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Objective: To determine how mobility device use impacts quality of life in children with Friedreich ataxia. Study Design: Data from 111 pediatric patients with genetically confirmed Friedreich ataxia were collected from a prospective natural history study utilizing standardized clinical evaluations, including health-related quality of life using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Module. Results: Mobility device use was associated with worse mean PedsQL total, physical, emotional, social, and academic subscores, after adjusting for gender, age of disease onset, and Friedreich Ataxia Rating Scale score. The magnitude of the difference was greatest for the physical subscore (–19.5 points, 95% CI = –30.00, –8.99, P < .001) and least for the emotional subscore (–10.61 points, 95% CI = –20.21, –1.02, P = .03). Transition to or between mobility devices trended toward worse physical subscore (–16.20 points, 95% CI = –32.07, –0.33, P = .05). Conclusions: Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia. [ABSTRACT FROM AUTHOR]

Human T-cell lymphotropic virus (HTLV)-1-associated myelopathy (HAM) is well described. Clinical features are predominantly consistent with cord pathology, though imaging and autopsy studies also demonstrate brain inflammation. In general, this is subclinical; however, six cases have previously been reported of encephalopathy in HTLV-1-infected patients, without alternative identified aetiology. We describe three further cases of encephalitis in the UK HAM cohort (n = 142), whereas the annual incidence of acute encephalitis in the general population is 0.07-12.6 per 100,000. Clinical features included reduced consciousness, fever/hypothermia, headaches, seizures, and focal neurology. Investigation showed: raised CSF protein; pleocytosis; raised CSF:peripheral blood mononuclear cell HTLV-1 proviral load ratio; and MRI either normal or showing white matter changes in brain and cord. Four of the six previous case reports of encephalopathy in HTLV-infected patients also had HAM. Histopathology, reported in three, showed perivascular predominantly CD8+ lymphocytic infiltrates in the brain. One had cerebral demyelination, and all had cord demyelination. We have reviewed the existing six cases in the literature, together with our three new cases. In all seven with HAM, the spastic paraparesis deteriorated sub-acutely preceding encephalitis. Eight of the nine were female, and four of the seven treated with steroids improved. We propose that HTLV-associated encephalopathy may be part of the spectrum of HTLV-1-induced central nervous system disease. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia is a disease caused by a decrease in the levels of expression or loss of functionality of the mitochondrial protein frataxin (FXN). The development of an active and stable recombinant variant of FXN is important for protein replacement therapy. Although valuable data about the mature form FXN81‐210 has been collected, not enough information is available about the conformation of the frataxin precursor (FXN1‐210). 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 Escherichia coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing. The protein was found to be stable and monomeric, with the N‐terminal stretch (residues 1–89) mostly unstructured and the C‐terminal domain properly folded. The experimental data suggest a complex picture for the folding process of full‐length frataxin in vitro: the presence of the N‐terminal region increased the tendency of FXN to aggregate at high temperatures but this could be avoided by the addition of low concentrations of GdmCl. The purified precursor was translocated through cell membranes. In addition, immune response against His6‐TAT‐FXN1‐210 was measured, suggesting that the C‐terminal fragment was not immunogenic at the assayed protein concentrations. Finally, the recognition of recombinant FXN by cellular proteins was studied to evaluate its functionality. In this regard, cysteine desulfurase NFS1/ISD11/ISCU was activated in vitro by His6‐TAT‐FXN1‐210. Moreover, the results showed that His6‐TAT‐FXN1‐210 can be ubiquitinated in vitro by the recently identified frataxin E3 ligase RNF126, in a similar way as the FXN1‐210, suggesting that the His6‐TAT extension does not interfere with the ubiquitination machinery. [ABSTRACT FROM AUTHOR]

Abstract: Friedreich ataxia (FA) is a rare disease caused by deficiency of frataxin, a mitochondrial protein. As there is no cure available for this disease, many strategies have been developed to reduce the deleterious effects of such deficiency. One of these approaches is based on delivering frataxin to the tissues by coupling the protein to trans‐activator of transcription (TAT) peptides, which enables cell membranes crossing. In this study, we tested the efficiency of TAT‐MTScs‐FXN fusion protein to decrease neurodegeneration markers on frataxin‐depleted neurons obtained from dorsal root ganglia (DRG), one of the most affected tissues. In mice models of the disease, we tested the ability of TAT‐MTScs‐FXN to penetrate the mitochondria and its effect on lifespan. In DRG neurons, treatment with TAT‐MTScs‐FXN increased cell survival, decreased neurite degeneration and reduced apoptotic markers, such as α‐fodrin cleavage and caspase 9 activation. Also, we show that heat‐shock protein 60 (HSP60), a molecular chaperone targeted to mitochondria, suffered an impaired processing in frataxin‐deficient neurons that was relieved by TAT‐MTScs‐FXN addition. In mice models of the disease, administration of TAT‐MTScs‐FXN was able to reach muscle mitochondria, restore the activity of the succinate dehydrogenase and produce a significant lifespan increase. These results support the use of TAT‐MTScs‐FXN as a treatment for Friedreich ataxia. [ABSTRACT FROM AUTHOR]

Synchrotron radiation based nanoscopic X-ray fluorescence (SR nano-XRF) analysis can visualize trace level elemental distribution in a fully quantitative manner within single cells. However, in-air XRF analysis requires chemical fixation modifying the cell’s chemical composition. Here, we describe first nanoscopic XRF analysis upon cryogenically frozen (-150°C) fibroblasts at the ID16A-NI ‘Nano-imaging’ end-station located at the European Synchrotron Radiation Facility (ESRF) in Grenoble (France). Fibroblast cells were obtained from skin biopsies from control and Friedreich’s ataxia (FRDA) patients. FRDA is an autosomal recessive disorder with dysregulation of iron metabolism as a key feature. By means of the X-ray Fundamental Parameter (FP) method, including absorption correction of the ice layer deposited onto the fibroblasts, background-corrected mass fraction elemental maps of P, S, Cl, K, Ca, Fe and Zn of entire cryofrozen human fibroblasts were obtained. Despite the presence of diffracting microcrystals in the vitreous ice matrix and minor sample radiation damage effects, clusters of iron-rich hot-spots with similar mass fractions were found in the cytoplasm of both control and FRDA fibroblasts. Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm. [ABSTRACT FROM AUTHOR]

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We discuss the assessment and differential diagnoses of a young adult Hungarian man with a 1-year history of a progressive and symmetric amyotrophic lateral sclerosis-like syndrome, along with irregular action tremor and stimulus-sensitive myoclonus of the arms. MR scan of the brain showed isolated cerebellar atrophy and formal neuropsychometric testing identified significant subclinical deficits in attention, processing speed and memory. We suspected a form of GM2 gangliosidosis, and white cell enzyme analysis showed markedly reduced enzymatic activity of β-hexosaminidase A. Genetic testing subsequently revealed two heterozygous pathogenic mutations in the HEXA gene (c.1499delT p.(Leu500fs) and c.805G>A p. (Gly269Ser)), confirming the very rare diagnosis of adult-onset Tay-Sachs disease. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels detected in patients with the disorder was achieved, leading to decreased cellular viability, increased susceptibility to hydrogen peroxide-induced oxidative stress, dysregulation of key anti-oxidant molecules and deficiencies in both cell proliferation and differentiation. Bone marrow stem cells are being investigated extensively as potential treatments for a wide range of neurological disorders, including Friedreich's ataxia. The potential neuroprotective effects of bone marrow-derived mesenchymal stem cells were therefore studied using our frataxin-deficient cell model. Soluble factors secreted by mesenchymal stem cells protected against cellular changes induced by frataxin deficiency, leading to restoration in frataxin levels and anti-oxidant defences, improved survival against oxidative stress and stimulated both cell proliferation and differentiation down the Schwann cell lineage. The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich's ataxia. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) values were calculated for the same H-MRS VOI. Clinical severity was evaluated using the International Cooperative Ataxia Rating Scale (ICARS). FRDA patients showed a significant reduction of N-acetyl-aspartate (NAA), a neuroaxonal marker, and choline (Cho), a membrane marker, both expressed relatively to creatine (Cr), and increased MD values. In FRDA patients NAA/Cr negatively correlated with MD values ( r = −0.396, p = 0.037) and with ICARS score ( r = −0.669, p < 0.001). Age-normalized NAA/Cr loss correlated with the GAA expansion ( r = −0.492, p = 0.008). The reduced cerebellar NAA/Cr in FRDA suggests that neuroaxonal loss is related to the microstructural changes determining higher MD values. The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia (FA) is a severe disorder with autosomal recessive inheritance that is caused by the abnormal expansion of GAA repeat in intron 1 of FRDA gen. This alteration leads to a partial silencing of frataxin transcription, causing a multisystem disorder disease that includes neurological and non-neurological damage. Recent studies have proven the effectiveness of neurotrophic factors in a number of neurodegenerative diseases. Therefore, we intend to determine if liver growth factor (LGF),which has a demonstrated antioxidant and neuroprotective capability, could be a useful therapy for FA. To investigate the potential therapeutic activity of LGF we used transgenic mice of the FXNtm1MknTg (FXN)YG8Pook strain. In these mice, intraperitoneal administration of LGF (1.6 µg/mouse) exerted a neuroprotective effect on neurons of the lumbar spinal cord and improved cardiac hypertrophy. Both events could be the consequence of the increment in frataxin expression induced by LGF in spinal cord (1.34-fold) and heart (1.2-fold). LGF also upregulated by 2.6-fold mitochondrial chain complex IV expression in spinal cord, while in skeletal muscle it reduced the relation oxidized glutathione/reduced glutathione. Since LGF partially restores motor coordination, we propose LGF as a novel factor that may be useful in the treatment of FA. [ABSTRACT FROM AUTHOR]

This commentary is on the original article by Salman et al on pages 341–347 of this issue. [ABSTRACT FROM AUTHOR]

Friedreich’s ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich’s ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich’s ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich’s ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs. [ABSTRACT FROM AUTHOR]

Purpose: To describe the clinical features of electric powered indoor/outdoor wheelchair (EPIOC) users with rare diseases (RD) impacting on EPIOC provision and seating.Method: Retrospective review by a consultant in rehabilitation medicine of electronic and case note records of EPIOC recipients with RDs attending a specialist wheelchair service between June 2007 and September 2008. Data were systematically extracted, entered into a database and analysed under three themes; demographic, diagnostic/clinical (including comorbidity and associated clinical features (ACFs) of the illness/disability) and wheelchair factors.Results: Fifty-four (27 male) EPIOC users, mean age 37.3 (SD 18.6, range 11–70) with RDs were identified and reviewed a mean of 64 (range 0–131) months after receiving their wheelchair. Diagnoses included 27 types of RDs including Friedreich’s ataxia, motor neurone disease, osteogenesis imperfecta, arthrogryposis, cerebellar syndromes and others. Nineteen users had between them 36 comorbidities and 30 users had 44 ACFs likely to influence the prescription. Tilt-in-space was provided to 34 (63%) users and specialised seating to 17 (31%). Four users had between them complex control or interfacing issues.Conclusions: The complex and diverse clinical problems of those with RDs present unique challenges to the multiprofessional wheelchair team to maintain successful independent mobility and community living.Implications for RehabilitationPowered mobility is a major therapeutic tool for those with rare diseases enhancing independence, participation, reducing pain and other clinical features.The challenge for rehabilitation professionals is reconciling the physical disabilities with the individual’s need for function and participation whilst allowing for disease progression and/or growth.Powered wheelchair users with rare diseases with a (kypho) scoliosis require a wheelchair system that balances spine stability and movement to maximise residual upper limb and trunk function.The role of specialised seating needs careful consideration in supporting joint derangements and preventing complications such as pressure sores. [ABSTRACT FROM AUTHOR]

It is well known that DNA replication affects the stability of several trinucleotide repeats, but whether replication profiles of human loci carrying an expanded repeat differ from those of normal alleles is poorly understood in the endogenous context. We investigated this issue using cell lines from Friedreich’s ataxia patients, homozygous for a GAA-repeat expansion in intron 1 of the Frataxin gene. By interphase, FISH we found that in comparison to the normal Frataxin sequence the replication of expanded alleles is slowed or delayed. According to molecular combing, origins never fired within the normal Frataxin allele. In contrast, in mutant alleles dormant origins are recruited within the gene, causing a switch of the prevalent fork direction through the expanded repeat. Furthermore, a global modification of the replication profile, involving origin choice and a differential distribution of unidirectional forks, was observed in the surrounding 850 kb region. These data provide a wide-view of the interplay of events occurring during replication of genes carrying an expanded repeat. [ABSTRACT FROM AUTHOR]

Friedreich’s ataxia (FRDA), the most commonly inherited ataxia in populations of European origin, is a neurodegenerative disorder caused by a decrease in frataxin levels. One of the hallmarks of the disease is the accumulation of iron in several tissues including the brain, and frataxin has been proposed to play a key role in iron homeostasis. We found that the levels of zinc, copper, manganese and aluminum were also increased in a Drosophila model of FRDA, and that copper and zinc chelation improve their impaired motor performance. By means of a candidate genetic screen, we identified that genes implicated in iron, zinc and copper transport and metal detoxification can restore frataxin deficiency-induced phenotypes. Taken together, these results demonstrate that the metal dysregulation in FRDA includes other metals besides iron, therefore providing a new set of potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia characterized by a combination of neurological involvement, cardiomyopathy, and skeletal and glucose metabolism disturbances. FRDA is caused by mutations in FXN gene that results in reduction of mRNA and protein levels of frataxin. Previous microarray and real-time quantitative PCR (qPCR) studies showed that the downregulation of FXN is associated with a complex gene expression profile. However, these studies showed a wide variability in the subset of genes with altered expression among tissues and models. Genes differentially expressed in peripheral blood cells (PBC) could potentially help in the understanding of FRDA pathophysiology and also function as reliable disease biomarkers obtained from an easily accessible tissue, which could have implications in clinical practice. This study aimed to validate by qPCR the expression of 26 genes, revealed as differentially expressed by other studies, using peripheral blood cells (PBC) of 11 FRDA patients compared to 11 healthy controls. We found a robust downregulation of FXN, but no statistically significant differences were found between FRDA and controls for the remaining genes. Except for FXN, our study did not find a differential gene expression profile in PBC of FRDA patients and a reliable gene expression profile biomarker in a clinical relevant and noninvasive tissue remains unclear. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to analyze the genotypic characteristics of Friedreich's ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings. Methods: The study included 1 29 indexed cases, who applied to the neurology department and were diagnosed with hereditary cerebellar ataxia through clinical, laboratory, and electrophysiological findings, and 15 sibling patients who were diagnosed through family scanning (144 cases in total); their genetic analyses were also performed. Detailed physical and neurological examinations, pedigree analyses, electroneurography, evoked potentials, cerebral-spinal magnetic resonance imaging, and echocardiographic analyses were performed for all cases. Blood samples were collected from patients, and the genotypic characteristics of autosomal dominant SCA types 1, 2, 3, and 6 were investigated. Statistical analyses were performed with the Statistical Package for the Social Sciences (SPSS Inc; Chicago, IL, USA) 17.0. Results: Almost 50% of patients were defined as FA. Moreover, two SCA 1 cases and one SCA6 case were detected. Conclusion: In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA 1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA. [ABSTRACT FROM AUTHOR]

Introduction: Dorsal root ganglia (DRG) are highly vulnerable to frataxin deficiency in Friedreich ataxia (FA), an autosomal recessive disease due to pathogenic homozygous guanine-adenine-adenine trinucleotide repeat expansions in intron 1 of the FXN gene (chromosome 9q21.11). An immunohistochemical and immunofluorescence study of DRG in 15 FA cases and 12 controls revealed that FA causes major primary changes in satellite cells and inflammatory destruction of neurons. A panel of antibodies was used to reveal the cytoplasm of satellite cells (glutamine synthetase, S100, metabotropic glutamate receptors 2/3, excitatory amino acid transporter 1, ATP-sensitive inward rectifier potassium channel 10, and cytosolic ferritin), gap junctions (connexin 43), basement membranes (laminin), mitochondria (ATP synthase subunit beta and frataxin), and monocytes (CD68 and IBA1). Results: Reaction product of the cytoplasmic markers and laminin confirmed proliferation of satellite cells and processes into multiple perineuronal layers and residual nodules. The formation of connexin 43-reactive gap junctions between satellite cells was strongly upregulated. Proliferating satellite cells in FA displayed many more frataxin- and ATP5B-reactive mitochondria than normal. Monocytes entered into the satellite cell layer, appeared to penetrate neuronal plasma membranes, and infiltrated residual nodules. Satellite cells and IBA1-reactive monocytes displayed upregulated ferritin biosynthesis, which was most likely due to leakage of iron from dying neurons. Conclusions: We conclude that FA differentially affects the key cellular elements of DRG, and postulate that the disease causes loss of bidirectional trophic support between satellite cells and neurons. [ABSTRACT FROM AUTHOR]

Background Hereditary ataxias are a heterogeneous group of degenerative diseases of the cerebellum, brainstem, and spinal cord. They may present with isolated ataxia or with additional symptoms going beyond cerebellar deficits. There are an increasing number of clinical studies with the goal to define the natural history of these disorders, develop biomarkers, and investigate therapeutic interventions. Especially, early and preclinical disease stages are currently of particular interest. Methods and Results Evidence-based, we review standards for sampling and storage of biomaterials, clinical and neuropsychological assessment, as well as neurophysiology and neuroimaging and recommendations for standardized assessment of ataxia patients in multicenter studies. Conclusions DNA, RNA, serum, and, if possible, cerebrospinal fluid samples should be processed following established standards. Clinical assessment in ataxia studies must include use of a validated clinical ataxia scale. There are several validated clinical ataxia scales available. There are no instruments that were specifically designed for assessing neuropsychological and psychiatric symptoms in ataxia disorders. We provide a list of tests that may prove valuable. Quantitative performance tests have the potential to supplement clinical scales. They provide additional objective and quantitative information. Posturography and quantitative movement analysis-despite valid approaches-require standardization before implemented in multicenter studies. Standardization of neurophysiological tools, as required for multicenter interventional trials, is still lacking. Future multicenter neuroimaging studies in ataxias should implement quality assurance measures as defined by the ADNI or other consortia. MRI protocols should allow morphometric analyses. [ABSTRACT FROM AUTHOR]

There is no current approved therapy for the ultimately lethal neuro- and cardio-degenerative disease Friedreich's ataxia (FA). Finding minimally-invasive molecular biomarkers of disease progression and drug effect could support smaller, shorter clinical trials. Since we and others have noted a deficient oxidative stress response in FA, we investigated the expression of 84 genes involved in oxidative stress, signaling, and protection in control and FA lymphoblasts ranging from 460 to 1122 GAA repeats. Several antioxidant genes responded in a dose-dependent manner to frataxin expression at the mRNA and protein levels, which is inversely correlated with disease progression and severity. We tested the effect of experimental Friedreich’s ataxia therapies dimethyl fumarate (DMF) and type 1 histone deacetylase inhibitor (HDACi) on biomarker mRNA expression. We observed that exposure of lymphoblasts to DMF and HDACi dose-dependently unsilenced frataxin expression and restored the potential biomarkers NCF2 and PDLIM1 expression to control levels. We suggest that in addition to frataxin expression, blood lymphoblast levels of NCF2 and PDLIM1 could be useful biomarkers for disease progression and drug effect in future clinical trials of Friedreich’s ataxia. [ABSTRACT FROM AUTHOR]

Background and purpose SPG7 is one of the most common forms of autosomal recessive hereditary spastic paraplegia. The phenotype has been shown to be heterogeneous, varying from a complex spastic ataxia to pure spastic paraplegia or pure ataxia. The aim of this study was to clinically and genetically characterize patients with SPG7 in Norway. Methods Six Norwegian families with a clinical diagnosis of hereditary spastic paraplegia were diagnosed with SPG7 through Sanger sequencing and whole-exome sequencing. Haplotypes were established to identify a possible founder mutation. All patients were thoroughly examined and the clinical and molecular findings are described. Results The core phenotype was spastic paraparesis with ataxia, bladder disturbances and progressive external ophthalmoplegia. The variant p.H701P was identified in homozygous state in one family and in compound heterozygous state in three families. Haplotype analysis of seven surrounding single nucleotide polymorphisms supports that this variant resides on a founder haplotype. Four of the families were compound heterozygous for the previously well-described p.A510V variant. Conclusion SPG7 is a common subgroup of hereditary spinocerebellar disorders in Norway. The broad phenotype in the Norwegian SPG7 population illustrates the challenges with the traditional dichotomous classification of hereditary spinocerebellar disorders into hereditary spastic paraplegia or hereditary ataxia. A Norwegian founder mutation p.H701P was identified in four out of six families, making it a major cause of SPG7 in Norway. [ABSTRACT FROM AUTHOR]

Background and Purpose: Imaging biomarkers of disease progression are desirable in inherited ataxias. MRI has demonstrated brain damage in Friedreich ataxia (FRDA) in form of regional atrophy of the medulla, peridentate cerebellar white matter (WM) and superior cerebellar peduncles (visible in T1-weighted images) and of change of microstructural characteristics of WM tracts of the brainstem, cerebellar peduncles, cerebellum, and supratentorial structures (visible through diffusion-weighted imaging). We explored the potential of brain MR morphometry and diffusion tensor imaging (DTI) to track the progression of neurodegeneration in FRDA. Methods: Eight patients (5F, 3M; age 13.4-41.2 years) and 8 healthy controls (2F, 6M; age 26.2-48.3 years) underwent 2 MRI examinations (mean 3.9 and 4.1 years apart, respectively) on the same 1.5T scanner. The protocol included 3D T1-weighted images and axial diffusion-weighted images (b-value 1,000 s/mm(2)) for calculating maps of fractional anisotropy, mean, axial and radial diffusivity, and mode of anisotropy. Tensor-based morphometry was used to investigate regional volume changes and tract-based spatial statistics was used to investigate microstructural changes in WM tracts. Results: Longitudinal analyses showed no differences in regional volume changes but a significant difference in axial diffusivity changes in cerebral and corpus callosum WM of patients as compared to controls (mean longitudinal rate of change for axial diffusivity: -.02 × 10(-3) mm(2)/s/year in patients vs. .01 × 10(-3) mm(2)/s/year in controls). No correlation with number of triplets, disease duration, and worsening of the clinical deficit was observed. Conclusion: DTI can track brain microstructural changes in FRDA and can be considered a potential biomarker of disease progression. [ABSTRACT FROM AUTHOR]

Conclusion: The prevalence of low-tone hearing loss (LTHL) is significantly high in spinocerebellar degeneration (SCD) with cerebellar predominance, including multiple-system atrophy C (MSA-C) and cortical cerebellar atrophy (CCA).Objective: This study aimed to test the hypothesis that SCD with cerebellar predominance, MSA-C and CCA may cause auditory symptoms.Methods: The shape and threshold of pure-tone audiograms were evaluated for MSA-C (n = 47; mean (± SD) age, 61.6 ± 8.9 years), CCA (n = 16; 62.8 ± 9.5 years), and age-matched controls (n = 169; 62.5 ± 10.7 years). To differentiate specific hearing loss for MSA-C and CCA from presbycusis, the shape of audiograms was examined based on previously established audiological criteria.Results: When audiogram shape was defined according to audiological criteria, the odds ratio for LTHL in SCD compared to controls was 2.492 (95% confidence interval (CI) = 1.208–5.139;p < 0.05, Pearson’s Chi-square test) in MSA-C and 2.194 (95% CI = 0.709–6.795) in CCA. When the selection of audiogram shape according to these criteria was verified by three certified audiologists, odds ratios for LTHL in MSA-C and CCA were 3.243 (95% CI = 1.320–7.969) and 3.692 (95% CI = 1.052–12.957), respectively, significantly higher than in controls. [ABSTRACT FROM PUBLISHER]

Reduced levels of frataxin, an essential mitochondrial protein involved in the regulation of iron-sulfur cluster biogenesis, are responsible for the recessive neurodegenerative Friedreich Ataxia (FRDA). Expansion of a GAA triplet in the first intron of the FRDA is essential for disease development which causes partial silencing of frataxin. In the vast majority of cases, patients are homozygotes for the expansion, but a small number of FRDA patients are heterozygotes for expansion and point mutations in the frataxin coding frame. In this study, we analyze the effects of a point mutation G137V. The patient P94-2, with a history of alcohol and drug abuse, showed a FRDA onset at the border between the classic and late onset phenotype. We applied a combination of biophysical and biochemical methods to characterize its effects on the structure, folding and activity of frataxin. Our study reveals no impairment of the structure or activity of the protein but a reduced folding stability. We suggest that the mutation causes misfolding of the native chain with consequent reduction of the protein concentration in the patient and discuss the possible mechanism of disease. [ABSTRACT FROM AUTHOR]

At least 35% patients present with atypical clinical picture (variants), including LOFA (late-onset cerebellar ataxia) and VLOFA (very late-onset cerebellar ataxia). Diffusion tensor imaging and tract-based spatial stastistics analysis in Friedreich's ataxia patients. Friedreich's ataxia (ATX-FXN) was described by Nikolaus Friedreich's in 1863 and is the most common autosomal recessive ataxia worldwide [[1]-[3]]. [Extracted from the article]

Background: Friedreich ataxia is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene that results in epigenetic silencing of the FXN promoter. This silencing mechanism is seen in patient-derived lymphoblastoid cells but it remains unknown if it is a widespread phenomenon affecting multiple cell types and tissues. Methodology / Principal Findings: The humanized mouse model of Friedreich ataxia (YG8sR), which carries a single transgenic insert of the human FXN gene with an expanded GAA triplet-repeat in intron 1, is deficient for FXN transcript when compared to an isogenic transgenic mouse lacking the expanded repeat (Y47R). We found that in YG8sR the deficiency of FXN transcript extended both upstream and downstream of the expanded GAA triplet-repeat, suggestive of deficient transcriptional initiation. This pattern of deficiency was seen in all tissues tested, irrespective of whether they are known to be affected or spared in disease pathogenesis, in both neuronal and non-neuronal tissues, and in cultured primary fibroblasts. FXN promoter function was directly measured via metabolic labeling of newly synthesized transcripts in fibroblasts, which revealed that the YG8sR mouse was significantly deficient in transcriptional initiation compared to the Y47R mouse. Conclusions / Significance: Deficient transcriptional initiation accounts for FXN transcriptional deficiency in the humanized mouse model of Friedreich ataxia, similar to patient-derived cells, and the mechanism underlying promoter silencing in Friedreich ataxia is widespread across multiple cell types and tissues. [ABSTRACT FROM AUTHOR]

Friedreich’s ataxia (FRDA), the most common inherited ataxia in the Caucasian population, is a multisystemic disease caused by a significant decrease in the frataxin level. To identify genes capable of modifying the severity of the symptoms of frataxin depletion, we performed a candidate genetic screen in a Drosophila RNAi-based model of FRDA. We found that genetic reduction in TOR Complex 1 (TORC1) signalling improves the impaired motor performance phenotype of FRDA model flies. Pharmacologic inhibition of TORC1 signalling by rapamycin also restored this phenotype and increased the lifespan and ATP levels. Furthermore, rapamycin reduced the altered levels of malondialdehyde + 4-hydroxyalkenals and total glutathione of the model flies. The rapamycin-mediated protection against oxidative stress is due in part to an increase in the transcription of antioxidant genes mediated by cap-n-collar (Drosophila ortholog of Nrf2). Our results suggest that autophagy is indeed necessary for the protective effect of rapamycin in hyperoxia. Rapamycin increased the survival and aconitase activity of model flies subjected to high oxidative insult, and this improvement was abolished by the autophagy inhibitor 3-methyladenine. These results point to the TORC1 pathway as a new potential therapeutic target for FRDA and as a guide to finding new promising molecules for disease treatment. [ABSTRACT FROM AUTHOR]

Frataxin is an evolutionary conserved protein that participates in iron metabolism. Deficiency of this small protein in humans causes a severe neurodegenerative disease known as Friedreich's ataxia. A number of studies indicate that frataxin binds iron and regulates Fe-S cluster biosynthesis. Previous structural studies showed that metal binding occurs mainly in a region of high density of negative charge. However, a comprehensive characterization of the binding sites is required to gain further insights into the mechanistic details of frataxin function. In this work, we have solved the X-ray crystal structures of a cold-adapted frataxin from a psychrophilic bacterium in the presence of cobalt or europium ions. We have identified a number of metal-binding sites, mainly solvent exposed, several of which had not been observed in previous studies on mesophilic homologues. No major structural changes were detected upon metal binding, although the structures exhibit significant changes in crystallographic B-factors. The analysis of these B-factors, in combination with crystal packing and RMSD among structures, suggests the existence of localized changes in the internal motions. Based on these results, we propose that bacterial frataxins possess binding sites of moderate affinity for a quick capture and transfer of iron to other proteins and for the regulation of Fe-S cluster biosynthesis, modulating interactions with partner proteins. [ABSTRACT FROM AUTHOR]

Background: Friedreich's ataxia (FRDA) is the most common hereditary autosomal recessive form of ataxia. In this disease there is early manifestation of gait ataxia, and dysmetria of the arms and legs which causes impairment in daily activities that require fine manual dexterity. To date there is no cure for this disease. Some novel therapeutic approaches are ongoing in different steps of clinical trial. Development of sensitive outcome measures is crucial to prove therapeutic effectiveness. The aim of the study was to assess the reliability and sensitivity of quantitative and objective assessment of upper limb performance computed by means of the robotic device and to evaluate the correlation with clinical and functional markers of the disease severity. Methods: Here we assess upper limb performances by means of the In Motion Arm Robot, a robot designed for clinical neurological applications, in a cohort of 14 children and young adults affected by FRDA, matched for age and gender with 18 healthy subjects. We focused on the analysis of kinematics, accuracy, smoothness, and submovements of the upper limb while reaching movements were performed. The robotic evaluation of upper limb performance consisted of planar reaching movements performed with the robotic system. The motors of the robot were turned off, so that the device worked as a measurement tool. The status of the disease was scored using the Scale for the Assessment and Rating of Ataxia (SARA). Relationships between robotic indices and a range of clinical and disease characteristics were examined. Results: All our robotic indices were significantly different between the two cohorts except for two, and were highly and reliably discriminative between healthy and subjects with FRDA. In particular, subjects with FRDA exhibited slower movements as well as loss of accuracy and smoothness, which are typical of the disease. Duration of Movement, Normalized Jerk, and Number of Submovements were the best discriminative indices, as they were directly and easily measurable and correlated with the status of the disease, as measured by SARA. Conclusions: Our results suggest that outcome measures obtained by means of robotic devices can improve the sensitivity of clinical evaluations of patients' dexterity and can accurately and efficiently quantify changes over time in clinical trials, particularly when functional scales appear to be no longer sensitive. [ABSTRACT FROM AUTHOR]

Our objective was to determine whether substantia nigra (SN) hyperechogenicity is greater in spinocerebellar ataxias (SCA) with nigrostriatal affectation than in ataxias without it. A cross-sectional case-control study analyzing four groups of patients was conducted: 1) nigrostriatal ataxias (SCA3 and SCA6), 2) nigrostriatal healthy controls matched by age and sex, 3) non-nigrostriatal ataxias (FRDA and SCA7), and 4) non-nigrostriatal healthy controls matched by age and sex. All the patients underwent a transcranial ultrasound performed by an experienced sonographer blinded to the clinical, genetic, and neuroimaging data. The SN area was measured and compared in the four groups. The SN area was also correlated with clinical features and genetic data in the two ataxia groups. We examined 12 patients with nigrostriatal ataxia (11 SCA3 and 1 SCA6), 12 nigrostriatal healthy control patients, 7 patients with non-nigrostriatal ataxia (5 FRDA and 2 SCA7), and 7 non-nigrostriatal healthy control patients. The median (IQR) SN area (cm) was greater in the nigrostriatal ataxias compared with the controls (right SN, 0.43 [0.44] vs. 0.11 [0.25]; P = 0.001; left SN, 0.32 [0.25] vs. 0.11 [0.16]; P = 0.001), but was similar among the non-nigrostriatal ataxias and controls. There were no statistically significant differences in the SN area between the nigrostriatal and non-nigrostriatal ataxias, although there was a tendency for a greater left SN area in the nigrostriatal compared with the non-nigrostriatal ataxias (0.32 [0.25] vs. 0.16 [0.24], P = 0.083). SN echogenicity is markedly greater in ataxias with nigrostriatal pathology than in controls. The role of SN hyperechogenicity in differentiating ataxias with and without nigrostriatal pathology should be elucidated in future studies. [ABSTRACT FROM AUTHOR]

Frataxin (Yfh1 in yeast) is a conserved protein and deficiency leads to the neurodegenerative disease Friedreich’s ataxia. Frataxin is a critical protein for Fe-S cluster assembly in mitochondria, interacting with other components of the Fe-S cluster machinery, including cysteine desulfurase Nfs1, Isd11 and the Isu1 scaffold protein. Yeast Isu1 with the methionine to isoleucine substitution (M141I), in which the E. coli amino acid is inserted at this position, corrected most of the phenotypes that result from lack of Yfh1 in yeast. This suppressor Isu1 behaved as a genetic dominant. Furthermore frataxin-bypass activity required a completely functional Nfs1 and correlated with the presence of efficient scaffold function. A screen of random Isu1 mutations for frataxin-bypass activity identified only M141 substitutions, including Ile, Cys, Leu, or Val. In each case, mitochondrial Nfs1 persulfide formation was enhanced, and mitochondrial Fe-S cluster assembly was improved in the absence of frataxin. Direct targeting of the entire E. coli IscU to ∆yfh1 mitochondria also ameliorated the mutant phenotypes. In contrast, expression of IscU with the reverse substitution i.e. IscU with Ile to Met change led to worsening of the ∆yfh1 phenotypes, including severely compromised growth, increased sensitivity to oxygen, deficiency in Fe-S clusters and heme, and impaired iron homeostasis. A bioinformatic survey of eukaryotic Isu1/prokaryotic IscU database entries sorted on the amino acid utilized at the M141 position identified unique groupings, with virtually all of the eukaryotic scaffolds using Met, and the preponderance of prokaryotic scaffolds using other amino acids. The frataxin-bypassing amino acids Cys, Ile, Leu, or Val, were found predominantly in prokaryotes. This amino acid position 141 is unique in Isu1, and the frataxin-bypass effect likely mimics a conserved and ancient feature of the prokaryotic Fe-S cluster assembly machinery. [ABSTRACT FROM AUTHOR]

Purpose: To measure corneal sensitivity and tear function in neurodegenerative diseases (NDs) and to compare them with age and sex-matched controls. Methods: Twenty patients with Alzheimer's disease (AD), 20 patients with multiple sclerosis (MS), 30 patients with Parkinson's disease (PD), 10 patients with Friedreich's ataxia (FA) and 21 patients with epilepsy (EP) who were recruited from the Kırıkkale University Neurology Department during 2012 were included in this prospective study. Five groups of age and sex-matched subjects were selected as controls. Corneal sensitivity was measured using a Cochet-Bonnet esthesiometer. Tear function tests included tear break-up time (TBUT) and Schirmer's 1 tests. Results: Compared to their controls, mean corneal sensitivity was significantly reduced in AD, MS, PD and EP patients (all p < 0.05), mean TBUT level was significantly shorter in patients with AD and MS (all p < 0.05) and mean Schirmer's 1 test score was significantly lower in EP patients ( p < 0.05). When all groups were compared with each other, reduction of mean corneal sensitivity in AD and PD groups were significantly more than in FA and MS groups (overall p = 0.034). Mean TBUT levels in AD, MS and PD groups were significantly shorter than in FA and EP groups (overall p = 0.001). Mean Schirmer's 1 test scores in AD and PD groups were significantly lower than in MS, FA and EP groups (overall p = 0.040). Conclusions: Neurodegenerative diseases may be associated with reduced corneal sensitivity and abnormal tear function. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FA) is an autosomal recessive disease with a complex neurological phenotype, but the most common cause of death is heart failure. This study presents a systematic analysis of 15 fixed and 13 frozen archival autopsy tissues of FA hearts and 10 normal controls (8 frozen) by measurement of cardiomyocyte hypertrophy; tissue frataxin assay; X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn) in polyethylene glycol-embedded samples of left and right ventricular walls (LVW, RVW) and ventricular septum (VS); metal quantification in bulk digests by inductively-coupled plasma optical emission spectrometry (ICP-OES); Fe histochemistry; and immunohistochemistry and immunofluorescence of cytosolic and mitochondrial ferritins and of the inflammatory markers CD68 and hepcidin. FA cardiomyocytes were significantly larger than normal and surrounded by fibrotic endomysium. Frataxin in LVW was reduced to less than 15 ng/g wet weight (normal 235.4±75.1 ng/g). All sections displayed characteristic Fe-reactive inclusions in cardiomyocytes, and XRF confirmed significant regional Fe accumulation in LVW and VS. In contrast, ICP-OES analysis of bulk extracts revealed normal total Fe levels in LVW, RVW, and VS. Cardiac Zn remained normal by XRF and assay of bulk digests. Cytosolic and mitochondrial ferritins exhibited extensive co-localization in cardiomyocytes, representing translational and transcriptional responses to Fe, respectively. Fe accumulation progressed from a few small granules to coarse aggregates in phagocytized cardiomyocytes. All cases met the “Dallas criteria” of myocarditis. Inflammatory cells contained CD68 and cytosolic ferritin, and most also expressed the Fe-regulatory hormone hepcidin. Inflammation is an important factor in the pathogenesis of FA cardiomyopathy but may be more evident in advanced stages of the disease. Hepcidin-induced failure of Fe export from macrophages is a likely contributory cause of damage to the heart in FA. Frataxin replacement and anti-inflammatory agents are potential therapies in FA cardiomyopathy. [ABSTRACT FROM AUTHOR]

In eukaryotes, frataxin deficiency ( FXN) causes severe phenotypes including loss of iron-sulfur ( Fe- S) cluster protein activity, accumulation of mitochondrial iron and leads to the neurodegenerative disease Friedreich's ataxia. In contrast, in prokaryotes, deficiency in the FXN homolog, CyaY, was reported not to cause any significant phenotype, questioning both its importance and its actual contribution to Fe- S cluster biogenesis. Because FXN is conserved between eukaryotes and prokaryotes, this surprising discrepancy prompted us to reinvestigate the role of CyaY in E scherichia coli. We report that CyaY (i) potentiates E . coli fitness, (ii) belongs to the ISC pathway catalyzing the maturation of Fe- S cluster-containing proteins and (iii) requires iron-rich conditions for its contribution to be significant. A genetic interaction was discovered between cyaY and iscX, the last gene of the isc operon. Deletion of both genes showed an additive effect on Fe- S cluster protein maturation, which led, among others, to increased resistance to aminoglycosides and increased sensitivity to lambda phage infection. Together, these in vivo results establish the importance of CyaY as a member of the ISC-mediated Fe- S cluster biogenesis pathway in E . coli, like it does in eukaryotes, and validate IscX as a new bona fide Fe- S cluster biogenesis factor. [ABSTRACT FROM AUTHOR]

Perceptual speech research in Friedreich ataxia (FRDA) has identified altered nasality as a key component of the dysarthria profile, however the incidence and severity of abnormal nasality remains unknown. Utilizing objective and perceptual methods, data on the relationship between resonance, disease duration, severity, age of onset and genetic profiles were collated. Thirty-seven participants with FRDA and 24 healthy controls provided contemporaneous speech samples for perceptual analysis, and single word samples for acoustic analysis. A subset of participants (eight participants with FRDA and eight controls) underwent nasometry assessment. Twenty-seven participants with FRDA presented with hypernasality and five with hyponasality on perceptual assessment. Acoustic analysis revealed participants with FRDA had greater nasality than controls ( p < 0.05). Perceptual ratings of hypernasality correlated with GAA2 repeat length ( ρ = 0.37, p = 0.03). Findings highlight the variability of nasality in FRDA, potentially reflecting variation in the neuropathological profile. Data also suggest the influence of genetic profiles on nasality. [ABSTRACT FROM AUTHOR]

Numerous human diseases are caused by protein folding defects where the protein may become more susceptible to degradation or aggregation. Aberrant protein folding can affect the kinetic stability of the proteins even if these proteins appear to be soluble in vivo. Experimental discrimination between functional properly folded and misfolded nonfunctional conformers is not always straightforward at near physiological conditions. The differences in the kinetic behavior of two initially folded frataxin clinical variants were examined using a high affinity chaperonin kinetic trap approach at 25 °C. The kinetically stable wild type frataxin (FXN) shows no visible partitioning onto the chaperonin. In contrast, the clinical variants FXN-p.Asp122Tyr and FXN-p.Ile154Phe kinetically populate partial folded forms that tightly bind the GroEL chaperonin platform. The initially soluble FXN-p.Ile154Phe variant partitions onto GroEL more rapidly and is more kinetically liable. These differences in kinetic stability were confirmed using differential scanning fluorimetry. The kinetic and aggregation stability differences of these variants may lead to the distinct functional impairments described in Friedreich's ataxia, the neurodegenerative disease associated to frataxin functional deficiency. This chaperonin platform approach may be useful for identifying small molecule stabilizers since stabilizing ligands to frataxin variants should lead to a concomitant decrease in chaperonin binding. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is an autosomal recessive disease with gait ataxia being the main source of morbidity. Mobility progressively declines, from initial symptom onset at approximately 10-15 years of age to being unable to ambulate 10-15 years later. Here, we sought to investigate the relationship between spatiotemporal gait parameters and clinical markers of disease severity. Thirteen people with FRDA walked along an 8.3-m GAITRite® mat six times each at their preferred fast and slow speeds. Relationships between spatiotemporal gait parameters and a range of clinical and disease characteristics were examined. Significant correlations were found between spatiotemporal gait characteristics at each of the walking speeds and Friedreich Ataxia Rating Scale (FARS) score and disease duration. During the fast-walking condition, gait speed and cadence decreased with an increase in disease duration and the FARS score. GAA1 repeat expansion negatively correlated with double-support percentage of the gait cycle in all speed conditions demonstrating a relationship between the genetic mutation and compensatory strategies for impaired dynamic balance. In all speed conditions, there were correlations between a range of spatiotemporal gait characteristics and the timed 25-ft walk test, a well-established measure of gait mobility. These findings suggest that spatiotemporal gait parameters are a sensitive measure of gait decline in individuals with FRDA and should be considered for inclusion in intervention studies whilst participants are still ambulant. [ABSTRACT FROM AUTHOR]

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Friedreich ataxia (FRDA) is the most common inherited neurodegenerative ataxia. Apart from predominant neurological features an involvement of the skeletal system in terms of scoliosis and foot deformities is frequent. Disease-related falls, mobility restrictions, and wheelchair-dependency in later disease stages might additionally compromise bone structure in FRDA. The aim of this pilot study was to systematically evaluate the bone status in a representative FRDA cohort. Twenty-eight FRDA patients became enrolled in this cross-sectional study. Neurological assessment, a questionnaire comprising the history of fractures and osteoporosis as well as osteodensitometric measurements complemented with general and bone-specific laboratory parameters were performed. The WHO Fracture Risk Assessment tool (FRAX®) was applied, calculating the 10-year risk of suffering an osteoporotic fracture. Six patients (21.4 %) presented with a bone mineral density below the expected range for age in at least one of the examined sites (femoral neck, lumbar spine, and forearm) irrespective of their gender. Corresponding Z scores were significantly lower compared to normative values for the femoral neck and lumbar spine. Vitamin D status was insufficient in 11 and deficient in 8 FRDA patients. There was a strong negative correlation between ataxia severity, GAA repeat expansion and bone density in the femoral neck of FRDA patients. This is the first report of an increased rate of low bone mineral density in FRDA. Given the increased risk of falls, this data rectifies routine bone mineral density measurements in FRDA which may help to initiate therapeutic interventions to prevent this condition. [ABSTRACT FROM AUTHOR]

Background Friedreich ataxia (FRDA) is a neurodegenerative disease caused by mutations in the frataxin (FXN) gene, resulting in reduced expression of the mitochondrial protein frataxin. Improved understanding of the pathophysiology of the disease has led to a growing need for informative biomarkers to assess disease progression and response to therapeutic intervention. Objective To evaluate the performance of frataxin measurements as a diagnostic tool using two different immunoassays. Methods Clinical and demographic information was provided through an ongoing longitudinal natural history study on FRDA. Frataxin protein levels from multiple cell types in controls, carriers and FRDA patients were measured and compared using a lateral flow immunoassay and a Luminex xMAP-based immunoassay. Receiver operating characteristic curve analyses were then performed to evaluate the sensitivity, specificity, and positive and negative predictive values for each immunoassay. Results For whole blood and buccal cells, analysing FRDA patients and carriers together in a cohort resulted in higher sensitivities and positive predictive values compared with analyzing controls and carriers together, with similar results between each tissue type. We then compared the usefulness of a lateral flow immunoassay with a multianalyte Luminex xMAP-based immunoassay, and showed that both assays demonstrate high positive predictive values with low rates of false negatives and false positives. Conclusions Frataxin measurements from peripheral tissues can be used to identify FRDA patients and carriers. While multiple cell types and assays may be useful for diagnostic purposes, each assay and cell type used has its advantages and disadvantages depending on study design and scope. [ABSTRACT FROM AUTHOR]

Background and purpose In Friedreich's ataxia ( FRDA), frataxin deficiency results in iron redistribution in the dentate nuclei ( DNC). Clusters of iron cause inhomogeneities in a magnetic field and result in a reduction in T2 relaxation time (T2). Methods T2 was prospectively evaluated in DNC, putamen, substantia nigra ( SN), cerebellar white matter ( CWM) and caudate and the correlation with clinical parameters was investigated. Thirty-five patients (range 9-51 years) and 44 controls (12-49 years) underwent T2 multi-echo sequence in a 3T scanner. Twenty-three patients (12-50 years) and 19 controls (14-49 years) were reassessed after 1 year. T2 was evaluated using specialized software (Aftervoxel) and severity of disease was quantified with the Friedreich Ataxia Rating Scale ( FARS). Results T2 of both DNC was significantly shorter in the FRDA group at baseline (right, 58.6 ± 8.3 ms vs. 63.7 ± 8.1 ms, P = 0.013; left, 56.7 ± 7.7 ms vs. 62.6 ± 6.8 ms, P = 0.001). No significant difference was found between groups regarding the SN, putamen, CWM and caudate T2. DNC T2 values correlated with age, FARS total score and FARS III subscore on both sides. Prospectively, there was a significant reduction of T2 in FRDA patients in right and left DNC ( P = 0.001 and 0.009) but not in other structures. Amongst controls, none of the regions significantly changed after 1 year. DNC T2 change over time correlated with GAA expansions and clinical deterioration (expressed by a change in FARS scores). Conclusions DNC T2 values are abnormal in FRDA, progress over time and correlate with ataxia severity. These results strongly suggest that DNC relaxometry can be a useful neuroimaging marker in FRDA. [ABSTRACT FROM AUTHOR]

Friedreich's ataxia ( FRDA) is linked to a deficiency of frataxin ( FXN), a mitochondrial protein involved in iron-sulfur cluster synthesis. FXN is a small protein with an α/β fold followed by the C-terminal region ( CTR) with a nonperiodic structure that packs against the protein core. In the present study, we explored the impact of the alteration of the CTR on the stability and dynamics of FXN. We analyzed several pathological and rationally designed CTR mutants using complementary spectroscopic and biophysical approaches. The pathological mutation L198R yields a global destabilization of the structure correlating with a significant and highly localized alteration of dynamics, mainly involving residues that are in contact with L198 in wild-type FXN. Variant FXN 90-195, which is closely related to the FRDA-associated mutant FXN 81-193, conserves a globular shape with a native-like structure. However, the truncation of the CTR results in an extreme alteration of global stability and protein dynamics over a vast range of timescales and encompassing regions far from the CTR, as shown by proton-water exchange rates and 15N-relaxation measurements. Increased sensitivity to proteolysis, observed in vitro for both mutants, suggests a faster degradation rate in vivo, whereas the enhanced tendency to aggregate exhibited by the truncated variant may account for the loss of functional FXN, with both phenomena providing an explanation as to why the alteration of the CTR causes FRDA. These results contribute to understanding how stability and activity are linked to protein motions and they might be useful for the design of target-specific ligands to control local protein motions for stability enhancement. [ABSTRACT FROM AUTHOR]

Friedreich ataxia (FRDA) is an autosomal recessive disease characterised by neurodegeneration and cardiomyopathy that is caused by an insufficiency of the mitochondrial protein, frataxin. Our previous studies described the generation of FRDA induced pluripotent stem cell lines (FA3 and FA4 iPS) that retained genetic characteristics of this disease. Here we extend these studies, showing that neural derivatives of FA iPS cells are able to differentiate into functional neurons, which don't show altered susceptibility to cell death, and have normal mitochondrial function. Furthermore, FA iPS-derived neural progenitors are able to differentiate into functional neurons and integrate in the nervous system when transplanted into the cerebellar regions of host adult rodent brain. These are the first studies to describe both in vitro and in vivo characterization of FA iPS-derived neurons and demonstrate their capacity to survive long term. These findings are highly significant for developing FRDA therapies using patient-derived stem cells. [ABSTRACT FROM AUTHOR]