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To determine the prevalence of intraspinal alterations in scoliosis due to Spinal Muscular Atrophy (SMA). Cross-sectional, observational, descriptive study. Fifty-six patients with SMA diagnosis required surgical treatment due to scoliosis. Inclusion criteria: scoliosis/kyphoscoliosis > 50 degrees in the coronal plane, clinical characteristics of Spinal Muscular Atrophy, accurate diagnosis by means of molecular or genetic study. Prior to the spinal surgery, and to find related intraspinal alterations, MRI of the spine and posterior cranial fossa was performed. Forty females, 16 males, mean age 11 years (range 6–14 years). 94% of the patients had Spinal Muscular Atrophy type 2. The mean angle value was 81 degrees (range 53–122 degrees) in the coronal plane and 62 degrees (range 35–80 degrees) in the sagittal plane. The prevalence of intraspinal alterations was 1.78%. One patient with cervical hydromyelia and no neurological surgical procedure prior to the spinal deformity surgery was reported. In the context of preoperative planning and strategy of patients with scoliosis due to Spinal Muscular Atrophy, MRI may have not to be requested.

Congenital fiber type disproportion (CFTD) is a rare congenital myopathy subtype defined by slow type 1 hypotrophy in the absence of any other major structural findings such as rods, central nuclei or cores. Dominant missense changes in slow alpha-tropomyosin coded by TPM3 gene are the main cause of the CFTD. There are only a few reports of recessive loss-of-function mutations in TPM3 causing severe Nemaline Myopathy and CFTD. We present two patients harboring TPM3 mutations. The first is a novel homozygous missense variant with a mild CFTD clinical phenotype inherited in a recessive fashion. The second is a previously reported heterozygous mutation presenting within pronounced early axial involvement and dropped head. This report expands the genotype-phenotype correlation in the TPM3 myopathy showing a recessive mutation causing a mild clinical phenotype and also shows that TPM3 mutations should be part of the investigation in patients with dropped head.

Laminopaties; Distròfia muscular; Múscul estriat Laminopatías; Distrofia muscular; Músculo estriado Laminopathies; Muscular dystrophy; Striated muscle Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations. This work was supported by the AFM-Telethon, the Institut National de la Santé et de la Recherche Médicale (INSERM) and Sorbonne Université (R.B.Y., G.B.), intramural funds of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (C.G.B.), Cure-CMD (A.R., G.B., R.B.Y.), The Andres Marcio Fondation (G.B., R.B.Y). and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program (T.M.P).

Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations., Abbreviated summary Ben Yaou et al. report the largest cohort of LMNA-congenital muscular dystrophy. They identified phenotypic subgroups based on walking status and specific mutation and defined age range where most clinical progression occurs (5–15 years ago). This will help subject stratification and clinical endpoints designing for future clinical trials, Graphical Abstract Graphical Abstract

To assess the psychometric properties of the Pediatric Quality of Life Inventory™ (PedsQL™ 3.0), Neuromuscular Module, version in Spanish for Argentina, for children aged 2-18 years with neuromuscular disease.Observational, analytical, prospective validation study conducted in Hospital Garrahan between March 19th, 2019 and March 9th, 2020. The retest questionnaire was administered 10-15 days later to validate it among patients who reported a stable condition.A total of 185 children and their parents participated. In terms of the questionnaire's feasibility, its content was easily understood by participants. Its reliability was acceptable, with an internal consistency of 0.82 among children and 0.87 among parents and a retest intraclass correlation coefficient of 0.70 among children and 0.82 among parents. In relation to the construct validity, 8 of the 11 hypotheses established (72.7 %) were confirmed.The questionnaire's psychometric properties were validated.Objetivo: Evaluar las propiedades psicométricas del Cuestionario pediátrico de calidad de vida (PedsQLTM 3.0) Módulo Neuromuscular, versión en español para Argentina, en niños entre 2 y 18 años con enfermedades neuromusculares. Población y métodos: Estudio observacional, analítico, prospectivo, de validación, realizado en el Hospital Garrahan entre el 19 de marzo de 2019 y el 9 de marzo de 2020. A los 10-15 días se realizó el retest del cuestionario para validar en los pacientes que reportaron estabilidad. Resultados: Participaron 185 niños y sus padres. Sobre la factibilidad de la herramienta, los participantes comprendieron fácilmente su contenido. La confiabilidad resultó aceptable, con una consistencia interna de 0,82 en niños y 0,87 en padres y un coeficiente de correlación intraclase en el retest de 0,70 en niños y 0,82 en familiares. Sobre la validez del constructo se confirmaron 8 de 11 hipótesis establecidas (72,7 %). Conclusión: El cuestionario fue validado en sus propiedades psicométricas.

Intraneural perineurioma (IP) is an under-recognized hypertrophic peripheral nerve tumor. It affects young patients involving frequently the sciatic nerve and its branches and presents with a progressive, painless and predominantly motor deficit. Magnetic resonance neurography (MRN) is a useful tool to localize the lesion, evaluate its extension, and discriminate between different etiologies. We reviewed the clinical records of 11 patients with pathologically confirm IP. Eight patients were males with mean age 19 years. Initial complains were unilateral steppage (seven patients), bilateral steppage (one patient), unilateral gastrocnemius wasting (one patient), unilateral thigh atrophy (one patient), and unilateral hand weakness (one patient). Nine patients had mild painless sensory loss. Examinations revealed involvement of sciatic nerve extending into the peroneal nerve (eight patients), posterior tibial nerve (one patient), radial nerve (one patient), and femoral nerve (one patient). MRN revealed enlargement of the affected nerve isointense on T1-weighted, hyperintense on T2 fat-saturated images, and with avid enhancement on post-contrast imaging. In all patients, a nerve biopsy confirmed the diagnosis. MRN allows early and non-invasive identification of this tumor and is a key tool providing localization and differential diagnosis in patients with slowly progressive focal neuropathies.

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.

Introduction Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified. Methods Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described. Results All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies. Conclusions In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.

Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients’ muscle biopsies. We defined “dusty cores” the irregular areas of myofibrillar disorganisation characterised by a reddish-purple granular material deposition with uneven oxidative stain and devoid of ATPase activity, which represent the characteristic lesion in muscle biopsy in 54% of patients. We named Dusty Core Disease (DuCD) the corresponding entity of congenital myopathy. Dusty cores had peculiar histological and ultrastructural characteristics compared to the other core diseases. DuCD muscle biopsies also showed nuclear centralization and type1 fibre predominance. Dusty cores were not observed in other core myopathies and centronuclear myopathies. The other morphological groups in our cohort of patients were: Central Core (CCD: 21%), Core-Rod (C&R:15%) and Type1 predominance “plus” (T1P+:10%). DuCD group was associated to an earlier disease onset, a more severe clinical phenotype and a lowest level of RyR1 expression in muscle, compared to the other groups. Variants located in the bridge solenoid and the pore domains were more frequent in DuCD patients. In conclusion, DuCD is the most frequent histopathological presentation of RYR1-recessive myopathies. Dusty cores represent the unifying morphological lesion among the DuCD pathology spectrum and are the morphological hallmark for the recessive form of disease. Electronic supplementary material The online version of this article (10.1186/s40478-018-0655-5) contains supplementary material, which is available to authorized users.

International audience; Titin-related myopathies are heterogeneous clinical conditions associated with mutations in TTN. To define their histopathologic boundaries and try to overcome the difficulty in assessing the pathogenic role of TTN variants, we performed a thorough morphological skeletal muscle analysis including light and electron microscopy in 23 patients with different clinical phenotypes presenting pathogenic autosomal dominant or autosomal recessive (AR) mutations located in different TTN domains. We identified a consistent pattern characterized by diverse defects in oxidative staining with prominent nuclear internalization in congenital phenotypes (AR-CM) (n = 10), ± necrotic/regenerative fibers, associated with endomysial fibrosis and rimmed vacuoles (RVs) in AR early-onset Emery-Dreifuss-like (AR-ED) (n = 4) and AR adult-onset distal myopathies (n = 4), and cytoplasmic bodies (CBs) as predominant finding in hereditary myopathy with early respiratory failure (HMERF) patients (n = 5). Ultrastructurally, the most significant abnormalities, particularly in AR-CM, were multiple narrow core lesions and/or clear small areas of disorganizations affecting one or a few sarcomeres with M-band and sometimes A-band disruption and loss of thick filaments. CBs were noted in some AR-CM and associated with RVs in HMERF and some AR-ED cases. As a whole, we described recognizable histopathological patterns and structural alterations that could point toward considering the pathogenicity of TTN mutations.

Background Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases. Patient Description We present a 3.6-year-old girl with congenital scoliosis, equinovarus, and L5/S1 left hemivertebra who demonstrated delayed walking and lower extremities atrophy. She was negative for SMN1 deletion testing, and parents show no sign of disease. Results Whole exome sequencing of the affected girl showed a novel de novo heterozygous missense mutation c.1792C>T (p.Arg598Cys) in the tail domain of the DYNC1H1 gene encoding for cytoplasmic dynein heavy chain 1. The mutation changed a highly conserved amino acid and was absent from both parents. Conclusion De novo mutations of DYNC1H1 have been found in individuals with autosomal dominant mental retardation with neuronal migration defects. Dominantly inherited mutations of DYNC1H1 have been reported to cause spinal muscular atrophy with predominance of lower extremity involvement and Charcot-Marie-Tooth type 2O. This is the first report of a de novo DYNC1H1 mutation associated with the spinal muscular atrophy with predominance of lower extremity phenotype with a spinal deformity (lumbar hemivertebrae). This case also demonstrates the power of next generation sequencing to discover de novo mutations on a genome-wide scale.

International audience; Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in Comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients. (C) 2017 Elsevier B.V. All rights reserved.

International audience

Introduction Duchenne muscular dystrophy (DMD) is a severe muscular disease characterized by progressive loss of functional muscle mass followed by changes in body composition. Aim To describe body composition, resting energy expenditure (REE), and metabolic disorders in DMD patients followed-up at a tertiary care center. To analyze the association with type of steroid and ambulatory status, and to compare obese DMD patients with patients with multifactorial obesity. Population and methods A prospective, observational, cross-sectional study was conducted. Anthropometric measurements were taken, evaluating body composition with bioelectrical impedance analysis (BIA), REE with indirect calorimetry, and biochemical parameters in all DMD patients seen between June 2013 and April 2014. Results 63 boys between 5.4 and 18.7 years of age were evaluated. Diagnosis of obesity ranged from 28% measuring body mass indexZ-score (BMIZ-score) to 70% using percentage of fat mass (%FM). Patients who had lost gait had a significantly higher %FM than those in whom gait was preserved (72% vs 46%, p Insulin resistance was present in 29% associated with BMI Z-score and waist circumference and 40% had dyslipidemia associated with %FM, both of which were steroid independent. In obese DMD patients REE was lower than predicted and also lower than controls, and persist when dividing the patients into ambulators and non-ambulators. Conclusions A high prevalence of obesity was observed. BMI-Z-score underestimates the degree of FM. No correlation was found between steroid type and body composition or metabolic disorders. No differences were found in REE between ambulators and non-ambulators. Obese DMD patients have a lower REE than controls.

Las encefalitis son procesos inflamatorios de diverso origen, entre las cuales se incluyen las autoinmunes. La identificación de anticuerpos contra el receptor N-metil-D-aspartato permitió la caracterización clínico-inmunológica de una entidad susceptible a tratamiento inmunomodulador. Descripta originalmente en mujeres jóvenes, asociada a teratoma de ovario, es hoy una entidad reconocida en niños aun en ausencia de tumores detectables. El objetivo del trabajo, realizado a través de la revisión de historias clínicas, fue describir las características clínicas, evolutivas y los hallazgos en estudios complementarios de once niños con diagnóstico confirmado de esta entidad a través de la identificación de los anticuerpos específicos. Todos debutaron con síntomas psiquiátricos, en nueve de ellos asociando a convulsiones, y dos a movimientos extrapiramidales. En su evolución, todos presentaron compromiso del lenguaje, nueve, síntomas autonómicos graves, en uno con hipoventilación y requerimientos de ARM. La RM de cerebro fue anormal en tres. Ocho tuvieron EEG con asimetría del voltaje y/o amplitud, tres de ellos presentaron espigas. En el LCR seis tuvieron pleocitosis y tres de siete bandas oligoclonales positivas. Cinco, serologías IgM para micoplasma. El aumento de CPK en coincidencia con antipsicóticos ocurrió en cinco. Con el tratamiento inmunomodulador, cinco tuvieron recuperación total, tres, alteraciones conductuales/cognitivas y uno déficits severo. Un paciente resolvió su cuadro clínico sin tratamiento. En ninguno se detectó tumor asociado. Concluimos que frente a un niño con encefalopatía aguda y clínica compatible con esta entidad, una vez descartada causa infecciosa, se debe comenzar tratamiento inmunomodulador precozmente, evitar la utilización de fármacos antipsicóticos y realizar la búsqueda de posibles tumores ocultos.

Neuromuscular diseases are mostly genetic disorders, with chronic and progressive course. Affected people are at high risk of developing physical and emotional disabilities. In the last decades, the advance in technology and science has increased chronic pediatric patients survival rate, thus requiring an ongoing assistance in adult hospitals, making the transition a necessity and a challenge. This article reports the clinical practice designed between Hospital Garrahan and Hospital Ramos Mejia for the transition of 27 adolescents during 2015, setting achievements, findings and challenges resulting from this experience.

Background: Recent short-term clinical trials in patients with Duchenne Muscular Dystrophy (DMD) have indicated greater disease variability in terms of progression than expected. In addition, as average life-expectancy increases, reliable data is required on clinical progression in the older DMD population. Objective: To determine the effects of corticosteroids on major clinical outcomes of DMD in a large multinational cohort of genetically confirmed DMD patients. Methods: In this cross-sectional study we analysed clinical data from 5345 genetically confirmed DMD patients from 31 countries held within the TREAT-NMD global DMD database. For analysis patients were categorised by corticosteroid background and further stratified by age. Results: Loss of ambulation in non-steroid treated patients was 10 years and in corticosteroid treated patients 13 years old (p = 0.0001). Corticosteroid treated patients were less likely to need scoliosis surgery (p < 0.001) or ventilatory support (p < 0.001) and there was a mild cardioprotective effect of corticosteroids in the patient population aged 20 years and older (p = 0.0035). Patients with a single deletion of exon 45 showed an increased survival in contrast to other single exon deletions. Conclusions: This study provides data on clinical outcomes of DMD across many healthcare settings and including a sizeable cohort of older patients. Our data confirm the benefits of corticosteroid treatment on ambulation, need for scoliosis surgery, ventilation and, to a lesser extent, cardiomyopathy. This study underlines the importance of data collection via patient registries and the critical role of multi-centre collaboration in the rare disease field. This work was supported by TREAT-NMD operating grants, FP6 LSHM-CT-2006-036825, 20123307 UNEW FY2013 and AFM 16104. Further support came from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444 (RD-Connect) and 305121 (Neuromics) and Medical Research Council UK (reference G1002274, grant ID 98482). Sí

J. A. Bevilacqua, N. Monnier, M. Bitoun, B. Eymard, A. Ferreiro, S. Monges, F. Lubieniecki, A. L. Taratuto, A. Laquerriere, K. G. Claeys, I. Marty, M. Fardeau, P. Guicheney, J. Lunardi and N. B. Romero (2011) Neuropathology and Applied Neurobiology37, 271–284 Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization Aims: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). Methods: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. Results: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. Conclusion: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.

Background/Purpose: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials. The aim of this study was to provide clinical and molecular data of a series of Argentinean children with SMA to establish a comprehensive genotype-phenotype correlation. Methods: 144 Argentinean children with SMA (56 children with type I, 58 with type II, and 30 with type III) were evaluated. The copy number of SMN2, SERF1A, and NAIP genes was established using MLPA (Multiplex Ligation-dependent Probe Amplification) and then correlated with the patients clinical subtypes. To improve clinical characterization we considered the initial symptoms that prompted the consultation, age of acquisition of motor abilities to independent walking and age at loss of gait. We also evaluated clinical and molecular features of sibling pairs in seven families. Results: A strong correlation was observed between the SMN2 copy number and SMA phenotype while SERF1A and NAIP copy number showed a moderate correlation. We observed intra- and inter-family differences among the SMA types. Conclusion: This first genotype-phenotype correlation study in Argentinean SMA children provides data to improve patient stratification and define more adequate follow-up parameters. Fil: Medrano, Sofía. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Monges, Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Gravina, Luis Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Alías, Laura. Hospital de la Santa Creu i Sant Pau; España. CIBERER; España Fil: Mozzoni, Julieta. Hospital de la Santa Creu i Sant Pau; España Fil: Aráoz, Hilda Verónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Bernal, Sara. Hospital de la Santa Creu i Sant Pau; España. CIBERER; España Fil: Moresco, Angélica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Chertkoff, Lilien Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Tizzano, Eduardo. Hospital Valle Hebron; España. CIBERER; España

Background Congenital myopathies (CM) are a group of rare inherited muscle disorders characterized by particular histopathological alterations on muscle biopsy. Core-rod myopathy is a CM presenting with cores and rods as distinctive muscle morphological features. Methods/results: We describe 3 young patients presenting congenital core-rod myopathy with bilateral foot-drop associated with autosomal recessive nebulin gene (NEB) mutations detected by exome sequencing. Conclusions This report illustrates that core-rod congenital myopathy with foot-drop is frequently associated with NEB gene mutations and should be considered in the differential diagnosis of early onset distal myopathies.

International audience

Introducción: La enfermedad de Pompe (EP) es un desorden metabólico autosómico recesivo infrecuente que se produce por ausencia o deficiencia de la enzima lisosomal alfa-glucosidasa ácida en los tejidos de los individuos afectados. Objetivo: El objetivo del presente consenso es revisar las pautas actuales y brindar recomendaciones para un correcto diagnóstico, evaluación, manejo y tratamiento de los pacientes con EP. Métodos: Se organizó un consenso que reunió profesionales nacionales y un invitado extranjero con experiencia en la EP en las áreas de clínica médica, clínica pediátrica, diagnóstico de laboratorio, neuropatología, neumonología, nutrición, neurología, enfermedades metabólicas, enfermedades neuromusculares (ENM) y rehabilitación de pacientes con ENM. Se realizó una revisión bibliográfica de las publicaciones y los artículos relevantes sobre EP existentes hasta la fecha, en forma individual y en reuniones en pequeños grupos, organizados según el área de trabajo y la especialidad. Los términos finales del documento fueron consensuados por todo el grupo de trabajo. Cada participante proporcionó su declaración de conflicto de intereses. Conclusiones: Se elaboró el Consenso Argentino para la Enfermedad de Pompe, considerando aspectos de la fisiopatología, la clínica, el diagnóstico y el tratamiento de esta enfermedad. Tratándose de una afección infrecuente, en la que los datos disponibles son limitados, las presentes recomendaciones deben ser consideradas como opinión de expertos. Introduction: Pompe disease (PD) is a rare autosomal recessive metabolic disorder which is caused by the absence or deficiency of the acid alpha-glucosidase lysosomal enzyme in the tissues of affected individuals. Objective: The objective of this consensus is to review the current guidelines and provide recommendations for a correct diagnosis, evaluation, management, and treatment of patients with PD. Methods: We organized a consensus with a foreign guest and national professionals experienced in PD in the areas of clinic, pediatric clinic, laboratory diagnosis, neuropathology, neumonology, nutrition, neurology, metabolic diseases, neuromuscular diseases (NMD) and rehabilitation of patients with MND. We conducted a literature review of the existing publications and articles relevant to EP up to date, individually and in small group meetings organized by field of work and specialty. The final terms of the document were agreed upon by the entire working group. Each participant provided their declaration of conflict of interests. Conclusions: The Argentine Consensus for Pompe disease was developed, considering aspects of the pathophysiology, clinical manifestations, diagnosis and treatment of this disease. Being a rare condition for which the available data are limited, these recommendations should be considered as expert opinion. Fil: Dubrovsky, Alberto. Fundación Favaloro; Argentina Fil: Fulgenzi, Ernesto. Unidad Asistencial Doctor César Milstein; Argentina Fil: Amartino, Hernán. Hospital Universitario Austral. Servicio de Neurología Infantil; Argentina Fil: Carlés, Daniel. Hospital Perrando. Servicio de Neumonología; Argentina Fil: Corderi, José. Fundación Favaloro; Argentina Fil: de Vito, Eduardo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Fainboim, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Ferradás, Nélida. International Life Sciences Institute ; Argentina Fil: Guelbert, Norberto. Hospital de Niños de la Santísima Trinidad. Sección de Enfermedades Metabólicas; Argentina Fil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Mazia, Claudio. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Mesa, Lilia. Fundación Favaloro; Argentina Fil: Monges, Soledad. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Pesquero, Joao. Universidade de Sao Paulo; Brasil Fil: Reisin, Ricardo. Hospital Británico de Buenos Aires; Argentina Fil: Rugiero, Marcelo. Hospital Italiano; Argentina Fil: Schenone, Andrea. Fundación para el Estudio de Enfermedades Neurometabólicas; Argentina Fil: Szlago, Marina. Fundación para el Estudio de Enfermedades Neurometabólicas; Argentina Fil: Taratuto, Ana Lía. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Zgaga, Marisa. Instituto de Lucha Antipoliomielítica y Rehabilitación del Lisiado; Argentina. Hospital Escuela Eva Perón. Servicio de Rehabilitación; Argentina

Encephalitis are an inflammatory processes of various origin, among which include autoimmune origin. The identification of antibodies against the N-methyl-D- aspartate, allowed clinical immunological characterization of an entity susceptible to immunomodulatory therapy. Originally described in young women associated with ovarian teratoma, is now a recognized entity in children even in the absence of detectable tumors. The aim of the study was conducted through review of medical records, was to describe the clinical, developmental and findings in further studies of eleven children with confirmed diagnosis of this entity through identification of specific antibodies. All debuted with psychiatric symptoms in nine associating seizures, and two extrapyramidal movements. In the evolution of language all had commitment nine severe autonomic symptoms, one with hypoventilation and requirements of ARM. Brain MRI was abnormal in three. Eight had voltage EEG asymmetry and / or amplitude, three of them had spikes. Six had CSF pleocytosis and three of seven positive oligoclonal bands. Five IgM serology for mycoplasma were positive. CPK increase occurred in conjunction with antisychotics in five. With immunomodulatory treatment, five had complete recovery three behavioral disorders / cognitive deficits and one severe. A patient's clinical picture resolved without treatment. In any associated tumor was detected. We conclude that in front of a child with acute encephalopathy and clinical support this entity after infectious cause were ruled out, immunomodulatory therapy should be started early, avoid the use of antipsychotic drugs and search for possible hidden tumors.

DMD nonsense and frameshift mutations lead to severe Duchenne muscular dystrophy while in-frame mutations lead to milder Becker muscular dystrophy. Exceptions are found in 10% of cases and the production of alternatively spliced transcripts is considered a key modifier of disease severity. Several exonic mutations have been shown to induce exon-skipping, while splice site mutations result in exon-skipping or activation of cryptic splice sites. However, factors determining the splicing pathway are still unclear. Point mutations provide valuable information regarding the regulation of pre-mRNA splicing and elements defining exon identity in the DMD gene. Here we provide a comprehensive analysis of 98 point mutations related to clinical phenotype and their effect on muscle mRNA and dystrophin expression. Aberrant splicing was found in 27 mutations due to alteration of splice sites or splicing regulatory elements. Bioinformatics analysis was performed to test the ability of the available algorithms to predict consequences on mRNA and to investigate the major factors that determine the splicing pathway in mutations affecting splicing signals. Our findings suggest that the splicing pathway is highly dependent on the interplay between splice site strength and density of regulatory elements, This study was supported by grants from Fondo de Investigación Sanitaria (PI08/0347) and CIBER de Enfermedades Raras (U-705) initiatives of Instituto de Salud Carlos III (www.isciii.es)

Heterozygous missense mutations of transient receptor potential vanilloid 4 channel (TRPV4) cause a spectrum of skeletal disorders, including brachyolmia, spondylometaphyseal dysplasia Kozlowski type, metatropic dysplasia, parastremmatic dysplasia, and spondyloepimetaphyseal dysplasia Maroteaux type. Similarly, heterozygous missense mutations of TRPV4 cause a spectrum of peripheral neuropathy, including hereditary motor and sensory neuropathy type IIC, congenital spinal muscular atrophy, and scapuloperoneal spinal muscular atrophy. There are no apparent differences in the amino acid positions affected or type of change predicted by the TRPV4 mutations responsible for the two disease spectrums; nevertheless, no fundamental phenotypic overlap has been shown between the two spectrums. Here, we report on three patients who had both skeletal dysplasia and peripheral neuropathy caused by heterozygous TRPV4 missense mutations. The skeletal and neurologic phenotypes of these patients covered the wide spectrum of reported TRPV4-pathies (disease caused by TRPV4 mutations). The molecular data are complementary, proving that “neuropathic” mutations can cause skeletal dysplasia but also the “skeletopathic” mutations can lead to neuropathies. Our findings suggest that pathogenic mechanisms of TRPV4-pathies in skeletal and nervous systems are not always mutually exclusive and provide further evidence that there is no clear genotype–phenotype correlation for either spectrum. Co-occurrence of skeletal dysplasia and degenerative neuropathy should be kept in mind in clinical practice including diagnostic testing, surgical evaluation, and genetic counseling. © 2012 Wiley Periodicals, Inc.

Nebulin (NEB) is a sarcomeric structural protein. Mutations in NEB genes particularly cause autosomal recessive nemaline myopathy (NM) and core-rod myopathy. Clinical presentations range from a severe neonatal form to a mild adult-onset form as part of the different diagnosis of distal myopathy. We describe the clinical, histopathological, and molecular findings of three patients with different phenotypes of NEB gene mutations. Case 1: A 5-year-old boy with distal finger retractions, hypotonia, and motor development delay since birth with mainly distal general weakness and hyperlaxity. At age 1 he developed progressive respiratory difficulties needing ongoing invasive ventilation by tracheostomy. He was never able to walk. Spine surgery was performed at 4 years. Cognitive development was normal. Quadriceps muscle biopsy showed NM consisting of rod structures, type 1 predominance and atrophy. Exome sequencing showed mutations in exon 139 and 172. Case 2: A 2.5-year-old girl presenting with motor developmental delay, hypomimia, and hypotonia since birth. At 18 months of age she walked independently and steppage gait was noticed. She is still improving. Deltoid biopsy showed NM consisting of rod structures and type 1 predominance. Exome sequencing showed mutations in intron 12 and exon 150. Case 3: A 22-year-old girl had frequent falls since she started to walk at 1 year, linked to distal hyperlaxity, as well as distal weakness, arreflexia, and steppagge gait. Slow symptom progression was seen. EMG ruled out neuropathic disease and muscle biopsy showed rod and core structures with type 1 predominance. Exome sequencing showed mutations in exon 129 and exon 74 to exon144. Conclusion: NEB-related NM has a broad clinical spectrum particularly including congenital and distal myopathy forms that may mimic a neurogenic process. Our three patients presented with predominantly distal weakness and muscle biopsies showed rod or core-rod myopathies.

Mutations in the FKRP gene account for a broad spectrum of patients ranging from CMD to the much milder LGMD2I. We describe the first 3 children with FKRP muscular dystrophy from Argentina. In all of them muscular dystrophy with deficit of alpha-dystroglycan was observed on muscle biopsy. Case 1: An 18-month-old boy with a history of poor sucking at birth, respiratory difficulties, delayed milestones, microcephaly, proximal weakness, and calf hypertrophy. CPK: 5100 IU/l. Normal brain MRI. Molecular studies: homozygous mutation c.946C>Gp.Pro318Ala. He was able to walk independently at 3 years of age. At 5 years old he was started on nocturnal non-invasive ventilation. Case 2: A 9-year-old girl with progressive weakness and hypotonia, generalized, mainly proximal and lower-limb weakness, a waddling, tiptoe gait, bilateral scapular winging, and difficulty getting up from the floor, running, and jumping. CPK: 15920 IU/l. Molecular studies: 3 heterozygous variants were identified: C.826C>A p.Leu276Ile, C.946C>G p.Pro316Ala, c.970G>C p.Glu324Gln. She is currently 10 years old and stable. Cardiological and respiratory studies are normal. Case 3: An 11-year-old boy with difficulty running since 5 years of age, calf pain, and fatigue. He had proximal muscle weakness, mainly in the lower limbs, marked calf hypertrophy, and a waddling gait. CPK: 8737 IU/l. Molecular studies: 3 heterozygous variants were identified: C.545A>G p.Tyr182Cys, C.946C>Gp.Pro316Ala, c.970G>C p.Glu324Gln. The mother showed the heterozygous variant C.545A>G p.Tyr182Cys. He is currently 13 years old, shows a waddling, tiptoe gait, difficulty climbing stairs, running, and jumping. There is no evidence of cardiomyopathy. Conclusion: Case 1 presented as a CMD while the other two mainly have a LGMD2I phenotype. The last two cases presented with two identical, not previously reported variants.

Muscular dystrophy related to lamin A/C gene (LMNA/C) mutations is characterized by muscle weakness, joint contractures, dilated cardiomyopathy, and arrhythmias. It includes autosomal dominant and rare recessive forms of Emery-Dreifuss (EDMD) as well as limb-girdle muscular dystrophy (LGMD1B), dilated cardiomyopathy with conduction system disease and congenital muscular dystrophy (CMD). We describe the clinical and pathological spectrum of 13 patients with an LMNA/C gene mutation. Results: 13 patients (6 females/7 males) were studied. Eight patients with EDMD had progressive weakness with proximal hypotrophy in the upper limbs and distal hypotrophy of the lower limbs with neck, elbow, and Achilles heel contractures, and conduction-system cardiac involvement. Three patients with a CMD form, presented dropped-head syndrome with clinical onset in the first years of life. They had weakness and proximal hypotrophy of the upper limbs and distal hypotrophy of the lower limbs. One patient never walked and another lost ambulation afterwards. None of our patients showed cardiac involvement or elbow contractures. Two of our patients assumed as LGMD1B had proximal weakness without contractures. In one of them, the first sign was a dilated cardiomypathy that required transplantation. Four patients had a family history of heart disease or weakness. Muscle biopsy showed a variable degree of inflammatory and/or dystrophic changes, with lobulated fibers or type 1 atrophy and variable oxidative defects or increase in central oxidative activity. Ultrastructural study showed nuclear changes and focal sarcomeric disorganization. All patients had mutations of the LMNA/C gene. Conclusion: There is a broad clinical spectrum of laminopathies, including a congenital form. Even when muscle biopsy shows inflammation or features suggestive of congenital myopathy, the clinical phenotype should prompt molecular testing for lamin A/C mutations to prevent cardiac complications.

Objective Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. Methods Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. Results ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). Interpretation This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials. ANN NEUROL 2010;68:511–520

We report four heterozygous dynamin 2 (DNM2) mutations in five centronuclear myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related centronuclear myopathy from the classic mild form to the more severe neonatal phenotype.