Referencias científicas Nº 162

Differentially Regulated Cell-Free MicroRNAs in the Plasma of Friedreich’s Ataxia Patients and Their Association with Disease Pathology

Subrahamanyam Dantham1*, Achal K. Srivastava2, Sheffali Gulati3, Moganty R. Rajeswari1

  • 1Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
  • 2Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
  • 3Department of Paediatrics Neurology, All India Institute of Medical Sciences, New Delhi, India


Friedreich’s ataxia (FRDA) is a multisystem disease affecting the predominately nervous system, followed by muscle, heart, and pancreas. Current research focused on therapeutic interventions aimed at molecular amelioration, but there are no reliable noninvasive signatures available to understand disease pathogenesis. The present study investigates the alterations of plasma cell-free microRNAs (miRNAs) in FRDA patients and attempts to find the significance in relevance with the pathogenesis. Total RNA from the plasma of patients and healthy controls were subjected to miRNA microarray analysis using Agilent Technologies microarray platform. Differentially regulated miRNAs were validated by SYBR-green real-time polymerase chain reaction (Thermo Fisher Scientific). The study identified 20 deregulated miRNAs (false discovery rate < 0.01, fold change ≥ 2.0 ≤) in comparison with healthy controls; out of which 17 miRNAs were upregulated, and 3 miRNAs were downregulated. Target and pathway analysis of these miRNAs have shown association with neurodegenerative and other clinical features in FRDA. Further validation (n = 21) identified a set of significant (p < 0.05) deregulated miRNAs; hsa-miR-15a-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-223–3p, hsa-24–3p, and hsa-miR-21–5p in comparison with healthy controls. These miRNAs were reported to influence various pathological features associated with FRDA. The present study is expected to aid in the understanding of disease pathogenesis.

Do whole body vibration exercises affect lower limbs neuromuscular activity in populations with a medical condition? A systematic review

Authors: Dionello, Carla Fontouraab* | de Souza, Patrícia Lopesab | Sá-Caputo, Danubiaabc | Morel, Danielle Soaresab | Moreira-Marconi, Eloábd | Paineiras-Domingos, Laisa Lianeab | Frederico, Eric Heleno Freire Ferreirabe | Guedes-Aguiar, Elianebf | Paiva, Patricia de Castrobg | Taiar, Redhah | Chiementin, Xavierh | Marín, Pedro J.i | Bernardo-Filho, Mariob

Affiliations: [aPrograma de Pós-graduação em Ciências Médicas, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil | [bLaboratório de Vibrações Mecânicas e Práticas Integrativas e Complementares; Departamento de Biofísica e Biometria, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil | [cCurso de Fisioterapia, Faculdade Bezerra de Araújo, Rio de Janeiro, RJ, Brazil | [dPrograma de Pós-graduação em Fisiopatologia Clínica e Experimental, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil | [ePrograma de Pós-Graduação em Biociências, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil | [fPrograma de Pós-graduação em Ciências da Saúde, Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte, Natal, Rio Grande do Norte, Brazil | [gMestrado Profissional em Saúde, Medicina Laboratorial e Tecnologia Forense, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil | [hUniversité du Reims Champagne Ardenne, Moulain de la Housse, Reims, France | [iCyMO Research Institute, Valladolid, Spain

Correspondence: [*] Corresponding author: Carla Fontoura Dionello, Departamento de Biofísica e Biometria, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, Av. 28 de setembro, 87, fundos, 4°. andar, Vila Isabel, Rio de Janeiro, RJ, 20551-030, Brazil. Tel./Fax: +55 21 28688332; E-mail:



Abstract: Background:The use of surface electromyography (sEMG) to evaluate muscle activation when executing whole body vibration exercises (WBVE) in studies provide neuromuscular findings, in healthy and diseased populations. Objectives:Perform a systematic review of the effects of WBVE by sEMG of lower limbs in non-healthy populations. Methods:The search using the defined keywords was performed in PubMed, PEDRo and EMBASE databases by three independent researchers. Applying the PRISMA statement several studies were selected according to eligibility criteria and organized for the review. Full papers were included if they described effects of WBVE for the treatment of illnesses, evaluated by sEMG of lower limbs independently on the year of the publication; in comparison or associated with other treatment and evaluation techniques. Results:Seven publications were selected; two in spinal cord injury patients, one in Friedreich’s ataxia patients, three in stroke patients and one study in breast cancer survivors. Reported effects of WBV in were muscle activation by sEMG and also on strength, blood flow and exercise resistance; even in paretic limbs. Conclusion:By the use of sEMG it was verified that WBVE elicits muscle activation in diseased population. These results may lead to the definition of exercise protocols to maintain or increase muscular activation. However, due to the heterogeneity of methods among studies, there is currently no consensus on the sEMG signal processing. These strategies might also induce effects on muscle strength, balance and flexibility in these and other illnesses.

Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor.

Amelie Hu, Myriam Rai, Simona Donatello,  View ORCID ProfileMassimo Pandolfo


Epigenetic suppression of frataxin (FXN) expression caused by the presence of expanded GAA repeats at the FXN locus is the key pathogenic event in Friedreich ataxia (FRDA), a recessive neurodegenerative and systemic disease. FXN is involved in iron-sulfur (Fe-S) cluster biogenesis in mitochondria, its deficiency causes multiple Fe-S protein deficiencies, mitochondrial dysfunction and oxidative stress. Primary sensory neurons (PSNs) in the dorsal root ganglia (DRGs) are the most vulnerable cells in FRDA, whose abnormal development and degeneration leads to the onset and early progression of ataxia. We generated PSNs from induced pluripotent stem cells (iPSCs) from FRDA patients and showed that they recapitulate the key pathogenic events in FRDA, including low FXN levels, loss of Fe-S proteins and impaired antioxidant responses. We also showed that FXN deficiency in these cells may be partially corrected by a pimelic benzamide histone deacetylase inhibitor, a class of potential therapeutics for FRDA. We generated and validated a cellular model of the most vulnerable neurons in FRDA, which can be used for further studies on pathogenesis and treatment approaches.

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Hong Lin, Jordi Magrane, Amy Rattelle, Anna Stepanova, Alexander Galkin, Elisia M. Clark, Yi Na Dong, Sarah M. Halawani, David R. Lynch


Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

Insights on the conformational dynamics of human frataxin through modifications of loop-1

Author links open overlay panelMartín E.NogueraaMartínAranbClaraSmalbDiego S.VazquezaMaría GeorginaHerreraaErnesto A.RomanaNadineAlaimocMarianaGallocdJavierSantosa


Human frataxin (FXN) is a highly conserved mitochondrial protein involved in iron homeostasis and activation of the iron-sulfur cluster assembly. FXNdeficiency causes the neurodegenerative disease Friedreich’s Ataxia. Here, we investigated the effect of alterations in loop-1, a stretch presumably essential for FXN function, on the conformational stability and dynamics of the native state. We generated four loop-1 variants, carrying substitutions, insertions and deletions. All of them were stable and well-folded proteins. Fast local motions (ps-ns) and slower long-range conformational dynamics (μs-ms) were altered in some mutants as judged by NMR. Particularly, loop-1 modifications impact on the dynamics of a distant region that includes residues from the β-sheet, helix α1 and the C-terminal. Remarkably, all the mutants retain the ability to activate cysteine desulfurase, even when two of them exhibit a strong decrease in iron binding, revealing a differential sensitivity of these functional features to loop-1 perturbation. Consequently, we found that even for a small and relatively rigid protein, engineering a loop segment enables to alter conformational dynamics through a long-range effect, preserving the native-state structure and important aspects of function.





C-terminal region




heteronuclear 1H-15N NOE


heteronuclear single quantum coherence


contribution of the exchange to the transversal relaxation rate


15N spin-lattice relaxation time


15N spin-spin relaxation time


chemical shift perturbation


Friedreich’s Ataxia

Teaching Video NeuroImages: Spastic ataxia syndrome

The Friedreich-like phenotype of ARSACS

  1. Paula Saffie, MD
  2. Marcelo A. Kauffman, MD, PhD
  3. Jose Manuel Fernandez, MD
  4. Ignacio Acosta, MD
  5. Alberto J. Espay, MD, MScand 
  6. Andrés de la Cerda, MD

Correspondence to Dr. Espay:


A 24-year-old Chilean man with slowly progressive ataxia since age 2 presented with spastic ataxia, hyperreflexia, pes cavus, axonal polyneuropathy, incomplete right-bundle branch block on ECG, and impaired glucose tolerance test, suggesting Friedreich ataxia (figure; video at However, the combination of hyperreflexia and cerebellar (rather than cervical cord) atrophy with T2-weighted linear hypointensity in the pons on brain MRI suggested autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Biallelic mutations were found (c.4492C>T p.[R1498X] and c.2388dupA p.[L797Ifs*4]) in the SACS gene (NCBI sequence NM_001278055). ARSACS is the second most common cause of autosomal recessive spastic ataxia syndrome (SACS mutations account for 37% of Friedreich-negative cases)1 and should be considered in any population with suggestive MRI abnormalities.2

FIGURE Key clinical and MRI findings

Friedreich-like pes cavus (A, B) and suggestive MRI findings: liner hypointensity on axial T2-weighted brain MRI (classic abnormality) (C) and cerebellar anterosuperior vermal cerebellar atrophy (nonspecific; D).


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Drs. Saffie, Fernandez, Acosta, and de la Cerda: acquisition of data, analysis and interpretation, critical revision of the manuscript for important intellectual content. Dr. Kauffmann: genetic analysis, critical revision of the manuscript for important intellectual content. Dr. Espay: report analysis and interpretation, critical revision of the manuscript for important intellectual content.

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No targeted funding reported.

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  1. Saffie reports no disclosures relevant to the manuscript. M. Kauffman is an employee of the CONICET. He has received grant support from Ministry of Science and Technology of Argentina and Ministry of Health of Buenos Aires. J. Fernandez and I. Acosta report no disclosures relevant to the manuscript. A. Espay has received grant support from NIH (K23MH092735), Great Lakes Neurotechnologies, and the Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for AbbVie, TEVA, Impax, Merz, Acadia, Cynapsus, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from AbbVie, UCB, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology, and the Movement Disorders Society. A. de la Cerda reports no disclosures relevant to the manuscript. Go to Neurology.orgfor full disclosures.

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Agilis Biotherapeutics Announces Orphan Product Designation Approval in Europe for the Treatment of Friedreich Ataxia

First Gene Therapy Treatment Candidate to Receive Orphan Designation in EU and USA

October 31, 2017 07:30 AM Eastern Daylight Time

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that the European Commission (EC) has granted Orphan Medicinal Product (OMP) designation in the European Union (EU) to the Company’s gene therapy product candidate, AGIL-FA, being developed for the treatment of Friedreich ataxia (FA), an inherited degenerative neuromuscular disorder resulting in loss of motor coordination and strength, hearing, vision, speech and often premature death. The EC’s approval follows a positive opinion in July 2017 from the European Medicine Agency’s (EMA) Committee for Orphan Medicinal Products (COMP). This follows the Orphan Drug Designation for AGIL-FA granted by the U.S. Food and Drug Administration (FDA) last year. The Company’s gene therapies for AADC deficiency and Angelman syndrome have previously received orphan status in both the EU and US.

Agilis Announces Orphan Product Designation Approval in Europe for the Treatment of Friedreich Ataxia

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“Receiving the first orphan designations for a gene therapy product candidate from the FDA and now the EU for the treatment of FA is an honor,” said Mark Pykett, President and CEO of Agilis. “The orphan designation is another step on our path to bring this important new therapy to patients who currently lack treatment options.”

AGIL-FA is a gene-therapy product consisting of a unique gene construct developed in partnership with Intrexon Corporation (NYSE: XON) delivered with adeno-associated virus technology. The Company has completed extensive characterization of AGIL-FA, including analyses in inducible pluripotent stem cell systems, a genetic model of FA, and multiple large animal studies demonstrating reproducible transduction of the FXN gene and expression of frataxin protein in target CNS cells integral to the neurological manifestations in FA in support of human clinical studies. The Company has completed a Pre-IND meeting with the FDA and is on track to open an IND in 2018.

“We are extremely pleased to receive this designation, as we move our FA development program forward,” said Kirsten Gruis, MD, Agilis’ Chief Medical Officer. “With each of our IND and clinical stage pipeline candidates having now received Orphan Designation in two major markets, our programs are well positioned to advance innovative therapeutics for patients with rare genetic diseases affecting the CNS.”

Friedreich ataxia (FA) is a rare and life-shortening neurodegenerative disease caused by a defect in the FXN gene that reduces production of the frataxin protein. AGIL-FA is focused on delivering corrective DNA to specific CNS cells to restore frataxin protein levels. Agilis has worked closely with the Friedreich’s Ataxia Research Alliance (FARA) to focus the development program on patient needs. “FARA is delighted to continue our support of Agilis and their innovative approach to the treatment of FA,” said Jennifer Farmer, MS, Executive Director of FARA. “We look forward to continuing our partnership to advance this important potential therapy, as well as supporting research to identify biomarkers and clinical outcome measures, which will advance the development of the product candidate into clinical trials.”

The EU orphan designation provides Agilis with development and commercial incentives, including 10 years of market exclusivity, prioritized consultation by EMA on the development of the drug, including clinical studies, and certain exemptions from or reductions in regulatory fees in Europe. Orphan designation is granted to drugs that are intended for the treatment of life threatening or chronically debilitating rare diseases where no therapeutic options either exist or are satisfactory. Rare diseases are those defined as having a prevalence of less than five in 10,000 people in the European Union.

Personality and Neuropsychological Profiles in Friedreich Ataxia

  • Sabrina Sayah
  • Jean-Yves Rotgé
  • Hélène Francisque
  • Marcela Gargiulo
  • Virginie Czernecki
  • Damian Justo
  • Khadija Lahlou-Laforet
  • Valérie Hahn
  • Massimo Pandolfo
  • Antoine Pelissolo
  • Philippe Fossati
  • Alexandra Durr



Friedreich ataxia, an autosomal recessive mitochondrial disease, is the most frequent inherited ataxia. Many studies have attempted to identify cognitive and affective changes associated with the disease, but conflicting results have been obtained, depending on the tests used and because many of the samples studied were very small. We investigated personality and neuropsychological characteristics in a cohort of 47 patients with genetically confirmed disease. The neuropsychological battery assessed multiple cognition domains: processing speed, attention, working memory, executive functions, verbal memory, vocabulary, visual reasoning, emotional recognition, and social cognition. Personality was assessed with the Temperament and Character Inventory, and depressive symptoms were assessed with the Beck Depression Inventory. We found deficits of sustained attention, processing speed, semantic capacities, and verbal fluency only partly attributable to motor deficit or depressed mood. Visual reasoning, memory, and learning were preserved. Emotional processes and social cognition were unimpaired. We also detected a change in automatic processes, such as reading. Personality traits were characterized by high persistence and low self-transcendence. The mild cognitive impairment observed may be a developmental rather than degenerative problem, due to early cerebellum dysfunction, with the impairment of cognitive and emotional processing. Disease manifestations at crucial times for personality development may also have an important impact on personality traits.