Artículos publicados en la red relativos a la ataxia que pueden ser de interés para investigadores y profesionales médicos (En inglés)

Specific Cytokines Therapy Protected Neurons in Humanized Mouse Study


JANUARY 19, 2017


A cocktail of clinically approved cytokines for other diseases shows promising neuro-protective effects in a Friedreich’s ataxia (FA) humanized mouse model.

The study, “Cytokine therapy-mediated neuroprotection in a Friedreich’s ataxia mouse model,” was published in the journal Annals of Neurology.

FA is a severe neurological disease that affects the nervous system, with patients progressively losing control of their muscles (ataxia) and experiencing impaired speech. There is no approved treatment for FA. However, a group of specific cytokines and growth factors may carry therapeutic potential to protect and mediate the damages in the nervous system of FA patients. Cytokines are small proteins that are secreted by specific cells of the immune system and affect cells’ behavior and cell-cell interactions.

In the study, a group of researchers investigated the neuro-protective effects of the cytokines granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) using a humanized mouse model of FA. A humanized mouse is a mouse carrying functioning human genes, cells, tissues, and/or organs.

Researchers treated mice with monthly cytokines infusions applied subcutaneously (directly under the skin). Specifically, subcutaneous injection of G-CSF and/or SCF was administered once a day for five consecutive days during one month. As controls, a group of mice were treated with a saline solution during the same period.

Researchers then performed several behavioral motor performance tests. After six months of treatment, authors performed neurophysiological analysis, especially to assess the ability of electrical conduction of both sensory and motor nerves. Final analysis included profiling of certain regions of the nervous system (including dorsal root ganglion, spinal cord and cerebellum) for mRNA (molecules that are then transformed into protein) and protein expression, accompanied by a histological analysis of these tissues.

Researchers observed that cytokines infusion showed a neuro-protective effect in the humanized mouse model of FA, with treatment leading to significant reversal of biochemical, neuropathological, neurophysiological and behavioral parameters linked to FA. Treated mice exhibited significant improvements in motor coordination and locomotor activity, even after onset of clinical symptoms.

Additionally, administration of G-CSF and/or SCF restored conduction of sensory nerves and increased frataxin expression. The effects of cytokines infusion also led to reduction in inflammation and increases in neural stem cell numbers in areas of tissue injury in the mouse.

These results support the use of a combination of specific cytokines, already approved for other disorders, as a potential treatment for FA.

Researchers Use Test to Differentiate Between Spinocerebellar and Friedreich’s Ataxia

JANUARY 5, 2017



Patients with different muscular-coordination conditions, or ataxia, exhibit different eye reflexes after head impulses, a finding that could help doctors determine the severity of a patient’s disease.

The video head impulse tests (vHIT) that researchers used showed differences in eye movements between patients with spinocerebellar ataxias and patients with Friedreich’s ataxia. The study included three kinds of spinocerebellar ataxia — types 1, 2 and 3, or SCA1, SCA2 and SCA3.

The research, “Vestibulo-ocular reflex dynamics with head-impulses discriminates spinocerebellar ataxias types 1, 2 and 3 and Friedreich ataxia,” was published in the Journal of Vestibular Research.

Researchers decided to compare patients’ vestibulo-ocular (VOR) ability, or ability to maintain visual stability during head movements.

The vHIT test allowed them to count saccades, rapid eye movements with changes of focus triggered by a head impulse.

Previous research has shown that rapid eye movements are a normal response to head impulse in patients with central nervous system disorders. Other research has indicated that patients with inherited ataxias also respond to head impulses with rapid eye movements.

Those findings prompted researchers to use vHIT tests to try to determine which type of ataxia a patient had.

They tested 23 patients with spinocerebellar ataxia, nine with Friedreich’s ataxia, and 40 healthy controls. The spinocerebellar patients included four with SCA1, four with SCA2, and 15 with SCA3.

One measurement they used was VOR latency, or the time required for the eyes to adjust to a head impulse. Another was instant VOR gain and a third was VOR loss. The gains and losses were measured at 40-, 60- and 80-millisecond intervals.

The VOR latency that researchers found in Friedreich’s ataxia patients was considerably higher than in spinocerebellar patients, enough that they concluded they could use the results to differentiate the two. They also found higher latency in SCA3 patients, but not to the degree in Friedreich’s patients.

In addition, the team found lower VOR-gain and VOR-loss levels in Friedreich’s and SCA3 patients, but only SCA3 patients had levels low enough to distinguish them from other patients.

The team looked at two kinds of rapid eye movements — those that occurred during a head impulse and those that occurred afterward.

They discovered that only SCA3 patients showed rapid eye movements during a head impulse, while all patients showed movements after an impulse.

Researchers also found that the higher the VOR regression score, the lower the patient’s score on the Scale for the Assessment and Rating of Ataxia (SARA). That suggested that increases in VOR gain may be used as a biomarker for determining disease severity.


miRNAs as biomarkers of neurodegenerative disorders

Vijitha Viswambharan,1, Ismail Thanseem,1, Mahesh M Vasu2, Suresh A Poovathinal3 & Ayyappan Anitha*,1

*Author for correspondence:

Authors contributed equally

Neurodegenerative diseases (NDDs) are the result of progressive deterioration of neurons, ultimately leading to disabilities. There is no effective cure for NDDs at present; ongoing therapies are mainly aimed at treating the most bothersome symptoms. Since early treatment is crucial in NDDs, there is an urgent need for specific and sensitive biomarkers that can aid in early diagnosis of these disorders. Recently, altered expression of miRNAs has been implicated in several neurological disorders, including NDDs. miRNA expression has been extensively investigated in the cells, tissues and body fluids of patients with different types of NDDs. The aim of this review is to provide a comprehensive overview of miRNAs as biomarkers and therapeutic targets for NDDs.

Targeting Class I Histone Deacetylases in a “Complex” Environment

Christopher J. Millard2


Peter J. Watson2


Louise Fairall2


John W.R. Schwabe

2These authors contributed equally to this work

Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer’s disease, and Friedreich’s ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Designing isoform-selective inhibitors has proven challenging due to similarities in the structure and chemistry of HDAC active sites. However, the fact that HDACs 1, 2, and 3 are recruited to several large multi-subunit complexes, each with particular biological functions, raises the possibility of specifically inhibiting individual complexes. This may be assisted by recent structural and functional information about the assembly of these complexes. Here, we review the available structural information and discuss potential targeting strategies.


All currently licenced HDAC drugs (HDAC inhibitors) are pan-inhibitors that work by targeting the active-site zinc.

HDAC inhibitors are used in the clinic as anticancer therapeutics, but due to their nonselective nature, many patients experience significant side effects.

The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients.

HDACs 1, 2, and 3 are of particular interest as they are recruited to multiprotein complexes to mediate gene transcription. As part of these complexes, the HDACs become maximally activated, and are targeted to specific genes.

The recruitment of class I HDACs into multiprotein assemblies opens up the possibility of using alternative strategies to develop complex-specific HDAC inhibitors.

Influence of substituent heteroatoms on the cytoprotective properties of pyrimidinol antioxidants



Recently, we described the optimization of novel pyrimidinol-based antioxidants as potential therapeutic molecules for targeting mitochondrial diseases. That study focused on improving the potency and metabolic stability of pyrimidinol antioxidants. This led us to consider the possibility of altering the positions of the exocyclic alkoxy and alkylamino substituents on the pyrimidinol scaffold. Twelve new analogues were prepared and their biological activities were investigated. The metabolic stability of the prepared regioisomers was also assessed in vitro using bovine liver microsomes. Unexpectedly, the 2-alkoxy-4-alkylamino substituted pyrimidinol antioxidants were found to have properties in protecting mitochondrial function superior to the isomeric 4-alkoxy-2-alkylamino substituted pyrimidinols evaluated in all earlier studies. This observation suggests a possible mode of action involving the intermediacy of an ortho-iminoquinone, a species not previously associated with mitochondrial respiratory chain function.

New Techniques for Ancient Proteins: Direct Coupling Analysis Applied on Proteins involved in Iron Sulfur Cluster Biogenesis

Marco Fantini, Duccio Malinverni, Paolo De Los Rios, Annalisa Pastore


Direct coupling analysis (DCA) is a powerful tool based on protein evolution and introduced to predict protein fold and protein-protein interactions which has been applied also to the prediction of entire interactomes. We have used DCA to analyse three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that, although based on a relatively small number of sequences due to its distribution in genomes, we can correctly recapitulate all the features of the fold of the CyaY/frataxin family, a protein involved in the human disease Friedreich’s ataxia. This result gave us confidence in the use of this tool. Application of DCA to the iron-sulfur cluster scaffold protein IscU, which has been suggested to function both as an ordered and a disordered form, allows us to clearly distinguish evolutionary traces of the structured species, suggesting that, if present in the cell, the disordered form has not left any evolutionary imprinting. We observe instead, for the first time, direct indications of how the protein can dimerize head-to-head and bind 4Fe4S clusters. Analysis of the alternative scaffold protein IscA provides strong support to a coordination of the cluster mediated by a dimeric rather than a tetrameric form as previously suggested. Our analysis also suggests the presence in solution of a mixture of monomeric and dimeric species and guide us to the prevalent one. Finally, we used DCA to analyse protein-protein interactions between some of these proteins and discuss the potentialities and the limitations of the method.

What is quality of life and how do we measure it? Relevance to Parkinson’s disease and movement disorders

  1. Pablo Martinez-Martin MD, PhD



Health-related quality of life is a patient-reported outcome that complements clinical evaluation and provides information about disease activity and effects of the treatment. The objective of this review is to present the conceptual framework, the measures, and some of their most relevant applications in the field of Parkinson’s disease and movement disorders. Health-related quality of life is a subjective, individual, and multidimensional construct, and its main dimensions are physical, mental, and social, besides global perceptions of health and personal domains. Health-related quality of life measurement is carried out by means of questionnaires or scales, ideally self-applied by patients, and has a diversity of important applications for clinical practice, research, and health policy. Movement disorders and Parkinson’s disease are complex conditions impacting all components of patients’ health-related quality of life. The use of health-related quality of life tools provides important information on a variety of aspects that are important to patients while complementing clinical evaluations. In particular, studies using this kind of assessment can identify and monitor the most important health-related quality of life determinant factors, allowing tailored assistance and prioritized interventions. In addition, maintaining or improving the patients’ health-related quality of life is an objective of care for chronic diseases and, therefore, it has to be monitored over time and as an outcome of clinical trials. Several methods are available for the interpretation of the change in scores of health-related quality of life measures, although a definitive agreement on the most appropriate method is yet to be determined. Presently, health-related quality of life assessment is an important outcome for research and management of chronic conditions such as Parkinson’s disease and other movement disorders

Sex Differences in Redox Biology: A Mandatory New Point of View Approaching Human Inflammatory Diseases

Straface Elisabetta, Malorni Walter, and Pietraforte Donatella. Antioxidants & Redox Signaling. January 2017, 26(1): 44-45. doi:10.1089/ars.2016.6931.

Cells from females and males respond differently to chemical and microbial stressors. “Male neurons” are more sensitive to stress induced by oxidants and excitatory neurotransmitters, whereas “female neurons” are more susceptible to some stimuli that prompt apoptosis. The growing interest for the redox medicine in human health has recently suggested a reappraisal of the disease-triggering oxidant-generating enzymes as suitable disease-relevant therapeutic targets. In the light of the reported lines of evidence, a sex- and gender perspective should drive future basic research and pre-clinical studies before starting any pharmacological research aimed at the development of new drugs candidates to counteract redox-related human diseases.

Two different genetic diseases in the same patient: Coincident, concomitant, or causally related?


·        Julia Graf MD, Yorck Hellenbroich MD, Norbert Veelken MD,   Karla P. Figueroa MS,     Simone Wolff MD    Stefan Pulst MD,   Norbert Brüggemann MD

  • A 17-year-old high school student started falling behind his peers and developed cramps at the age of 5 years, diagnosis of myotonic dystrophy was genetically confirmed. He developed progressive ataxia and prominent dysarthria. On examination, besides generalized muscle weakness and myotonic reactions, he showed saccadic pursuit, gaze-evoked nystagmus, dysmetria, gait ataxia, loss of deep-tendon reflexes, and an impaired sense of position and vibration. At the age of 15 years, genetic testing confirmed an additional diagnosis of Friedreich ataxia.
    Our findings have several important implications: Although genetic testing is the gold standard for a large number of neurological diseases, it does not replace a detailed neurological examination and careful taking of the family history. In some patients, a broad phenotypic spectrum may be a result of the existence of more than 1 gene defect. Although the occurrence of mutations in 2 genes is most likely coincidental in our patients, the possibility of a potential common predisposition to mutations should also be considered.
  • _,_.___

This report discusses the need for an integrated and cyclical approach to managing health technology in order to mitigate clinical and financial risks, and ensure acceptable value for money.

The proliferation of high-cost drugs and rising drug prices are raising pressure on public health services. Governments need to work with industry and regulators to define a new way of approaching the development and use of new health technologies that encourage innovation while making it more affordable and that justifies better the benefit that it brings.

According to the study, “the launch of cancer and rare diseases drugs is rising, sometimes without an assessment of the increased benefits they produce for the health of patients. In this sense, the OECD exemplifies this situation in the case of the United States “where the launch price of cancer drugs per year of life gained has increased fourfold in just 20 years, in constant terms, and already exceeds $ 200,000 “.
Mitochondrial iron-sulfur cluster biogenesis from molecular understanding to clinical disease
  Majid   Alfadhel,  Marwan   Nashabat,  Qais   Abu Ali,  Khalid   Hundallah
Iron_sulfur clusters (ISCs) are known to play a major role in various protein functions. Located in the mitochondria, cytosol, endoplasmic reticulum and nucleus, they contribute to various core cellular functions. Until recently, only a few human diseases related to mitochondrial ISC biogenesis defects have been described. Such diseases include Friedreich ataxia, combined oxidative phosphorylation deficiency 19, infantile complex II/III deficiency defect, hereditary myopathy with lactic acidosis and mitochondrial muscle myopathy, lipoic acid biosynthesis defects, multiple mitochondrial dysfunctions syndromes and non ketotic hyperglycinemia due to glutaredoxin 5 gene defect. Disorders of mitochondrial import, export and translation, including sideroblastic anemia with ataxia, EVEN-PLUS syndrome and mitochondrial complex I deficiency due to nucleotide-binding protein-like protein gene defect, have also been implicated in ISC biogenesis defects. With advances in next generation sequencing technologies, more disorders related to ISC biogenesis defects are expected to be elucidated. In this article, we aim to shed the light on mitochondrial ISC biogenesis, related proteins and their function, pathophysiology, clinical phenotypes of related disorders, diagnostic approach, and future implications.

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

Nigel A. Calcutt,1 Darrell R. Smith,2 Katie Frizzi,1 Mohammad Golam Sabbir,2Subir K. Roy Chowdhury,2 Teresa Mixcoatl-Zecuatl,1 Ali Saleh,2 Nabeel Muttalib,1 Randy Van der Ploeg,2 Joseline Ochoa,1 Allison Gopaul,1 Lori Tessler,2 Jürgen Wess,3 Corinne G. Jolivalt,1 and Paul Fernyhough2,4


Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor–dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible.

Team Led By The Ohio State University Researchers Publish Method in JoVE Video Journal to Standardize Protocol for Testing Mitchondrial Function

Reliable, Replicable and Efficient Detection of Mitochondrial Impairment Has Implications on Research to Treat a Wide Range of Metabolic Syndromes and Genetic Diseases


Today, researchers at The Ohio State University in collaboration with scientists at the University of Pennsylvania and the National Institute of Aging published a reproducible method to noninvasively measure in vivo human skeletal muscle mitochondrial function in JoVE Video Journal, the world’s first and only peer-reviewed scientific video journal. JoVE publishes high-quality video demonstrations of scientific experiments – offering researchers an easy and reliable way to replicate complex experimental techniques.

The video demonstration details a standard protocol for 31PMRS examination that affords serial, noninvasive and in vivo measurement of human skeletal muscle mitochondrial function. Aberrant mitochondrial impairment is a hallmark of a wide range of metabolic syndromes and genetic diseases, from common conditions such as aging and diabetes to rare disorders such as Friedreich’s ataxia. The protocol holds considerable appeal when considering the breadth of investigations needed to reduce growing burden of metabolic syndrome that contributes to significant disability and death worldwide. Importantly, this 31PMRS protocol requires a minimal amount of scanner time and can be incorporated into comprehensive metabolic investigations in subjects at any center with commercially-available PMRS facilities.

“Reliable methods to adequately define in vivo skeletal muscle function in a feasible, cost-effective, and reproducible manner are critical to improving outcomes for individuals with a range of diseases that affect mitochondrial function,” explained Dr. Subha Raman, MD the principal investigator of the experiment. “By publishing in JoVE Video Journal, our research team presents a protocol that any researcher can reliably replicate and use to test new ideas to improve mitochondrial function in patients.”

Until now, the approach has not been widely adopted in translational and clinical research in part due to variations in methodology and limited guidance from the literature. This work’s optimization, standardization, and dissemination of methods for in vivo 31PMRS will facilitate the development of targeted therapies to improve skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity to favorably impact cardiovascular and metabolic health.

The research team’s work was supported in part by an OSU Davis Heart and Lung Research Institute Trifit Award as well as the Intramural Research Program of the NIH National Institute on Aging.

Friedreich’s Ataxia and Variants


Among hereditary ataxias, Friedreich’s ataxia (FRDA) is the most common of the early-onset hereditary ataxias in Caucasians, caused by expansion of a GAA triplet located within the first intron of the frataxin gene on chromosome 9q13. Detailed genetic and family studies emphasize the potential heterogeneity in presenting phenotype as well as age of onset of patients with FRDA. The discovery of the frataxin gene has allowed genotype–phenotype correlations and confirmation that the FRDA expansion is responsible for classical FRDA, late-onset FRDA (LOFA), Friedreich’s ataxia with retained reflexes (FARR), and Acadian ataxia. The disease affects the central and peripheral nervous system, as well as the heart, skeleton, and endocrine system, and there is a clear correlation between age at onset, size of the expanded repeat and severity of the phenotype. Deficiency of frataxin has resulted in mitochondrial iron accumulation, defects in specific mitochondrial enzymes, and enhanced sensitivity to oxidative stress. Based on these findings, therapeutic approaches aimed at improving mitochondrial functioning and to increase frataxin expression, which may have lead to new realistic treatments in the future.

Establishment and Maintenance of Primary Fibroblast Repositories for Rare Diseases—Friedreich’s Ataxia Example

To cite this article:
Li Yanjie, Polak Urszula, Clark Amanda D., Bhalla Angela D., Chen Yu-Yun, Li Jixue, Farmer Jennifer, Seyer Lauren, Lynch David, Butler Jill S., and Napierala Marek. Biopreservation and Biobanking. August 2016,

Author information

Yanjie Li,1 Urszula Polak,2 Amanda D. Clark,1 Angela D. Bhalla,1 Yu-Yun Chen,1 Jixue Li,1 Jennifer Farmer,3 Lauren Seyer,3 David Lynch,3 Jill S. Butler,1 and Marek Napierala1,4

1Department of Biochemistry and Molecular Genetics, UAB Stem Cell Institute, University of Alabama at Birmingham, Birmingham, Alabama.

2Department of Molecular Carcinogenesis, Center for Cancer Epigenetics, University of Texas MD Anderson Cancer Center, Smithville, Texas.

3Division of Neurology and Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania.

4Department of Molecular Biomedicine, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.

Address correspondence to:

Jill S. Butler, PhD

Department of Biochemistry and Molecular Genetics

UAB Stem Cell Institute

University of Alabama at Birmingham

1825 University Boulevard

Birmingham, AL 35294


Marek Napierala, PhD

Department of Biochemistry and Molecular Genetics

UAB Stem Cell Institute

University of Alabama at Birmingham

1825 University Boulevard

Birmingham, AL 35294



Friedreich’s ataxia (FRDA) represents a rare neurodegenerative disease caused by expansion of GAA trinucleotide repeats in the first intron of the FXN gene. The number of GAA repeats in FRDA patients varies from approximately 60 to <1000 and is tightly correlated with age of onset and severity of the disease symptoms. The heterogeneity of Friedreich’s ataxia stresses the need for a large cohort of patient samples to conduct studies addressing the mechanism of disease pathogenesis or evaluate novel therapeutic candidates. Herein, we report the establishment and characterization of an FRDA fibroblast repository, which currently includes 50 primary cell lines derived from FRDA patients and seven lines from mutation carriers. These cells are also a source for generating induced pluripotent stem cell (iPSC) lines by reprogramming, as well as disease-relevant neuronal, cardiac, and pancreatic cells that can then be differentiated from the iPSCs. All FRDA and carrier lines are derived using a standard operating procedure and characterized to confirm mutation status, as well as expression of FXN mRNA and protein. Consideration and significance of creating disease-focused cell line and tissue repositories, especially in the context of rare and heterogeneous disorders, are presented. Although the economic aspect of creating and maintaining such repositories is important, the benefits of easy access to a collection of well-characterized cell lines for the purpose of drug discovery or disease mechanism studies overshadow the associated costs. Importantly, all FRDA fibroblast cell lines collected in our repository are available to the scientific community.

Friedreich Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia

Arnulf H. Koeppen, MD

Alyssa B. Becker, BA

Jiang Qian, MD, PhD

Paul J. Feustel, PhD


After Friedreich’s description in 1877, depletion of myelinated fibers in the dorsal columns, dorsal spinocerebellar and lateral corticospinal tracts, and neuronal loss in the dorsal nuclei of Clarke columns were considered unique and essential neuropathological features of Friedreich ataxia (FA). Lack of large neurons in dorsal root ganglia (DRG), thinning of dorsal roots (DR), and poor myelination in sensory nerves are now recognized as key components of FA. Here, we measured cross-sectional areas of the mid-thoracic spinal cord (SC) and neuronal sizes in lumbosacral DRG of 24 genetically confirmed FA cases. Mean thoracic SC areas in FA (24.17 mm2) were significantly smaller than those in 12 normal controls (37.5 mm2); DRG neuron perikarya in FA (1362 µm2) were also significantly smaller than normal (2004 µm2). DRG neuron sizes were not correlated with SC areas. The FA patients included a wide range of disease onset and duration suggesting that the SC undergoes growth arrest early and remains abnormally small throughout life. Immunohistochemistry for phosphorylated neurofilament protein, peripheral myelin protein 22, and myelin proteolipid protein confirmed chaotic transition of axons into the SC in DR entry zones. We conclude that smaller SC areas and lack of large DRG neurons indicate hypoplasia rather than atrophy in FA.

New hearts for Friedreich patients

David Pleasure

Neurology, UC Davis, c/o Shriners Hospital, 2425 Stockton Blvd, Sacramento , CA 95817, United States

·        Abstract


·        Most individuals with Friedreich ataxia (FRDA) have an abnormal electrocardiogram and elevated serum concentrations of cardiac troponin 1. Many eventually develop cardiac hypertrophy, and heart failure is a frequent cause for their death. Histological evaluation of the heart shows enlarged cardiomyocytes encircled by fibrotic endomysium. Some of the enlarged cardiac myocytes, and also some macrophages that have accumulated in endomysium, contain iron-positive inclusions, but total cardiac iron content is not increased.  
Cardiac transplantation in Friedreich Ataxia: Extended follow-up


Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder most commonly caused by guanine-adenine-adenine (GAA) trinucleotide repeat expansions in both alleles of the FXN gene. Although progressive ataxia remains the hallmark clinical feature, patients with FRDA are at high risk of developing cardiomyopathy, often resulting in premature death. There is no specific treatment for FRDA-associated cardiomyopathy; even in advanced cardiac failure cardiac transplantation is not commonly pursued. This case series describes extended follow-up of three FRDA cases with end-stage heart failure but mild neurologic disease who underwent successful heart transplantation. We also review and examine the ethical considerations for heart transplantation in the setting of neurodegenerative disease.

Impact of cerebellar atrophy on cortical gray matter and cerebellar peduncles as assessed by voxel-based morphometry and high angular resolution diffusion imaging

Dayan M., Olivito G., Molinari M., Cercignani M., Bozzali M., Leggio


In recent years the cerebellum has been attributed amore important role in higher-level functions than previously believed. We examined a cohort of patients suffering from cerebellar atrophy resulting in ataxia, with two main objectives: first to investigate which regions of the cerebrum were affected by the cerebellar degeneration, and second to assess whether diffusion magnetic resonance imaging (dMRI) metrics within the medial (MCP) and superior cerebellar peduncle (SCP) – namely fractional anisotropy (FA) and radial diffusivity (RD) – could be used as a biomarker in patients with this condition.
Structural and dMRI data of seven patients with cerebellar atrophy (2 with spinocerebellar atrophy type 2, 1 with Friedreich’s ataxia, 4 with idiopathic cerebellar ataxia) and no visible cortical lesions or cortical atrophy were investigated with Freesurfer and voxel-based morphometry (VBM) of gray matter (GM) as well as MCP and SCP FA maps. Correlations of MCP and SCP mean FA with ataxia scores and subscores were also evaluated. Freesurfer showed that patients had significantly reduced volume of the thalamus, ventral diencephalon and pallidum. VBM also demonstrated significantly lower local GM volumes in patients, notably in the head of the caudate nucleus, posterior cingulate gyrus and orbitofrontal cortex bilaterally, as well as in Broca’s area in the left hemisphere, and a significant increase in RD in the MCP and SCP of both hemispheres. A significant correlation was found between MCP mean FA and total ataxia score (R=−0.7, p=0.03), and subscores for kinetic functions (R=−0.74, p=0.03) and oculomotor disorders (R=−0.70, p=0.04).
The regions of the cerebrum found to have significantly lower local GM volumes have been described to be involved in higher-level cerebellar functions such as initiation of voluntary movements, emotional control, memory retrieval and general cognition. Our findings
corroborate recent research pointing to a more extensive corticocerebellar system than previously thought.
The significant difference in the MCP and SCP dMRI metrics between patients and controls as well as the significant correlation with ataxia total score and subscores support the use of dMRI metrics as an imaging biomarker for cerebellar degeneration and ataxia.

Otoneurological Abnormalities in Patients with Friedreich’s Ataxia

Bianca Simone Zeigelboim1, Juliana Cristina Mesti2, Vinicius Ribas Fonseca2, João Henrique Faryniuk1, Jair Mendes Marques1, Rafaella Cardosa Cardoso1, Hélio Afonso Ghizoni Teive3

  • 1Department of Communication Disorders, Universidade Tuiuti do Paraná, Curitiba, Brazil
  • 2Department of Otorhinolaringology, Hospital da Cruz Vermelha, Curitiba, Brazil
  • 3Department of Internal Medicine, Hospital das Clínicas, Curitiba, Brazil


Introduction Friedreich’s ataxia is a neurodegenerative disease and progressive by nature. It has autosomal recessive inheritance and early onset in most cases. Nystagmus and hearing loss (in some cases) make up some of the common symptoms seen in this disorder.

Objective The objective of this study is to examine vestibular disorders in patients with Friedreich ataxia.

Methods We conducted a retrospective cross-sectional study. We evaluated 30 patients with ages ranging from six to 72 years (mean age of 38.6 ( ±  14.7). The patients underwent the following procedures: anamnesis, ENT, and vestibular evaluations.

Results Clinically, the patients commonly had symptoms of incoordination of movement (66.7%), gait disturbances (56.7%), and dizziness (50%). In vestibular testing, alterations were predominantly evident under caloric testing (73.4%), gaze nystagmus testing (50.1%), rotational chair testing (36.7%), and optokinetic nystagmus testing (33.4%). The presence of alterations occurred under examination in 90% of subjects, with the majority occurring in those with central vestibular dysfunction (70% of the examinations).

Conclusion The most evident neurotological symptoms were incoordination of movement, gait disturbances, and dizziness. Alterations in vestibular examinations occurred in 90% of patients, mostly in the caloric test, with a predominance of deficient central vestibular system dysfunction.

Synthetic genome readers target clustered binding sites across diverse chromatin states

  1. Graham S. Erwina,
  2. Matthew P. Grieshopa,1,
  3. Devesh Bhimsariaa,b,1,
  4. Truman J. Doa,
  5. José A. Rodríguez-Martíneza,
  6. Charu Mehtaa,
  7. Kanika Khannaa,
  8. Scott A. Swansonc,
  9. Ron Stewartc,
  10. James A. Thomsonc,d,
  11. Parameswaran Ramanathanb, and
  12. Aseem Z. Ansaria,d,2

Author Affiliations

  1. Edited by Tom W. Muir, Princeton University, Princeton, NJ, and accepted by Editorial Board Member Brenda A. Schulman October 9, 2016 (received for review March 24, 2016)


Targeting specific genomic loci with synthetic molecules remains a major goal in chemistry, biology, and precision medicine. Identifying how synthetic genome readers bind the chromatinized genome in cells would facilitate their development, but doing so remains a formidable challenge. We map the genome-wide binding patterns for two structurally distinct synthetic molecules. To achieve this goal, we couple our cross-linking of small molecules to isolate chromatin approach to next-generation sequencing. In addition to binding high-affinity sites, these molecules, surprisingly, bind clustered low-affinity sites. The data also show that these genome readers target sites in both open and closed chromatin. Our findings highlight the importance of genome-guided design for molecules that will serve as precision-targeted therapeutics.


Targeting the genome with sequence-specific DNA-binding molecules is a major goal at the interface of chemistry, biology, and precision medicine. Polyamides, composed of N-methylpyrrole and N-methylimidazole monomers, are a class of synthetic molecules that can be rationally designed to “read” specific DNA sequences. However, the impact of different chromatin states on polyamide binding in live cells remains an unresolved question that impedes their deployment in vivo. Here, we use cross-linking of small molecules to isolate chromatin coupled to sequencing to map the binding of two bioactive and structurally distinct polyamides to genomes directly within live H1 human embryonic stem cells. This genome-wide view from live cells reveals that polyamide-based synthetic genome readers bind cognate sites that span a range of binding affinities. Polyamides can access cognate sites within repressive heterochromatin. The occupancy patterns suggest that polyamides could be harnessed to target loci within regions of the genome that are inaccessible to other DNA-targeting molecules.

A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study

  • Authors
  • Luca Leonardi
  • Maria Gabriella Aceto
  • Christian Marcotulli
  • Giuseppe Arcuria
  • Mariano Serrao
  • Francesco Pierelli
  • Paolo Paone
  • Alessandro Filla
  • Alessandro Roca
  • Carlo Casali



The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. Eleven adult patients with a confirmed genetic diagnosis of autosomal dominant spinocerebellar ataxia or Friedreich’s ataxia were asked to wear an active device for 3 weeks. Assessments were performed at baseline, after the device use (T1), and 3 weeks after (T2). SARA, 9-HPT, PATA, 6MWT, and spatial and temporal gait parameters, measured with a BTS-G-Walk inertial sensor, were used as study endpoints. As expected, no adverse effects were reported. Statistically significant improvements in SARA, 9HPT dominant hand, PATA test, 6MWT, cadence, length cycle, support right/cycle, support left/cycle, flight right/cycle, flight left/cycle, double support right/cycle, double support left/cycle, single support right/cycle, and single support left/cycle were observed between T0 and T1. All parameters improved at T1 did not show statistically significant differences a T2, with the exception of length of cycle. This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.,14727?month=2&year=2017



Two PhD student positions are available at the Department of Molecular Biomedicine, Institute of Bioorganic Chemistry PAS in Poznan.

NCN Project OPUS10: “Role of microRNAs in regulation iron metabolism in Friedreich’s ataxia

Friedreich’s ataxia (FRDA) is the most frequent inherited form of ataxia in humans. The most common FRDA symptoms include muscle weakness and loss of coordination, vision impairment and hearing loss, heart muscle abnormalities, scoliosis, and diabetes. First symptoms can usually be noticed between the ages of 5 and 15 and they progressively worsen with time. Cardiac failure is the primary cause of death in FRDA patients. The goals of this project are to define changes in the expression and activity of microRNAs in FRDA, and analyze how these abnormalities affect the activity of genes which are responsible for the localization and amount of iron in neuronal and heart cells of patients with Friedreich’s ataxia. We will define relationship between miRNA molecules and iron availability.  We will also uncover the pattern of detectable microRNA molecules that is specific to FRDA. This “microRNA signature” characteristic for FRDA will help to evaluate the effectiveness of therapeutic approaches intended to increase activity of the frataxin gene or to regulate distribution of iron in neurons and cardiac cells of FRDA patients. Misregulated microRNAs as well as genes under their control may also become new targets for therapeutic intervention in FRDA.