UNDERLYING GENETIC CAUSE IN CEREBELLAR ATAXIAS: EVALUATION OF AN IRISH COHORT

Petya Bogdanova-Mihaylova, Raymond PJ Murphy, Richard A Walsh1, Sinéad M Murphy; J Neurol Neurosurg Psychiatry 2016;87:e1 doi:10.1136/jnnp-2016-315106.203

At the National Ataxia Clinic, Tallaght Hospital, from December 2014–April 2016, 137 patients with inherited ataxias were assessed. In December 2014, 53% of 133 patients had a genetically confirmed diagnosis. The commonest in the autosomal-recessive (AR) group were Friedreich's ataxia, Ataxia-telangiectasia (AT), Ataxia with oculomotor apraxia 1&2 (AOA1&2) and, in the autosomal-dominant group, SCA2, SCA3 and SCA14.

Paradoxical Abnormalities of Intra and Postoperative Neuroelectrical Recording of a Scoliotic Child with Friedreich’s Ataxia

Ahmed B. Bayoumi, Zafer Orkun Toktas, Baran Yılmaz, Orkun Koban, Murat Sakir Eksi, Hulya Aydin Gungor and Deniz Konya; EC Neurology 3.2 (2016): 350-353.

Scoliotic patients with Friedrich’s ataxia may show no response during the intra operative neuromonitoring by using MEP or SEP. A wake-up test setting must be planned with anesthesiology team to be done intra operatively for this subset of population to ensure the safety of the spinal procedure. To overcome such circumstances further and to plan the surgery in that fashion, pre-operative baseline neuromonitoring should be obtained in such neuromuscular scoliosis cases.

Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients

M Hadjivassiliou, J Martindale, P Shanmugarajah, R A Grünewald, P G Sarrigiannis, N Beauchamp, K Garrard, R Warburton, D S Sanders, D Friend, S Duty, J Taylor, N Hoggard; J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2016-314863

A total of 1500 patients were assessed over 20 years. Twenty per cent had a family history, the remaining having sporadic ataxia. The commonest cause of sporadic ataxia was gluten ataxia (25%). A genetic cause was identified in 156 (13%) of sporadic cases with other causes being alcohol excess (12%) and cerebellar variant of multiple system atrophy (11%). Using NGS, positive results were obtained in 32% of 146 patients tested. The commonest ataxia identified was EA2. A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich's ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%.

Mitochondria and Iron: current questions

Bibbin T. Paul, David H. Manz, Frank M. Torti, and Suzy V. Torti; Expert Review of Hematology Vol. 0 , Iss. 0,0 doi:10.1080/17474086.2016.1268047

Several genetic diseases can result in disrupted iron-sulfur cluster biogenesis and severe mitochondrial iron overload. For example, point mutations or homozygous unstable GAA trinucleotide expansion in the FXN gene can result in Friedreich's ataxia (FRDA), an autosomal recessive disease characterized by severe neurodegeneration and cardiomyopathy. These manifestations of FRDA are caused by an accumulation of intra-mitochondrial iron, which decreases mitochondrial function and increases sensitivity to oxidative stress.
Mitochondria serve a key role in the synthesis and assembly of heme and Fe-S clusters, and are therefore essential for the delivery of iron to client proteins. Appropriate levels of iron, however, are also important for the proper function of the mitochondria. Conditions of iron deficiency or excess disrupt a myriad of mitochondrial functions. This interdependence between iron and mitochondria is best demonstrated by diseases that simultaneously disrupt mitochondrial iron and mitochondrial function, such as Frederich’s Ataxia, infantile mitochondrial complex II/III deficiency, neonatal oxidative phosphorylation deficiency, and sideroblastic anemia.
To develop effective treatment for pathologies leading to localized mitochondrial iron overload or deficiency, we will first need to develop a more detailed understanding of mitochondrial iron regulation. We anticipate substantial progress towards this goal in the next five years.

Amélioration des paramètres spatiotemporels de la marche par des chaussures orthopédiques dans l’ataxie de Friedreich

Bastien Roche, Isabelle Husson, Neurophysiologie Clinique/Clinical Neurophysiology, Volume 46, Issues 4–5, November 2016, Pages 276-277, ISSN 0987-7053, doi:10.1016/j.neucli.2016.09.098

Alors que l’évolution de l’ataxie s’oriente vers une instabilité plus importante, puis une perte de la marche, l’utilisation des chaussures orthopédiques permet d’améliorer, comparativement à la marche pieds nus, la stabilité et la fonctionnalité de la marche.

Paediatric spinal conditions

Tomlinson JE, Gummerson NW, Surgery (2016), doi:10.1016/j.mpsur.2016.10.013

Achieving an upright posture, and balancing the 24 mobile segments of the spine in a vertical column, is clearly no easy task. The neuromuscular control of the spine involves brain, nerve and muscle (including feedback pathways). Problems anywhere in this pathway may lead to a neuromuscular scoliosis. Causes include cerebral palsy, Friedreich’s ataxia, syringomyelia, tumour, trauma, myelodysplasia, spinal muscular atrophy, poliomyelitis, Duchenne muscular dystrophy and arthrogryposis.
The treatment goals in this group of patients are to prevention of significant cardiorespiratory compromise, and maintain function. Function may often be maintenance of sitting balance, use of the upper limbs, the use of a wheelchair, or ease of hygiene and pressure area care rather than walking. Scoliosis surgery in neuromuscular conditions is a significant undertaking and other adaptations such as moulded seating should be considered, with surgery playing a role when other options have been exhausted. Surgery is usually a long posterior instrumented fusion, but unlike idiopathic curves, fixation is often to the pelvis.

Gradually Progressive Spastic Ataxia in a Young Man: Steadily Unsteady

Divyanshu Dubey, MD; Pravin Khemani, MD; Eric Remster, MD; Jeffrey L. Elliott, MD; JAMA Neurol. Published online December 12, 2016. doi:10.1001/jamaneurol.2016.1581

The final diagnosis was adult-onset FA. An atypical presentation of a more common condition such as FA, should always be considered as more likely than a common presentation of an extraordinarily rare disorder. It is now recognized that up to 25%of patients with FA may be considered atypical according to classical diagnostic criteria.
Patients with atypical FA may present with retained reflexes, spasticity, mild or absent limb ataxia, lack of dysarthria, and no cardiomyopathy. Among them, spastic ataxia with almost no sensory neuropathy has been associated with a limited GAA expansion. It is thought that GAA expansion size significantly affects the degree of involvement of the central somatosensory pathway and peripheral sensory axons, along with the overall severity of disease, as the clinical course of disease and neuropathology can be variable based on the degree of repeat expansion or heterozygosity of GAA mutation.

Automatic classification of gait in children with Early-Onset Ataxia or Developmental Coordination Disorder and controls using inertial sensors

Andrea Mannini, Octavio Martinez-Manzanera, Tjitske F. Lawerman, Diana Trojaniello, Ugo Della Croce, Deborah A. Sival, Natasha M. Maurits, Angelo Maria Sabatini; Gait & Posture, Available online 2 December 2016, ISSN 0966-6362, doi:10.1016/j.gaitpost.2016.12.002.

Early-Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) are two conditions that affect coordination in children. Phenotypic identification of impaired coordination plays an important role in their diagnosis. Gait is one of the tests included in rating scales that can be used to assess motor coordination. A practical problem is that the resemblance between EOA and DCD symptoms can hamper their diagnosis. In this study we employed inertial sensors and a supervised classifier to obtain an automatic classification of the condition of participants.
In absence of reliable distinctive biomarkers, the Scale for Assessment and Rating of Ataxia (SARA), is often used as an additional, supportive biomarker to indicate ataxia severity. Despite the high reliability of the scale, we have shown that pediatric SARA is confounded by other factors than ataxia, as well. Nevertheless, we have shown that the relative SARA gait subscore can support the recognition of an indisputable EOA phenotype in mildly affected participants. Presently available quantitative gait parameters [14] are still not ubiquitously implemented as a clinical tool. Based on the remarks reported above, we reasoned that clinically simple and reproducible quantitative gait analysis could be worthwhile for reliable EOA and DCD recognition.
In the present paper, we evaluate a method for the automatic and objective assessment of pediatric gait as compared to a clinical diagnosis in a similar way to what was previously done for other pathological conditions. Additionally, the accuracy of phenotypic assessments is estimated. Both methods classify patients into three groups (EOA, DCD and CTRL). To be effective, the automatic assessment is expected to guarantee both a limited increase of the complexity of the evaluation and a minimal impact on the gait patterns under evaluation. Hopefully, this study provides a first step towards incorporating a clinically objective and viable biomarker for uniform identification of EOA and DCD.

Vestibular findings in autosomal recessive ataxia

Bianca Simone Zeigelboim, Helio Afonso Ghizoni, Teive Hugo Amilton Santos de Carvalho, Edna Marcia da Silva Abdulmassih, Jair Mendes Marques and Rafaella Cristyne Cardoso. International Tinnitus Journal. 2013;18(2):156-162.

The most evident neurotological symptoms were dizziness, lack of coordination of movement, and imbalance when walking. Alterations in vestibular examinations occurred in 89.5% of patients, mostly in the caloric test, with a predominance of deficient central vestibular system dysfunction. This underscores the importance of the contribution of topodiagnostic labyrinthine evaluations for neurodegenerative diseases.

Liver Growth Factor (LGF) Upregulates Frataxin Protein Expression and Reduces Oxidative Stress in Friedreich’s Ataxia Transgenic Mice

Calatrava-Ferreras, L.; Gonzalo-Gobernado, R.; Reimers, D.; Herranz, A.S.; Casarejos, M.J.; Jiménez-Escrig, A.; Regadera, J.; Velasco-Martín, J.; Vallejo-Muñoz, M.; Díaz-Gil, J.J.; Bazán. Int. J. Mol. Sci. 2016, 17, 2066. doi:10.3390/ijms17122066 (registering DOI)

OPEN ACCESS

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.