands of individuals apparently not afflicted with any of these disorders to identify those carrying disease protective factors. Genome analysis of these resilient people could uncover naturally occurring, protective mechanisms that would serve as novel treatments for people affected by these diseases.
In this study, researchers analyzed DNA from 12 previously collected data sets, using a newly developed targeted sequencing panel to screen 874 genes for 584 distinct genetic diseases. The diseases, which were mostly metabolic conditions, neurological diseases, or developmental disorders, present in childhood with severe symptoms. All genomes analyzed were from adults who had never been diagnosed with any of these diseases. A sophisticated, in-depth analysis process identified 13 healthy people with genetic variants associated with eight diseases.
Wednesday, April 13, 2016
Italian program for independent research on drugs: 10 year follow-up of funded studies in the area of rare diseases
Giuseppe Traversa, Lucia Masiero, Luciano Sagliocca and Francesco Trotta. Orphanet Journal of Rare Diseases 2016 11:36 DOI: 10.1186/s13023-016-0420-4
OPEN ACCESS
Our data suggest that adequately powered randomized trials can represent the gold standard also for rare diseases. There are also important implications for clinical practice, as can be expected by projects characterized by clinical endpoints and extensive follow-up. It is unlikely that many of these studies may have been conducted in a for profit perspective, given the absence of commercial interest.
We documented that, even though it takes time to set up and conduct a funding program for independent research, the overall results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest.
OPEN ACCESS
Our data suggest that adequately powered randomized trials can represent the gold standard also for rare diseases. There are also important implications for clinical practice, as can be expected by projects characterized by clinical endpoints and extensive follow-up. It is unlikely that many of these studies may have been conducted in a for profit perspective, given the absence of commercial interest.
We documented that, even though it takes time to set up and conduct a funding program for independent research, the overall results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest.
Tuesday, April 12, 2016
Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions
Alexandra Essebier, Patricia Vera Wolf, Minh Duc Cao, Bernard J. Carroll, Sureshkumar Balasubramanian and Mikael Bodén, Front. Neurosci., 08 March 2016 doi:10.3389/fnins.2016.00092
Friedreich ataxia (FRDA) is a loss-of-function disease caused by an expanded intronic GAA repeat in the Frataxin (FXN) gene, and in our analysis it displayed the greatest number of epigenetic marks in its distance profile. Based on our statistical analyses of epigenetic marks around the repeat, specific hypotheses can be drawn to address this transition. For example, this is consistent with the findings that suggest that the inhibitors of histone deacetylase increase FXN expression levels. It would be interesting to assess whether blocking histone methyl transferase to prevent H3K9ac and H3K27ac would promote the stability of the GAA repeat.
Friedreich ataxia (FRDA) is a loss-of-function disease caused by an expanded intronic GAA repeat in the Frataxin (FXN) gene, and in our analysis it displayed the greatest number of epigenetic marks in its distance profile. Based on our statistical analyses of epigenetic marks around the repeat, specific hypotheses can be drawn to address this transition. For example, this is consistent with the findings that suggest that the inhibitors of histone deacetylase increase FXN expression levels. It would be interesting to assess whether blocking histone methyl transferase to prevent H3K9ac and H3K27ac would promote the stability of the GAA repeat.
Monday, April 11, 2016
Roles of Fe–S proteins: from cofactor synthesis to iron homeostasis to protein synthesis
Debkumar Pain, Andrew Dancis, Current Opinion in Genetics & Development, Volume 38, June 2016, Pages 45-51, ISSN 0959-437X, doi:10.1016/j.gde.2016.03.006.
Impairment of Fe–S cluster assembly creates diseases in diverse and surprising ways: the loss of function of lipoic acid synthase, the heme biosynthetic pathway in red cell precursors is specifically targeted and tRNA modifications arising from action of the cysteine desulfurase and/or Fe–S cluster proteins are lost. These defects can then result in cancer, neurologic dysfunction or type 2 diabetes.
Impairment of Fe–S cluster assembly creates diseases in diverse and surprising ways: the loss of function of lipoic acid synthase, the heme biosynthetic pathway in red cell precursors is specifically targeted and tRNA modifications arising from action of the cysteine desulfurase and/or Fe–S cluster proteins are lost. These defects can then result in cancer, neurologic dysfunction or type 2 diabetes.
Sunday, April 10, 2016
The Structure of the Complex Between Yeast Frataxin and Ferrochelatase: Characterization and pre-Steady State Reaction of Ferrous Iron Delivery and Heme Synthesis
Christopher G. Soderberg, Mallory E. Gillam, Eva-Christina Ahlgren, Gregory A. Hunter, Oleksandr Gakh, Grazia Isaya, Gloria C. Ferreira and Salam Al-Karadaghi, The Journal of biological chemistry: 2016 First Published on March 29, 2016, doi: 10.1074/jbc.M115.701128
They support the proposal that frataxin-mediated delivery of this potentially toxic substrate (Fe2+)overcomes formation of reactive oxygen species.
They support the proposal that frataxin-mediated delivery of this potentially toxic substrate (Fe2+)overcomes formation of reactive oxygen species.
Saturday, April 9, 2016
Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia
Charles J. Isaacs BA, Karlla W. Brigatti MS, Olena Kucheruk RN MPH, Sarah Ratcliffe PhD, Tom Sciascia MD, Shana E. McCormack MD, Steven M. Willi MD and David R. Lynch MD PhD, Muscle & Nerve, Accepted manuscript online: 7 APR 2016 DOI: 10.1002/mus.25136
Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient.
Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient.
Friday, April 8, 2016
Accessing the accelerated approval pathway for rare disease therapeutics
Emil D Kakkis, Sara Kowalcyk & Max G Bronstein, Nature Biotechnology 34, 380–383 (2016) doi:10.1038/nbt.3530
Improvements must be made to the qualification process for biomarkers as primary endpoints in pivotal clinical studies of treatments for the rarest of diseases.
Improvements must be made to the qualification process for biomarkers as primary endpoints in pivotal clinical studies of treatments for the rarest of diseases.
Thursday, April 7, 2016
Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie
Abnormal eye movements: Etiologic/topographic diagnostic tool in neurology / Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie
FMC, Volume 7, Issue 1, February 2016, Pages 16-24, ISSN 1878-7762, doi:10.1016/j.praneu.2015.12.003.
Acquired neurological nystagmus and other abnormal eye movements may be valuable diagnostic tools. We provide a “practical” approach, with the objective of highlighting for neurologists the importance of abnormal eye movement observation in order to improve the subtlety of clinical diagnosis.
Les nystagmus acquis centraux ou les autres types de mouvements oculaires anormaux d’origine neurologique ont pour certains une valeur séméiologique intéressante. Nous proposons une approche « pratique » visant à sensibiliser le neurologue à l’observation de mouvements oculaires anormaux pour améliorer la finesse du diagnostic clinique.
FMC, Volume 7, Issue 1, February 2016, Pages 16-24, ISSN 1878-7762, doi:10.1016/j.praneu.2015.12.003.
Acquired neurological nystagmus and other abnormal eye movements may be valuable diagnostic tools. We provide a “practical” approach, with the objective of highlighting for neurologists the importance of abnormal eye movement observation in order to improve the subtlety of clinical diagnosis.
Les nystagmus acquis centraux ou les autres types de mouvements oculaires anormaux d’origine neurologique ont pour certains une valeur séméiologique intéressante. Nous proposons une approche « pratique » visant à sensibiliser le neurologue à l’observation de mouvements oculaires anormaux pour améliorer la finesse du diagnostic clinique.
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