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Gastrocnemius and soleus spasticity and muscle length in Friedreich’s ataxia

·        Sarah C. Milnea, b, c, 1, 

·        Louise A. Corbenb, c, d, , 1, , 

·        Eppie Yiuc, e, 

·        Martin B. Delatyckib, c, f, 

·        Nellie Georgiou-Karistianisb



Lower limb spasticity compromises the independence of people with Friedreich’s ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n = 18) and non-ambulant (n = 13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.


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.


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.
Tissue atrophy and elevated iron concentration in the extrapyramidal motor system in Friedreich ataxia: the IMAGE-FRDA study

1.   Ian H Harding1, 

2.   Parnesh Raniga2, 

3.   Martin B Delatycki1,3,4, 

4.   Monique R Stagnitti1,

5.   Louise A Corben1,3,5, 

6.   Elsdon Storey6, 

7.   Nellie Georgiou-Karistianis1, 

8.   Gary F Egan2



Friedreich ataxia (FRDA) is an autosomal recessive disorder defined by progressive motor incoordination. FRDA results from reduced expression of the protein, frataxin, which is involved in cellular iron homeostasis and metabolism, antioxidant protection, and iron-sulfur cluster biogenesis. Disruption of one or more of these processes putatively underpins the pathophysiology of FRDA, which manifests in cell death preferentially targeted to tissues with high rates of frataxin transcription.1

In the brain, accumulation or redistribution of iron within, and atrophy of, the cerebellar dentate nuclei have been reported.1–3 The dentate nuclei are iron-laden structures pivotal to movement coordination. However, basal ganglia and midbrain structures also have high iron content, express high levels of frataxin, and play key roles in motor regulation. Furthermore, the dentate nuclei directly innervate the thalamus and red nuclei, and indirectly project to the striatum. This biology motivates the hypothesis that iron-related pathology and/or degeneration within these extrapyramidal stations may also feature in FRDA. To test this hypothesis, we analysed tissue volume and iron concentration within the dentate nuclei, midbrain (red nuclei, substantia nigra), basal ganglia (caudate, putamen and pallidum), and thalami in individuals with FRDA and healthy controls using magnetic resonance imaging (MRI)


Vivre avec la maladie de Friedreich : le vécu dysarthrique

·        Stéphanie Borel1, , , 

·        Geneviève Touretz-Hermer2, 

·        Sandrine Goutaland-Perrin2, 

·        Peggy Gatignol1



Cette étude porte sur l’auto-évaluation du handicap de la voix et de la parole des personnes atteintes de la maladie de Friedreich (FRDA), maladie neurodégénérative rare d’origine génétique de type autosomique récessive.


Après avoir été sensibilisés à la différence entre la production de la voix et celle de la parole, 26 participants atteints de la maladie de Friedreich ont rempli les versions françaises de deux questionnaires d’auto-évaluation du handicap ressenti, le Voice Handicap Index (VHI) et le Speech Handicap Index (SHI).


Les moyennes des deux scores aux questionnaires atteignent un niveau pathologique. Il n’y a pas de différence significative entre les moyennes au SHI et au VHI ce qui signifie que les patients ont évalué au même niveau leurs handicaps de voix et de parole. Les scores aux VHI et SHI sont corrélés. Une analyse complémentaire a mis en évidence deux groupes : l’un avec un ressenti du handicap de la voix plus important, et l’autre avec un ressenti du handicap de la parole plus important.


Dans le contexte de cette étude, l’utilisation du VHI et du SHI est appropriée pour mettre en évidence les différents profils dysarthriques des participants FRDA. Dans le cadre de l’évaluation orthophonique, l’utilisation conjointe de ces deux questionnaires semble inadaptée pour des raisons de durée de passation et de non-spécificité par rapport à la maladie de Friedreich. D’autres études sont nécessaires pour mieux connaître l’impact de la FRDA sur la qualité de vie des personnes atteintes, mais aussi l’outil le plus adapté pour le mesurer.


A Case of Ataxia with Isolated Vitamin E Deficiency Initially Diagnosed as Friedreich's Ataxia

Michael Bonello * and Partha Ray


Both idebenone and idebenol are localized near the lipid–water interface of the membrane and increase its fluidity

·        Victoria Gómez-Murcia, 

·        Alejandro Torrecillas, 

·        Ana M. de Godos, 

·        Senena Corbalán-García, 

·        Juan C. Gómez-Fernández


Idebenone is a synthetic analog of coenzyme Q; both share a quinone moiety but idebenone has a shorter lipophilic tail ending with a hydroxyl group. Differential scanning calorimetry experiments showed that both idebenone and idebenol widened and shifted the phase transition of 1,2-dipalmitoylphosphatidylcholine (DPPC) to a lower temperature and a phase separation with different concentrations of these molecules was observed. Also small angle X-ray diffraction and wide angle X-ray diffraction revealed that both, idebenone and idebenol, induced laterally separated phases in fluid membranes when included in DPPC membranes. Electronic profiles showed that both forms, idebenone and idebenol, reduced the thickness of the fluid membrane. 2H NMR measurements showed that the order of the membrane decreased at all temperatures in the presence of idebenone or idebenol, the greatest disorder being observed in the segments of the acyl chains close to the lipid–water interface. 1H NOESY MAS NMR spectra were obtained using 1-palmitoyl-2-oleoyl-phosphatidylcholine membranes and results pointed to a similar location in the membrane for both forms, with the benzoquinone or benzoquinol rings and their terminal hydroxyl group of the hydrophobic chain located near the lipid/water interface of the phospholipid bilayer and the terminal hydroxyl group of the hydrophobic chain of both compounds located at the lipid/water interface. Taken together, all these different locations might explain the different physiological behavior shown by the idebenone/idebenol compared with the ubiquinone-10/ubiquinol-10 pair in which both compounds are differently localized in the membrane.


AVC chez un patient de 25 ans atteint d’une maladie de Friedreich

·        Cyrielle Coignion1, , , 

·        Cyril Goizet2, 

·        Xavier Vandamme3



L’ataxie, la dysarthrie et la neuropathie périphérique sont les manifestations neurologiques les plus connues de la maladie de Friedreich. Peu d’accidents vasculaires cérébraux (AVC) ont été rapportés dans ce cadre.


Le diagnostic de maladie de Friedreich a été posé chez ce patient à l’âge de 14 ans sur un tableau clinique typique associé à une mutation sur les 2 copies du gène de la frataxine. À l’âge de 16 ans, une cardiomyopathie hypertrophique asymptomatique a été diagnostiquée, compliquée d’une hyperexcitabilité supra-ventriculaire sans fibrillation auriculaire (FA). Un traitement par bêta-bloquant a été introduit, associé à de l’idébénone. À 25 ans, le patient rapporte la survenue d’une hémianopsie latérale homonyme droite brutale. Le reste de l’examen neurologique était inchangé par rapport à la précédente évaluation 2 mois avant, à savoir une ataxie statique avec une marche possible uniquement sur quelques pas, une dysarthrie et des troubles de la déglutition. L’IRM cérébrale a mis en évidence une lésion ischémique récente dans le territoire de l’artère cérébrale postérieure gauche, sans occlusion artérielle sur la séquence TOF. La surveillance télémétrique a révélé plusieurs passages en FA. L’échographie cardiaque retrouvait une hypertrophie concentrique du ventricule gauche stable, avec une fraction d’éjection conservée. Le reste du bilan étiologique était sans particularité. Un traitement anticoagulant a été instauré.


La cardiomyopathie hypertrophique est la complication cardiaque la plus fréquente de la maladie de Friedreich, le plus souvent asymptomatique. Néanmoins, celle-ci contribue au développement d’une insuffisance cardiaque et aux troubles du rythme supra-ventriculaires. L’atteinte cardiaque serait responsable de 59 % des décès chez ces patients. L’idébénone pourrait avoir un effet protecteur en améliorant la fonction cardiaque.


L’association maladie de Friedreich et AVC est possible par le biais d’une cardiomyopathie hypertrophique et d’une FA qu’il est nécessaire de dépister afin de mettre en place un traitement cardioprotecteur.


Rosuvastatin (Crestor) in Friedreich Ataxia

This study is not yet open for participant recruitment. (see Contacts and Locations)

Verified March 2016 by Children's Hospital of Philadelphia


Children's Hospital of Philadelphia

Information provided by (Responsible Party):

David Lynch, Children's Hospital of Philadelphia Identifier:


Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34

·        Yan Shen,

·        Marissa Z. McMackin,

·        Yuxi Shan,

·        Alan Raetz,

·        Sheila David,

·        Gino Cortopassi



An inherited deficiency in the frataxin protein causes neurodegeneration of the dorsal root ganglia and Friedreich's ataxia (FA). Frataxin deficiency leads to oxidative stress and inflammatory changes in cell and animal models; however, the cause of the inflammatory changes, and especially what causes brain microglial activation is unclear. Here we investigated: 1) the mechanism by which frataxin deficiency activates microglia, 2) whether a brain-localized inflammatory stimulus provokes a greater microglial response in FA animal models, and 3) whether an anti-inflammatory treatment improves their condition. Intracerebroventricular administration of LPS induced higher amounts of microglial activation in the FA mouse model vs controls. We also observed an increase in oxidative damage in the form of 8-oxoguanine (8-oxo-G) and the DNA repair proteins MUTYH and PARP-1 in cerebellar microglia of FA mutant mice. We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1. Frataxin knockdown also induced a higher level of PARP-1 in MEF cells, and this was suppressed in MUTYH-/- knockout cells. Administration of the PARP-1 inhibitor PJ34 attenuated the microglial activation induced by intracerebroventricular injection of LPS. The combined administration of LPS and angiotensin II provoke an even stronger activation of microglia and neurobehavioral impairment. PJ34 treatment attenuated the neurobehavioral impairments in FA mice. These results suggest that the DNA repair proteins MUTYH and PARP-1 may form a pathway regulating microglial activation initiated by DNA damage, and inhibition of microglial PARP-1 induction could be an important therapeutic target in Friedreich's ataxia.


Near-infrared spectroscopy for medical applications: Current status and future perspectives

·        Akikazu Sakudo, 




NIR spectroscopy represents a useful tool for clinical laboratory test.

Non-invasive diagnosis has been approached by NIR spectroscopy.

NIR spectroscopy has been used for various applications in medical field.

Information of NIR spectra helps to understand pathophysiology of diseases.


The near-infrared radiation (NIR) window, also known as the “optical window” or “therapeutic window”, is the range of wavelengths that has the maximum depth of penetration in tissue. Indeed, because NIR is minimally absorbed by water and hemoglobin, spectra readings can be easily collected from the body surface. Recent reports have shown the potential of NIR spectroscopy in various medical applications, including functional analysis of the brain and other tissues, as well as an analytical tool for diagnosing diseases. The broad applicability of NIR spectroscopy facilitates the diagnosis and therapy of diseases as well as elucidating their pathophysiology. This review introduces recent advances and describes new studies in NIR to demonstrate potential clinical applications of NIR spectroscopy.

An Overview of Direct Somatic Reprogramming: The Ins and Outs of iPSCs

Siddharth Menon 1, Siny Shailendra 1, Andrea Renda 2, Michael Longaker 1,3,* and Natalina Quarto 1,2,*


Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, School of Medicine, Stanford University, 257 Campus Drive, Stanford, CA 94305, USA


Dipartimento di Scienze Biomediche Avanzate, Universita’ degli Studi di Napoli Federico II, Napoli 80131, Italy


Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA



: Stem cells are classified into embryonic stem cells and adult stem cells. An evolving alternative to conventional stem cell therapies is induced pluripotent stem cells (iPSCs), which have a multi-lineage potential comparable to conventionally acquired embryonic stem cells with the additional benefits of being less immunoreactive and avoiding many of the ethical concerns raised with the use of embryonic material. The ability to generate iPSCs from somatic cells provides tremendous promise for regenerative medicine. The breakthrough of iPSCs has raised the possibility that patient-specific iPSCs can provide autologous cells for cell therapy without the concern for immune rejection. iPSCs are also relevant tools for modeling human diseases and drugs screening. However, there are still several hurdles to overcome before iPSCs can be used for translational purposes. Here, we review the recent advances in somatic reprogramming and the challenges that must be overcome to move this strategy closer to clinical application.

The medical experience of a patient with a rare disease and her family

·      Roberta Garau


This letter considers the main challenges that people with rare diseases and their families face: delay in diagnosis, lack of appropriate support and information, and impaired access to treatment. The differences in medical experience between a patient with a rare disease and one with a common one are made through the use of a real-life example: the diagnosis of leiomyosarcoma received by my mother. I highlight how patients with rare disease are often misdiagnoses and how their symptoms are often overlooked. I also highlight the isolation patients with rare diseases and their families experience due to the lack of knowledge about their condition, the struggle to access treatment and the small amount of information and evidence based medicine for managing rare conditions.

This article was the winning entry in the Findacure essay contest ‘The Student Voice’. More information about Findacure can be found at http://​www.​findacure.​org.​uk.



Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy

·        Duncan E. Crombiea, b, 

·        Martin F. Perac, 

·        Martin B. Delatyckid, e, f, 

·        Alice Pébaya, b, , 




We discuss Friedreich Ataxia cardiomyopathy.

We summarise experimental models to study Friedreich Ataxia cardiomyopathy.

We focus on the use of human pluripotent stem cells as a disease model.


Friedreich ataxia (FRDA) is the most common of the inherited ataxias. It is an autosomal recessive disease characterised by degeneration of peripheral sensory neurons, regions of the central nervous system and cardiomyopathy. FRDA is usually due to homozygosity for trinucleotide GAA repeat expansions found within first intron of the FRATAXIN (FXN) gene, which results in reduced levels of the mitochondrial protein FXN. Reduced FXN protein results in mitochondrial dysfunction and iron accumulation leading to increased oxidative stress and cell death in the nervous system and heart. Yet the precise functions of FXN and the underlying mechanisms leading to disease pathology remain elusive. This is particularly true of the cardiac aspect of FRDA, which remains largely uncharacterized at the cellular level. Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease model

Iron Homeostasis in Health and Disease

Raffaella Gozzelino 1,*,† and Paolo Arosio 2,*,†


Inflammation and Neurodegeneration Laboratory, Chronic Diseases Research Center (CEDOC), Nova Medical School (NMS)/Faculdade de Ciências Médicas, University of Lisbon, Lisbon 1150-082, Portugal


Department of Molecular and Translational Medicine (DMMT), University of Brescia, Brescia 25123, Italy



: Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload.



Genome Editing of Structural Variations: Modeling and Gene Correction

·        Chul-Yong Park1, 

·        Jin Jea Sung1, 

·        Dong-Wook Kim1, , 


The analysis of chromosomal structural variations (SVs), such as inversions and translocations, was made possible by the completion of the human genome project and the development of genome-wide sequencing technologies. SVs contribute to genetic diversity and evolution, although some SVs can cause diseases such as hemophilia A in humans. Genome engineering technology using programmable nucleases (e.g., ZFNs, TALENs, and CRISPR/Cas9) has been rapidly developed, enabling precise and efficient genome editing for SV research. Here, we review advances in modeling and gene correction of SVs, focusing on inversion, translocation, and nucleotide repeat expansion.


SVs are found in healthy individuals and have a positive effect on genetic diversity. However, through development of genome-wide sequencing technologies, it has been revealed that SVs can be involved in some diseases.

The development of engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 has led to breakthroughs in the studies of diseases with SVs in terms of understanding mechanisms, disease modeling, and gene correction.

We discuss current advances and future strategies in modeling and gene correction of SVs using engineered nucleases.

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Mitochondrial iron overload: causes and consequences

·        Tracey A Rouault 


Pathological overload of iron in the mitochondrial matrix has been observed in numerous diseases, including sideroblastic anemias, which have many causes, and in genetic diseases that affect iron-sulfur cluster biogenesis, heme synthesis, and mitochondrial protein translation and its products. Although high expression of the mitochondrial iron importer, mitoferrin, appears to be an underlying common feature, it is unclear what drives high mitoferrin expression and what other proteins are involved in trapping excess toxic iron in the mitochondrial matrix. Numerous examples of human diseases and model systems suggest that mitochondrial iron homeostasis is coordinated through transcriptional remodeling. A cytosolic/nuclear molecule may affect a transcriptional factor to coordinate the events that lead to iron accumulation, but no candidates for this role have yet been identified.


Translatability: what does it mean in drug discovery?

·        Matthew Tudor

·        Jeffery Hermes

·        Jing Li, 


·         Note to users:
Uncorrected proofs are Articles in Press that have been copy edited and formatted, but have not been finalized yet. They still need to be proof-read and corrected by the author(s) and the text could still change before final publication.

Although uncorrected proofs do not have all bibliographic details available yet, they can already be cited using the year of online publication and the DOI, as follows: author(s), article title, Publication (year), DOI. Please consult the journal's reference style for the exact appearance of these elements, abbreviation of journal names and use of punctuation.

When the final article is assigned to volumes/issues of the Publication, the Article in Press version will be removed and the final version will appear in the associated published volumes/issues of the Publication. The date the article was first made available online will be carried over.



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