José Luis García-Giménez, Gisselle Pérez-Machado, Jesús Beltrán-García, Eva García-López, Ester Berenguer-Pascual, Carlos Romá-Mateo, Federico Pallaró, Salvador Mena-Mollá; GENÉTICA MÉDICA · 14 de marzo de 2018 Núm.00 Vol.0 Genética Médica y Genómica revistageneticamedica.com
La práctica clínica requiere de nuevas técnicas que permitan la identificación de los individuos en riesgo de desarrollar una enfermedad mediante su detección eficaz y precoz, pero la clínica también necesita de herramientas que permitan predecir la evolución de la patología a lo largo del tiempo, así como su respuesta frente a un tratamiento. En la actualidad, los principales indicadores clínicos se basan en técnicas de imagen y ciertos biomarcadores que presentan limitaciones y que, en algunos casos, los biomarcadores epigenéticos han demostrado superar.
La comprensión de los mecanismos epigenéticos (metilación del ADN, modulación de las modificaciones postraduccionales de las histonas, y los ARN no codificantes) ha permitido que en las últimas décadas aparezcan multitud de nuevos candidatos para su uso como biomarcadores de diagnóstico y pronóstico de las enfermedades. Por eso, en esta revisión describimos los fundamentos de algunos biomarcadores epigenéticos y algunas técnicas y tecnologías que se están utilizando para su detección.
En un futuro cercano, este tipo de tecnologías se incorporarán a los laboratorios clínicos y, por lo tanto, el uso de estos biomarcadores se implementará en la rutina de diagnóstico clínico, contribuyendo así a la aplicación real de la teragnosis y mejorando la medicina de precisión.
EN
Epigenetic biomarkers: towards their incorporation into clinical routine
Clinical routine requires novel techniques in order to guarantee the identification of individuals in risk of developing a disease, in terms of an efficient and early detection; however, clinical management also needs tools that permit prediction of the long-term pathological evolution, as well as its response to any particular treatment. Currently, the main clinical indicators are based in imaging techniques and certain biomarkers, which show several limitations that, to some extent, biomarkers of an epigenetic nature have shown to overcome.
Comprehension of epigenetic mechanisms (i.e. DNA methylation, modulation of posttranslational histone modifications, and non-coding RNAs) has provided the apparition, in the last decades, of multiple new candidates for their use as diagnostic and prognostic biomarkers. Thus, in this review we describe some epigenetic biomarkers and several techniques and technologies which are being used for their detection.
In the near future, this type of technologies will be incorporated into clinical laboratories and, hence, the use of these biomarkers will be implemented into clinical diagnostic routine, contributing to the real application of theragnosis and improving precision medicine.
Thursday, March 15, 2018
Wednesday, March 14, 2018
Large-scale computational drug repositioning to find treatments for rare diseases
Rajiv Gandhi Govindaraj, Misagh Naderi, Manali Singha, Jeffrey Lemoine & Michal Brylinski. npj Systems Biology and Applications 4, Article number: 13 (2018) doi:10.1038/s41540-018-0050-7
Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases.
Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed eMatchSite, a new computer program to compare drug-binding sites. In this study, eMatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases.
Genetic testing for clinically suspected spinocerebellar ataxias: report from a tertiary referral centre in India
Sowmya Devatha Venkatesh, Mahesh Kandasamy, Nagaraj S. Moily, Radhika Vaidyanathan, Lakshmi Narayanan Kota, Syama Adhikarla, Ravi Yadav, Pramod Kumar Pal, Sanjeev Jain, Meera Purushottam. J Genet (2018). doi:10.1007/s12041-018-0911-2
The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (n=100 (11.6%)) and SCA2 (n=98 (11.3%)) followed by SCA3 (n=40 (4.6%)), FRDA (n=20 (2.3%)) and SCA12 (n=8 (0.9%)).
The prevalence of the syndromes of SCA varies across the world and is known to be linked to the instability of trinucleotide repeats within the high-end normal alleles, along with susceptible haplotype. We estimated sizes of the CAG or GAA repeat expansions at the SCA1, SCA2, SCA3, SCA12 and frataxin loci among 864 referrals of subjects to genetic counselling and testing (GCAT) clinic, National Institute of Mental Health and Neurosciences, Bengaluru, India, with suspected SCA. The most frequent mutations detected were SCA1 (n=100 (11.6%)) and SCA2 (n=98 (11.3%)) followed by SCA3 (n=40 (4.6%)), FRDA (n=20 (2.3%)) and SCA12 (n=8 (0.9%)).
Tuesday, March 13, 2018
Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice
Kevin C Kemp, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark A Pook, Claire M Rice, Neil J Scolding and Alastair Wilkins; Annals of Neurology, Accepted manuscript online: 13 MAR 2018 DOI: 10.1002/ana.25207
Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation.
Our data provide proof-of-concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation.
Sunday, March 11, 2018
New Insights into the Role of Neuron-Specific Enolase in Neuro-Inflammation, Neurodegeneration, and Neuroprotection.
Haque A, Polcyn R, Matzelle D, Banik NL. Brain Sci. 2018 Feb;8(2) . doi:10.3390/brainsci8020033. PMID: 29463007; PMCID: PMC5836052.
Elevated NSE is thought to be a marker of oxidative damage and is the underlying parameter of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, rare familial forms Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS).
Regulation of NSE via Cat X or other avenues may be important therapeutic strategies for prevention of inflammation and neurodegeneration in SCI and many other neurodegenerative diseases. Future studies should focus on the regulation of NSE for optimum attenuation of neuro-inflammation and promotion of neuroprotection in neurodegenerative conditions.
Elevated NSE is thought to be a marker of oxidative damage and is the underlying parameter of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, rare familial forms Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS).
Regulation of NSE via Cat X or other avenues may be important therapeutic strategies for prevention of inflammation and neurodegeneration in SCI and many other neurodegenerative diseases. Future studies should focus on the regulation of NSE for optimum attenuation of neuro-inflammation and promotion of neuroprotection in neurodegenerative conditions.
Saturday, March 10, 2018
Pitfalls in molecular diagnosis of Friedreich ataxia
Giulia Barcia, Myriam Rachid, Maryse Magen, Zahra Assouline, Michel Koenig, Benoit Funalot, Christine Barnerias, Agnès Rötig, Arnold Munnich, Jean-Paul Bonnefont, Julie Steffann, European Journal of Medical Genetics, Available online 9 March 2018, ISSN 1769-7212, doi:10.1016/j.ejmg.2018.03.004.
We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4–5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients.
We report on an initial pitfall in the molecular characterization of a 15 year-old girl with Freidreich ataxia (FRDA) who carried a rare deletion in intron 1 of the FXN gene. Due to this deletion TP-PCR failed to amplify the GAA expansion. This exceptional configuration induced misinterpretation of the molecular defect in this patient, who was first reported as having no FXN expansion. NGS analysis of a panel of 212 genes involved in nuclear mitochondrial disorders further revealed an intragenic deletion encompassing exons 4–5 of the FXN gene. Modified TP-PCR analysis confirmed the presence of a classical (GAA)n expansion located in trans. This case points out the possible pitfalls in molecular diagnosis of FRDA in affected patients and their relatives: detection of the FXN expansion may be impaired by several non-pathological or pathological variants around the FXN (GAA)n repeat. We propose a new molecular strategy to accurately detect expansion by TP-PCR in FRDA patients.
Friday, March 9, 2018
Molecular genetic testing for hereditary ataxia-What every neurologist should know
Stephanie E. Wallace, Thomas D. Bird Neurology: Clinical Practice Feb 2018, 8 (1) 27-32; DOI: 10.1212/CPJ.0000000000000421
The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.
The majority of individuals with hereditary ataxias have nucleotide repeat expansions, pathogenic variants that are not detectable with clinical exome sequencing. Multigene panels that include specific assays to determine nucleotide repeat lengths should be considered first in individuals with hereditary ataxia.
Thursday, March 8, 2018
In the Clinic-Cerebellar Ataxia: How to Treat Cerebellar Ataxia — What the AAN Evidence-Based Guideline Suggests
Samson, Kurt. Neurology Today: March 8, 2018 - Volume 18 - Issue 5 - p 34–36 doi: 10.1097/01.NT.0000531206.29854.dd
A systematic review of studies on cerebellar motor dysfunction and ataxia revealed a dearth of good evidence for therapies. In part, the author panel found that the heterogeneous nature of the disorders that comprise cerebellar ataxia make it difficult to study.
A systematic review of studies on cerebellar motor dysfunction and ataxia revealed a dearth of good evidence for therapies. In part, the author panel found that the heterogeneous nature of the disorders that comprise cerebellar ataxia make it difficult to study.
Channelopathies influence on neurotransmitters monitorable by real time in situ voltammetry, a review and research proposal
Crespi F (2018). Med Clin Arch 2: DOI: 10.15761/MCA.1000128
It has been observed that 5-hydroxytryptophan, serotonin precursor, is more effective than placebo improving neurological symptoms in patients with Friedreich ataxia (FA). FA is an autosomal recessive genetic illness responsible for progressive damage to the nervous system in the spinal cord, in particular of sensory neurons basal for leading muscle motion of the arms and legs via link with the cerebellum.
It has been observed that 5-hydroxytryptophan, serotonin precursor, is more effective than placebo improving neurological symptoms in patients with Friedreich ataxia (FA). FA is an autosomal recessive genetic illness responsible for progressive damage to the nervous system in the spinal cord, in particular of sensory neurons basal for leading muscle motion of the arms and legs via link with the cerebellum.
Iron–sulfur clusters: from metals through mitochondria biogenesis to disease
Cardenas-Rodriguez, M., Chatzi, A. & Tokatlidis, K. J Biol Inorg Chem (2018). doi:10.1007/s00775-018-1548-6
Frataxin is involved in Fe–S clusters biogenesis. Thus, alterations linked to iron metabolism are present in FRDA. The pathophysiology of FRDA comprises deficit of aconitase and respiratory chain complexes, presence of oxidative damage markers in blood and urine, and intracellular iron accumulation [82, 84, 85, 86]. Currently, no successful treatment is available for FRDA. One main reason for this is the lack of understood detailed understanding of mechanisms of Fe–S cluster biogenesis and appropriate disease models.
Frataxin is involved in Fe–S clusters biogenesis. Thus, alterations linked to iron metabolism are present in FRDA. The pathophysiology of FRDA comprises deficit of aconitase and respiratory chain complexes, presence of oxidative damage markers in blood and urine, and intracellular iron accumulation [82, 84, 85, 86]. Currently, no successful treatment is available for FRDA. One main reason for this is the lack of understood detailed understanding of mechanisms of Fe–S cluster biogenesis and appropriate disease models.
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