Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease

INTRODUCTION: Peripheral nerve involvement is common in mitochondrial disease but often unrecognised due to the prominent central nervous system features. Identification of the underlying neuropathy may assist syndrome classification, targeted genetic testing and rehabilitative interventions. METHODS: Clinical data and the results of nerve conduction studies were obtained retrospectively from the records of four tertiary children's hospital metabolic disease, neuromuscular or neurophysiology services. Nerve conductions studies were also performed prospectively on children attending a tertiary metabolic disease service. Results were classified and analysed according to the underlying genetic cause. RESULTS: Nerve conduction studies from 27 children with mitochondrial disease were included in the study (mitochondrial DNA (mtDNA) – 7, POLG – 7, SURF1 – 10, PDHc deficiency – 3). Four children with mtDNA mutations had a normal study while three had mild abnormalities in the form of an axonal sensorimotor neuropathy when not acutely unwell. One child with MELAS had a severe acute axonal motor neuropathy during an acute stroke-like episode that resolved over 12 months. Five children with POLG mutations and disease onset beyond infancy had a sensory ataxic neuropathy with an onset in the second decade of life, while the two infants with POLG mutations had a demyelinating neuropathy. Seven of the 10 children with SURF1 mutations had a demyelinating neuropathy. All three children with PDHc deficiency had an axonal sensorimotor neuropathy. Unlike CMT, the neuropathy associated with mitochondrial disease was not length-dependent. CONCLUSIONS: This is the largest study to date of peripheral neuropathy in genetically- classified childhood mitochondrial disease. Characterising the underlying neuropathy may assist with the diagnosis of the mitochondrial syndrome and should be an integral part of the assessment of children with suspected mitochondrial disease

Non Destructive Evaluation of Containment Walls in Nuclear Power Plants

Two functions are regularly tested on the containment walls in order to anticipate a possible accident. The first is mechanical to resist at a possible internal over-pressure and the second is to prevent leakage. The reference accident LLOCA (Large Loss of Coolant Accident) is the rupture of a pipe in the primary circuit of a nuclear plant. In this case, the pressure and temperature can reach 5 bar and 180°C in 20 seconds. The national project ‘Non-destructive testing of the containment structures of nuclear plants’ aims at studying the non-destructive techniques capable to evaluate the concrete properties and its damaging or progression of cracks. This 4-year-project is segmented into two parts. The first consists in developing and selecting the most relevant NDEs (Non Destructive Evaluations) in the laboratory to reach these goals. These evaluations are developed in conditions representing the real conditions of the stresses generated during ten-yearly visits of the plants or those related to an accident. The second part consists in applying the selected techniques to two containment structures under pressure. The first (technique) is proposed by the ONERA (National Office for Aerospace Studies and Research of France) and the second is a mock-up of a containment wall on a 1/3 scale made by EDF (Electricity of France) within the VeRCoRs program. Communication bears on the part of the project that concerns the damaging and cracking follow-up. The tests are done in bending on 3 or 4 points in order to study the cracks’ generation, their propagation, as well as their opening and closing. The mostly ultrasonic techniques developed concern linear or non-linear acoustic: acoustic emission [1], LOCADIFF (Locating with diffuse ultrasound) [2], energy diffusion, surface waves velocity and attenuation, DAET (Dynamic Acousto-Elasticity Testing) [3]. The data contribute to providing the mapping of the parameters searched for, either in volume, in surface or globally. Image correlation is an important additional asset to validate the coherence of the data. The spatial normalization of the data allows proposing algorithms on the combination of the experimental data. The tests results are presented and they show the capacity and the limits of the evaluation of the volume, surface or global data. A data fusion procedure is associated with these results

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Phenotypic insights into ADCY5-associated disease

BACKGROUND: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. METHODS: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing. RESULTS: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. CONCLUSION: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Mutation in the Gene Encoding Ubiquitin Ligase LRSAM1 in Patients with Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred

Vertebrobasilar arterial occlusions in children

Three children with angiographically confirmed, sudden thrombosis involving the vertebro basilar arterial system are presented. Ten previously reported cases are reviewed with particular regard to possible etiologies. Vertebral artery trauma at the atlantoaxial level is suspected as one important cause. Les auteurs rapportent trois cas d'enfants présentant une trombose soudaine du système artériel vertébrobasilaire, confirmée angiographiquement. Ils revoient dix cas antérieurs, en particulier du point de vue éthiologique. Le traumatisme de l'artère vertébrale au niveau de la charnière cervico-occipitale semble être l'une des causes principale. 3 Kinder mit einer angiographisch nachgewiesenen plötzlich aufgetretenen thrombose des vertebro-basilären Systems werden geschildert, gleichzeitig wird ein Überblick über weitere 10 vorher veröffentlichte Fälle gegeben. Diskussion der möglichen Ätiologie. Es wird darauf verwiesen, daß ein Trauma der A. vertebralis in Höhe des atlanto-axialen Gelenkes eine wichtige Ursache sein kann.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46670/1/234_2004_Article_BF00341593.pd