Teresa Costabile, Veronica Capretti, Filomena Abate, Agnese Liguori, Francesca Paciello, Chiara Pane, Anna De Rosa, Silvio Peluso, Giuseppe De Michele, Alessandro Filla, Francesco Saccà; Cerebellum (2018). doi:10.1007/s12311-018-0918-5
Little effort has been made to understand the psychological and emotional burden of the disease. The aim of our study was to measure patients’ ability to recognize emotions using visual and non-verbal auditory hints, and to correlate this ability with psychological, neuropsychological, and neurological variables. FRDA patients have impaired emotion recognition that may be secondary to neuropsychological impairment. Depression and anxiety were not higher in FRDA as compared to HC and should not be considered as part of the disease.
Friday, January 12, 2018
Biophysical characterisation of the recombinant human frataxin precursor
Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini and Javier Santos; FEBS Open Bio (2018). Accepted Article. DOI: 10.1002/2211-5463.12376
We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes. His6-TAT-FXN1-210 was expressed in E. coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing.
We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes. His6-TAT-FXN1-210 was expressed in E. coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing.
Thursday, January 11, 2018
Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster
Juan A. Navarro and Stephan Schneuwly; Front Genet. 2017; 8: 223. Published online 2017 December 21. doi: 10.3389/fgene.2017.00223
Similar contradictory findings have been recently described in a Drosophila model of Friedreich's ataxia (FRDA). Impairment of transcription of the gene frataxin is the molecular cause underlying the disease. Most of the current evidences support a strong relation between frataxin and iron in several models, including the fly. Moreover, genetic and chemical manipulation of iron biology was found to have a positive impact in FRDA phenotypes. Remarkably, flies displaying reduced levels of frataxin also seemed to have altered levels of other metals such as Zn and Cu. Although the contribution of other metals was already suggested by studies in human samples, this fly work was the first one showing that therapies based on such metals might be beneficial. Indeed, Zn and Cu chelators improved frataxin deficiency without altering iron content. In this line, silencing either dZip42C.1, dZip42C.2 and dZip88E or dZnT35C, dZnT41F and dZnT63C also improved FRDA conditions via reduction of the iron content. All these results raise several interesting questions: Why are Cu and Zn accumulating in FRDA flies? Why does KD of genes with opposite function or acting in different cellular compartments trigger the same effect? Did they also modify the accumulation of Zn in FRDA flies? Is it possible that any of these transporters has also a mitochondrial function?
Similar contradictory findings have been recently described in a Drosophila model of Friedreich's ataxia (FRDA). Impairment of transcription of the gene frataxin is the molecular cause underlying the disease. Most of the current evidences support a strong relation between frataxin and iron in several models, including the fly. Moreover, genetic and chemical manipulation of iron biology was found to have a positive impact in FRDA phenotypes. Remarkably, flies displaying reduced levels of frataxin also seemed to have altered levels of other metals such as Zn and Cu. Although the contribution of other metals was already suggested by studies in human samples, this fly work was the first one showing that therapies based on such metals might be beneficial. Indeed, Zn and Cu chelators improved frataxin deficiency without altering iron content. In this line, silencing either dZip42C.1, dZip42C.2 and dZip88E or dZnT35C, dZnT41F and dZnT63C also improved FRDA conditions via reduction of the iron content. All these results raise several interesting questions: Why are Cu and Zn accumulating in FRDA flies? Why does KD of genes with opposite function or acting in different cellular compartments trigger the same effect? Did they also modify the accumulation of Zn in FRDA flies? Is it possible that any of these transporters has also a mitochondrial function?
Wednesday, January 10, 2018
Quantitative proteomics in Friedreich's ataxia B-lymphocytes: A valuable approach to decipher the biochemical events responsible for pathogenesis
Lorène Télot, Elodie Rousseau, Emmanuel Lesuisse, Camille Garcia, Bastien Morlet, Thibaut Léger, Jean-Michel Camadro, Valérie Serre, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 9 January 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.01.010.
To better understand the biochemical sequelae of frataxin reduction, global protein expression analysis was performed using quantitative proteomic experiments in Friedreich's ataxia patient-derived B-lymphocytes as compared to controls. We were able to confirm a subset of changes in these cells and importantly, we observed previously unreported signatures of protein expression. Among the novel protein signatures that we have identified, the decrease in CHCHD4 might partly explain some aspects of the molecular pathogenesis of FRDA.
The identification of a core set of proteins changing in the FRDA pathogenesis is a useful tool in trying to decipher the function(s) of frataxin in order to clarify the mitochondrial metabolic disease process.
To better understand the biochemical sequelae of frataxin reduction, global protein expression analysis was performed using quantitative proteomic experiments in Friedreich's ataxia patient-derived B-lymphocytes as compared to controls. We were able to confirm a subset of changes in these cells and importantly, we observed previously unreported signatures of protein expression. Among the novel protein signatures that we have identified, the decrease in CHCHD4 might partly explain some aspects of the molecular pathogenesis of FRDA.
The identification of a core set of proteins changing in the FRDA pathogenesis is a useful tool in trying to decipher the function(s) of frataxin in order to clarify the mitochondrial metabolic disease process.
Effect Of Diazoxide on Friedreich Ataxia Models
Antonella Santoro, Sara Anjomani Virmouni, Eleonora Paradies, Valentina L Villalobos Coa, Sahar Al-Mahdawi, Mee Khoo, Vito Porcelli, Angelo Vozza, Mara Perrone, Nunzio Denora, Franco Taroni, Giuseppe Merla, Luigi Palmieri, Mark A Pook, Carlo M T Marobbio, Human Molecular Genetics, ddy016, doi:10.1093/hmg/ddy016
In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mTOR pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mTOR pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.
Sunday, January 7, 2018
Compounded medication for patients with rare diseases
Marc Dooms and Maria Carvalho; Orphanet Journal of Rare Diseases 201813:1 doi:10.1186/s13023-017-0741-y
When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is important that there is evidence in the medical and/or pharmaceutical literature for such compounded medications.
When there is no on-label or even no off-label treatment for patients with rare diseases pharmacists have to compound the medication. This needs to be done in the best possible conditions by trained compounders following validates procedures.
In this way medicinal products of the best possible quality will be dispensed to our patients with rare diseases. “When it’s not in the book, it’s up to the cook”.
When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is important that there is evidence in the medical and/or pharmaceutical literature for such compounded medications.
When there is no on-label or even no off-label treatment for patients with rare diseases pharmacists have to compound the medication. This needs to be done in the best possible conditions by trained compounders following validates procedures.
In this way medicinal products of the best possible quality will be dispensed to our patients with rare diseases. “When it’s not in the book, it’s up to the cook”.
Psychometric properties of outcome measures evaluating decline in gait in cerebellar ataxia: a systematic review
Sarah C. Milne, Anna Murphy, Nellie Georgiou-Kristian’s, Eppie M. Yiu, Martin B. Delatycki, Louise A. Corben; Gait & Posture, Available online 4 January 2018, ISSN 0966-6362, doi:10.1016/j.gaitpost.2017.12.031.
Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia.
Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia.
Pediatric Ataxia: Focus on Chronic Disordersca
David R Lynch, Ashley McCormick, Kimberly Schadt, Elizabeth Kichula, Seminars in Pediatric Neurology, Available online 5 January 2018, ISSN 1071-9091, doi:10.1016/j.spen.2018.01.001.
The differential diagnosis of ataxia remains challenging, and efficiently ascertaining the correct cause difficult. Modern genetic diagnostic techniques have provided many answers, but complete understanding of genetic results still requires basic knowledge of the clinical phenotypes. While few ataxias are treatable, the growth in research and clinical trials for the disorders like FRDA and AT suggest that a new era of treatments may soon be available. This will increase the need for precise yet cost-conscious diagnostic approaches.
The differential diagnosis of ataxia remains challenging, and efficiently ascertaining the correct cause difficult. Modern genetic diagnostic techniques have provided many answers, but complete understanding of genetic results still requires basic knowledge of the clinical phenotypes. While few ataxias are treatable, the growth in research and clinical trials for the disorders like FRDA and AT suggest that a new era of treatments may soon be available. This will increase the need for precise yet cost-conscious diagnostic approaches.
Sunday, December 31, 2017
A case-control spectral analysis of sleep in Friedreich's Ataxia
R. Forbes, S.S. Smith, A. Ritchie, J.D. O'Sullivan, S. Mantovani, Sleep Medicine, Volume 40, Supplement 1, December 2017, Page e209, ISSN 1389-9457, doi:10.1016/j.sleep.2017.11.611.
This study shows that power spectral alterations are present in FA patients when compared to healthy controls. This may have impli- cations for understanding the nature of sleep difficulties in FA, while their role in the progression of disease remains uncertain.
This study shows that power spectral alterations are present in FA patients when compared to healthy controls. This may have impli- cations for understanding the nature of sleep difficulties in FA, while their role in the progression of disease remains uncertain.
Emerging therapeutics for the treatment of Friedreich’s ataxia
Elisabetta Indelicato & Sylvia Bösch; Expert Opinion on Orphan Drugs Vol. 6 , Iss. 1,2018 doi:10.1080/21678707.2018.1409109
Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.
Despite the several trials finalized in the past years, no therapeutic is currently available for the treatment of FRDA. A number of promising compounds failed to show a significant effect when shifted in a randomized, placebo-controlled setting, because of missing natural history data, poor study design or insufficient preclinical evidence.
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