Maya Kuperberg, Dorit Lev, Lubov Blumkin, Ayelet Zerem, Mira Ginsberg, Ilan Linder, Nirit Carmi, Sarah Kivity, Tally Lerman-Sagie, Esther Leshinsky-Silver; August 29, 2016, doi: 10.1177/0883073816664836
When a patient arrives with a suspected monogenic disease the authors first take detailed history, perform a full clinical exam, and create a family tree. If a specific genetic disease is suspected based on this data, direct traditional tests are to be performed. Only if the patient remains undiagnosed should the authors turn to whole exome sequencing. The authors were able to diagnose patients exhibiting nonspecific, atypical, or overlapping symptoms.
Over 300 genetic conditions are known to cause ataxia, and without additional specific symptoms achieving a diagnosis is very difficult. Whole exome sequencing studies on cerebellar ataxia have achieved a success rate of 18%-64%. The authors report a high success rate of 57.1% for patients with ataxia.
Tuesday, September 13, 2016
Saturday, September 10, 2016
The Application of Human Spinal Cord Magnetic Resonance Spectroscopy to Clinical Studies: A Review, Seminars in Ultrasound, CT and MRI
Patrik Oliver Wyss, Andreas Hock, Spyros Kollias, Available online 12 July 2016, ISSN 0887-2171, doi:10.1053/j.sult.2016.07.005.
Friedreich’s ataxia (FRDA) is an autosomal recessive degenerative disorder affecting the nervous system and the heart. Spectroscopic measurements in the brain showed decreased NAA in the vermis and the cerebellar hemispheres and increased myo-Inositol in the vermis. The total amount of Cr in the cerebellar hemispheres and Glu in the vermis was higher suggesting an alteration in the glutamatergic neurotransmission system. Findings in the spinal cord were in accordance with those of the brain showing a reduction of NAA by 40% and an increase of mI by 46% reflecting neuronal damage and gliosis.
Friedreich’s ataxia (FRDA) is an autosomal recessive degenerative disorder affecting the nervous system and the heart. Spectroscopic measurements in the brain showed decreased NAA in the vermis and the cerebellar hemispheres and increased myo-Inositol in the vermis. The total amount of Cr in the cerebellar hemispheres and Glu in the vermis was higher suggesting an alteration in the glutamatergic neurotransmission system. Findings in the spinal cord were in accordance with those of the brain showing a reduction of NAA by 40% and an increase of mI by 46% reflecting neuronal damage and gliosis.
Thursday, September 8, 2016
Introduction to Special Issue on Mitochondrial Redox Signaling in Health and Disease
Juan P. Bolaños, Enrique Cadenas, Michael R. Duchen, Mark B. Hampton, Giovanni E. Mann, Michael P. Murphy, Free Radical Biology and Medicine, Available online 5 August 2016, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.08.004.
The genetic deficiency of the mitochondrial protein frataxin is the cause of Friedreich ataxia. Frataxin deficiency is not associated with cognitive impairment, but with increased oxidative stress with alterations in lipid metabolism, which are discussed as potential therapeutic approaches in Friedreich ataxia. The mitochondrial Lon protease is involved in several neurological disorders, such as hereditary Parkinson’s disease, Friedreich ataxia, familial amyotrophic lateral sclerosis, brain ischemia and stroke. In these disorders, the physiological functions of the Lon protease are altered: as a protease, as a chaperone,and as a mtDNA binding protein.
The genetic deficiency of the mitochondrial protein frataxin is the cause of Friedreich ataxia. Frataxin deficiency is not associated with cognitive impairment, but with increased oxidative stress with alterations in lipid metabolism, which are discussed as potential therapeutic approaches in Friedreich ataxia. The mitochondrial Lon protease is involved in several neurological disorders, such as hereditary Parkinson’s disease, Friedreich ataxia, familial amyotrophic lateral sclerosis, brain ischemia and stroke. In these disorders, the physiological functions of the Lon protease are altered: as a protease, as a chaperone,and as a mtDNA binding protein.
Wednesday, September 7, 2016
Functional and Gait Assessment in Children and Adolescents Affected by Friedreich’s Ataxia: A One-Year Longitudinal Study
Gessica Vasco , Simone Gazzellini, Maurizio Petrarca, Maria Luisa Lispi, Alessandra Pisano, Marco Zazza, Gessica Della Bella, Enrico Castelli, Enrico Bertini, PLoS ONE 11(9): e0162463. doi:10.1371/journal.pone.0162463
Open access
Open access
Tuesday, September 6, 2016
Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington’s Disease Models
Luana Naia, Tatiana R. Rosenstock, Ana M. Oliveira, Sofia I. Oliveira-Sousa, Gladys L. Caldeira, Catarina Carmo, Mário N. Laço, Michael R. Hayden, Catarina R. Oliveira, A. Cristina Rego; Mol Neurobiol (2016). doi:10.1007/s12035-016-0048-3
In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.
In this study, we tested the influence of resveratrol (RESV, a SIRT1 activator) versus nicotinamide (NAM, a SIRT1 inhibitor) in counteracting mitochondrial dysfunction in HD models. Further studies revealed decreased PGC-1α and TFAM protein levels, linked to mitochondrial DNA loss in HD lymphoblasts. Remarkably, RESV completely restored these parameters, while NAM increased NAD+ levels, providing a positive add on mitochondrial function in in vitro HD models. In general, RESV decreased while NAM increased H3 acetylation at lysine 9. In agreement with in vitro data, continuous RESV treatment for 28 days significantly improved motor coordination and learning and enhanced expression of mitochondrial-encoded electron transport chain genes in YAC128 mice. In contrast, high concentrations of NAM blocked mitochondrial-related transcription, worsening motor phenotype. Overall, data indicate that activation of deacetylase activity by RESV improved gene transcription associated to mitochondrial function in HD, which may partially control HD-related motor disturbances.
Friedreich ataxia induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor
Franca Codazzi, Amelié Hu, Myriam Rai, Floramarida Salerno Scarzella, Elisabeth Mangiameli, Ilaria Pelizzoni, Fabio Grohovaz and Massimo Pandolfo3; Hum. Mol. Genet. (2016) doi: 10.1093/hmg/ddw308 First published online: September 4, 2016
Findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.
Findings suggest that correction of frataxin deficiency may not only stop disease progression, but also lead to clinical improvement by rescuing still surviving, but dysfunctional neurons.
Monday, September 5, 2016
R loops and links to human disease
Patricia Richard, James L. Manley, Journal of Molecular Biology, Available online 4 September 2016, ISSN 0022-2836, doi:10.1016/j.jmb.2016.08.031.
More than 40 genetic disorders are caused by gene-specific repeat expansions. These include Huntington’s disease (HD) (CAG repeats in huntingtin (HTT)), myotonic dystrophy type 1 (MD1) (CTG repeats in dystrophia myotonica protein kinase (DMPK)), spinocerebellar ataxia type 1 (SCA1) (CAG repeats in ataxin1 (ATXN1)), fragile X mental retardation or fragile X syndrome (FXS) (CGG repeats in fragile X mental retardation 1 (FMR1)) and Friedreich ataxia (FDRA) (GAA repeats in frataxin (FXN)).
More than 40 genetic disorders are caused by gene-specific repeat expansions. These include Huntington’s disease (HD) (CAG repeats in huntingtin (HTT)), myotonic dystrophy type 1 (MD1) (CTG repeats in dystrophia myotonica protein kinase (DMPK)), spinocerebellar ataxia type 1 (SCA1) (CAG repeats in ataxin1 (ATXN1)), fragile X mental retardation or fragile X syndrome (FXS) (CGG repeats in fragile X mental retardation 1 (FMR1)) and Friedreich ataxia (FDRA) (GAA repeats in frataxin (FXN)).
Friday, September 2, 2016
Biomarkers and progress of antioxidant therapy for rare mitochondrial disorders
Lucia Chico, Daniele Orsucci, Annalisa Lo Gerfo, Letizia Marconi, Michelangelo Mancuso & Gabriele Siciliano. Expert Opinion on Orphan Drugs Volume 4, Issue 6, 2016, DOI:10.1080/21678707.2016.1178570
Promising clinical trials have been recently described including the use of different compounds and molecules that can reduce oxidative stress levels and simultaneously act as electron carriers to modulate mitochondrial electron flow.
Several compounds and therapies have been demonstrated to possess mitochondrial restoring and antioxidant properties such as vitamins and cofactors like Coenzyme Q10 (CoQ10) folic acid, vitamin B12, riboflavin, L-carnitine, and creatine, electron acceptors like vitamin C, free radical scavengers like idebenone, EPI-743, vitamin E, alpha lipoic acid, and curcumin, inhibitors of toxic metabolites (dicholoroacetate). Therapeutic potentials of these compounds have been suggested to restoring mitochondrial functions, transport and synaptic plasticity, and showed some neuroprotective role not only in rare mitochondrial disease, but also in other neurodegenerative disorders.
More evidence supports also the use of a combination of “mitococktails”, this referring to as the combination of several and different vitamins, with antioxidant supplements tailored for individual patients to increase mitochondrial respiration and scavenge free radicals to reduce ROS produced in mitochondria diseases.
Promising clinical trials have been recently described including the use of different compounds and molecules that can reduce oxidative stress levels and simultaneously act as electron carriers to modulate mitochondrial electron flow.
Several compounds and therapies have been demonstrated to possess mitochondrial restoring and antioxidant properties such as vitamins and cofactors like Coenzyme Q10 (CoQ10) folic acid, vitamin B12, riboflavin, L-carnitine, and creatine, electron acceptors like vitamin C, free radical scavengers like idebenone, EPI-743, vitamin E, alpha lipoic acid, and curcumin, inhibitors of toxic metabolites (dicholoroacetate). Therapeutic potentials of these compounds have been suggested to restoring mitochondrial functions, transport and synaptic plasticity, and showed some neuroprotective role not only in rare mitochondrial disease, but also in other neurodegenerative disorders.
More evidence supports also the use of a combination of “mitococktails”, this referring to as the combination of several and different vitamins, with antioxidant supplements tailored for individual patients to increase mitochondrial respiration and scavenge free radicals to reduce ROS produced in mitochondria diseases.
Wednesday, August 31, 2016
Pharmacological treatments for Friedreich ataxia
Kearney M, Orrell RW, Fahey M, Brassington R, Pandolfo M. Pharmacological treatments for Friedreich ataxia. Cochrane Database of Systematic Reviews 2016, Issue 8. Art. No.: CD007791. DOI: 10.1002/14651858.CD007791.pub4.
Tuesday, August 30, 2016
Optimization of pyrimidinol antioxidants as mitochondrial protective agents: ATP production and metabolic stability
Arnaud Chevalier, Mohammad Parvez Alam, Omar M. Khdour, Margaret Schmierer, Pablo M. Arce, Cameron D. Cripe, Sidney M. Hecht,Bioorganic & Medicinal Chemistry, Available online 23 August 2016, ISSN 0968-0896, doi:10.1016/j.bmc.2016.08.039.
The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.
The compounds were evaluated for their ability to suppress ROS and lipid peroxidation, and for their effects on mitochondrial membrane potential, and their ability to protect cultured FRDA lymphocytes from oxidative stress induced by glutathione depletion. The compounds were also evaluated for their ability to increase ATP levels in FRDA lymphocytes.
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