G.P.4.07 Skeletal muscle regeneration in amyotrophic lateral sclerosis

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Abstracts / Neuromuscular Disorders 19 (2009) 543–660

We would like to emphasize that an isolated axonal sensory– motor neuropathy with early onset and rapid and severe progression prompt us to mutations in GDAP1 with recessive inheritance. doi:10.1016/j.nmd.2009.06.072

G.P.4.04 A new MTMR2 mutation is responsible for a congenital form of Charcot-Marie-Tooth disease (CMT4B1) and vocal cord paresis M. Tazir1, S. Nouioua 1, T. Hamadouche 2, R. Bernard 3, D. Grid 4, N. Levy 3, J.M. Vallat 5 CHU Mustapha, Neurology, Algiers, Algeria, 2 Université Mohamed Bougara, Laboratoire de Biologie Moléculaire, Boumerdés, Algeria, 3 Hôpital de La Timone, Biologie Médicale, Marseille, France, 4 Genethon, Evry, France, 5 CHU de Limoges, Service et Laboratoire de Neurologie, Limoges, France 1

The distinct form of autosomal recessive demyelinating sensory– motor neuropathy designed CMT4B1 is characterized pathologically by the presence of focally folded myelin sheaths and genetically by molecular alterations in the MTMR2 gene. Here, we report a consanguineous CMT4B1 Algerian family with three affected sibs. Age of onset was around 2-year-old for the two first brothers and 1-year-old for the third one. The proband is a 4-year-old male with a steppage gait, severe chest deformity and a permanent stridor with vocal cord paresis. The older brother, 7-year-old, presented a steppage gait with foot deformities, areflexia, moderate chest deformity and a minor stridor. The youngest brother was 12-month-old and presented only a moderate chest deformity, a global hypotrophy and areflexia. Median motor conduction velocity was between 13 and 15 m/s and nerve biopsy showed severe chronic demyelinating lesions with typical myelin outfoldings which orientate towards MTMR2 genetic analysis. The three siblings thus harbored a novel homozygous nonsense mutation c.330_331insA (p.Arg111LysfsX15) in exon 4 of the MTMR2 gene. Vocal cord paresis was already described in hereditary motor and sensory neuropathy, mainly in CMT4A linked to the GDAP1 gene, but not in CMT4B CMT subtypes. Genetic counseling was given to the family. doi:10.1016/j.nmd.2009.06.073

G.P.4.05 Clinical and electrophysiological findings in the course of childhood Guillain–Barré syndrome: 10 years experience in a pediatric neuromuscular unit A.P. Gutiérrez Mata, A.E. Nascimento Osorio, C.I. Ortez González, J. Colomer Oferil Sant Joan de Déu Hospital, Neuromuscular Unit, Barcelona, Spain Retrospective study of 42 children diagnosed of GBS according to international criteria established were performed in a pediatric neuromuscular unit from May 1998 to January 2008. We report on clinical, electrophysiological and biological findings in the course of the illness. Results: Forty-two children with a mean age of 6.6 years were analyzed. (21 boys, 21 girls). 75% had suffered from an infection during the previous 4 weeks (50% respiratory infections). Microbiological diagnosis was confirmed in 30% of the children (Mycoplasma pneumoniae 12%). The most frequent symptoms at diagnosis were weakness and/or inability to walk (95%) and neuropathic pain (73%). 88% had diminished/abolished deep tendon reflexes, 40% presented cranial nerve dysfunction, 14% respiratory impairment (seven

had to be intubated). CSF was analyzed in 85% of children (mean 7 days, range 1–41 days) and 70% presented albumino-cytological dissociation. Electrophysiological study was performed in all the patients; 90% showed a demyelinnating neuropathy (AIDP) and 10% an axonal neuropathy (AMAN). All the studies performed in the first week (23 patients – 52%) allowed us to confirm the diagnosis and to differentiate between demyelinating/axonal forms. All the patients received intravenous immunoglobulins treatment. Sixty-six percent improved since the first week of evolution. All the children who lost walk ability (65%) recovered it at 33 days median (9– 94 days). Conclusions: Childhood GBS had good prognosis despite severe initial disability and independently on demyelinating/axonal subtypes. Electrophysiological study is the most useful tool for detecting and defining neuropathy, even in the first week of evolution. doi:10.1016/j.nmd.2009.06.074

G.P.4.06 Dislocation of neuronal nitric oxide synthase contributes to muscle atrophy in amyotrophic lateral sclerosis N. Suzuki1, M. Aoki 1, H. Warita 1, S. Takeda 2, Y. Itoyama 1 1

Tohoku University School of Medicine, Department of Neurology, Sendai, Japan, 2 National Institute of Neuroscience, National Center of Neurology and Psychiatry, Department of Molecular Therapy, Kodaira, Japan Previously, we examined the expression and function of the members of the dystrophin glycoprotein complex (DGC) in skeletal muscle during tail suspension, a model of unloading, and demonstrated that neuronal nitric oxide synthase (nNOS), a member of the DGC, is activated in unloading conditions and promotes muscle atrophy (J Clin Invest 2007). Furthermore, we showed the involvement of nNOS in denervation-induced muscle atrophy process. Here, we found cytoplasmic nNOS staining of angulated muscle fibers in patients with amyotrophic lateral sclerosis (ALS). We also examined a mouse ALS model and found cytoplasmic nNOS staining even before the onset of muscle atrophy. In the ALS mouce model, nNOS was largely extracted with 100 mM NaCl and barely detected in the pellet fraction. We also showed elevated expression of atrogin1, key molecules in muscle atrophy at the end stage. A common nNOS dislocation/ atrogin-1 pathway among tail suspension, denervation and ALS-induced muscle atrophy is suggested. nNOS modulation therapy may be beneficial in several types of muscle atrophy. doi:10.1016/j.nmd.2009.06.075

G.P.4.07 Skeletal muscle regeneration in amyotrophic lateral sclerosis A. Scaramozza1, A. Corbu 2, A. Aiti 2, V. Papa 2, L. Tarantino 2, L. Badiali De Giorgi 3, E. Pegoraro 4, G. Soraru 4, C. Angelini 4, G.N. Martinelli 2, G. Cenacchi 2 1

University of Bologna, Clinical Dept. of Radiology and Histopathology, Bologna, Italy, 2 University of Bologna, Bologna, Italy, 3 S.Orsola-Malpighi Hospital, Bologna, Italy, 4 Dept. of Neurological Sciences and VIMM, Padova, Italy Amyotrophic Lateral Sclerosis, ALS, is a progressive neurodegenerative disorder characterized by selective degeneration and death of both upper and lower motor neurons, resulting in paralysis due to muscle weakness and atrophy. Generally skeletal myofibers are

Abstracts / Neuromuscular Disorders 19 (2009) 543–660

able to regenerate after injury, thanks to Satellite Cells (SCs), myogenic precursor cells located between the basal lamina and the sarcolemma of mature myofibers. In ALS patients the regenerative capacity of skeletal muscle is compromised. In order to study in more detail the molecular mechanism, the proliferative and differentiative ability of SCs, we isolated SCs from ALS aging human muscle biopsies and analyzed their morphology by TEM and ICC and their capacity to grow in vitro. Moreover RTPCR were performed to evaluate the expression of MRFs. ALS SCs showed a high ability to proliferate, but their capacity to proceed through the myogenic program and actively form myotubes seems to be altered compared to the aging control samples. In addition we observed in vitro that differentiating ALS SCs display an altered morphology which could be linked to their impaired regenerative potential. doi:10.1016/j.nmd.2009.06.076

G.P.4.08 Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene S. Yamashita1, E. Kimura 1, F. Yamamoto 1, A. Migita 1, S. Mita 2, H. Teramoto 3, M. Uchino 1 1 Kumamoto University, Graduate School of Medical Sciences, Neurology, Kumamoto, Japan, 2 Kumamoto Saishunso Hospital, National Hospital Organization, Neurology, Kumamoto, Japan, 3 Miyazaki Hospital, National Hospital Organization, Neurology, Koyu, Japan

We present the cases of four patients with a histidine-to-arginine substitution at position 46 of the Cu/Zn superoxide dismutase gene. Consistent with previous reports, the initial symptom in each patient was unilateral weakness in the distal leg muscles. Remarkably, muscular atrophy in these patients during the early stage of the disease was more specific to the flexor muscle group, with the extensor muscle group remaining intact over long-term observation. Even in the advanced stage of the disease, the extensor muscle group was affected to a lesser extent than the flexor muscle group in the distal leg muscles. More interestingly, biopsy of the affected muscle in the early stage of the disease revealed necrotic and regenerative myofibers with infiltration of lymphocytes, resembling inflammatory myopathy. In common with the descriptions in previous reports, our patients also showed slow disease progression with intrafamilial variation in disease severity: in the younger sister, the disease progressed more rapidly than in the elder brother and mother. We propose two possible explanations for the myopathic phenotype: (i) oxidative stress resulting from the SOD1 mutation might affect mitochondrial function in the muscles as well as in nervous tissues and (ii) a deficit in protein transport, for example in transport through the endoplasmic reticulum (ER), might induce an abnormal muscle pathology. Our cases expand the phenotypic spectrum of ALS associated with SOD1 mutation to include a flexor muscle-dominant myopathy-like phenotype in the calf. These novel findings might provide further insights into the pathophysiology of familial amyotrophic lateral sclerosis. doi:10.1016/j.nmd.2009.06.077

G.P.4.09 Multiple analysis of hereditary spastic paraplegia N.H. Akcakaya 1, Ç. Atay 2, N. Isik 3, F.I. Uludað 4, F. Deymeer 1, P. Serdaroglu 1, E. Battaloðlu 2, Y. Parman1

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1 Istanbul University, Istanbul Medical Faculty, Neurology, Istanbul, Turkey, 2 Bogazici University, Molecular Biology and Genetics, Istanbul, Turkey, 3 Göztepe Teaching Hospital, Neurology Dep, Istanbul, Turkey, 4 Tepecik Teaching Hospital, Neurology Dep, Izmir, Turkey

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders. Traditional classification of the disease involves the ‘pure HSP’ with typical paraplegia. In ‘complicated HSP’ additional features are present, including peripheral neuropathy, epilepsy, optic atrophy, retinopathy, ataxia, and deafness. Genetic analyses led identification of 21 loci and 17 genes unraveling the high genetic heterogeneity of the disease. Twenty-seven patients were included in our study. All underwent brain and spinal MRI, EMG, EEG, odiometric, and ophthalmologic examinations. We have also analysed the most frequently mutated autosomal dominant genes, SPG3A, SPG4, SPG6, and SPG31. Eighteen cases had apparently autosomal recessive inheritance due to presence of consanguineous parents, only six were autosomal dominant and three were considered as isolated cases. Interesting associated clinical features in some patients besides the classical HSP phenotype were epilepsy, sensorymotor polyneuropathy, sensory-neuronal hearing loss, thin corpus callosum and skin lesions. Sural nerve biopsies in two were compatible with an axonal neuropathy. According to these results, 12 patients were considered to be complicated HSP. Two SPG4 and an SPG3A gene mutation were identified in three pure HSP families. SPG4 mutations, c.310_311insA and c.1741C > T, were leading to a premature stop codon and hypothetically to truncated spastin proteins. The index patient in the third family was heterozygous for an SPG3A missense mutation (c.941A > G). All other cases tested negative for mutations in the analyzed genes. Our findings confirm the marked clinical and genetic heterogeneity of HSP. Identification of only three mutations in autosomal dominant genes can be expected since autosomal recessive cases were apparently common in this small cohort. The rest of the ADHSP genes should be analyzed in these patients along with ARHSP genes to unravel the genetic background of HSP in our population. doi:10.1016/j.nmd.2009.06.078

DISTAL MYOPATHIES AND MYOFIBRILLAR MYOPATHIES; POSTER PRESENTATIONS G.P.5.01 Retrospective study of 29 cases of distal myopathies J. Franques 1, E. Campana-Salort 1, S. Attarian 1, A. Verschueren 1, C. Fernandez 2, A. Maues de Paula 2, D. Figarella-Branger 2, J. Pouget1 1 Hopital la Timone, Centre de référence des maladies neuromusculaires, Marseille, France, 2 Laboratoire d’anatomie pathologique et neuropathologie, Marseille, France

Distal myopathies is a heterogeneous group of rare genetic disorders characterized by muscular weakness starting in the more distal parts of the limbs and histological lesions of myopathic changes. The classification of the MD profoundly evolved during the last 10 years. The recent progress in morphology and especially in molecular biology allowed a better understanding of the spectrum of these myopathies and to individualize new entities such as myofibrillar myopathies. Twenty-nine patients from 26 families with clinical and morphological diagnostic criteria of distal myopathies were studied in the reference centre of neuromuscular diseases and ALS of Marseille between 1981 and 2008. Morphological diagnosis was carried out in 76% of the cases, molecular diagnosis in 52% of the cases. Myofibrillar myopathies