G.P.136

Abstracts / Neuromuscular Disorders 24 (2014) 791–924 muscle strength and balance measured by the movement rate of the centre of foot pressure on a force plateform are compared between patients and age- and sex-matched healthy controls. DM1 patients and healthy controls (10 females and 7 males between 26 and 49 years old in each group) of similar mean height and weight were compared. The 6MWD in percentage of predicted value was significantly reduced in DM1 patients by about 50% (Mann Whitney, p < 0.001). No significant difference in balance was found but ankle muscle strength weakness could account for the reduced 6MWD. Indeed, no significant difference of the movement rate of the centre of foot pressure was observed with age or between patients and healthy subjects (ANCOVA) but significant decreases in ankle dorsi- and plantarflexion strength measured by a homemade ankle dynamometer were detected between patients and healthy subjects (Mann Whitney p < 0.001 and p < 0.01, respectively). Balance defect, however, seems affected for the weakest ankle muscle strengths. Moreover, the 6MWD was positively correlated to ankle dorsiflexion (rho 0.671, p < 0.01) and plantarflexion in patients (rho 0.637, p < 0.01), while it was positively correlated to plantarflexion only in healthy controls (rho 0.586, p < 0.05). No significant difference in hip flexion, knee extension, ankle dorsiflexion and big toe extension assessed by hand-held dynamometry could be evidenced between patients and healthy controls. Walking ability is thus mainly affected by weakness in ankle dorsi- and plantarflexion when measured by appropriate method. http://dx.doi:10.1016/j.nmd.2014.06.163

G.P.134 Liver functional impairment and glycolipid metabolic abnormality in myotonic dystrophy type 1 H. Takada 1, S. Kon 1, Y. Oyama 1, T. Kimura 1, F. Nagahata 2 1 Aomori Hospital, National Hospital Organization, Aomori, Japan; 2 Aomori Hospital, National Hospital Organization, 038-1331, Japan Recently, non-alcoholic steatohepatitis complicated in myotonic dystrophy type 1 (DM1) has been reported. Glucose intolerance is one of well-known complications in DM1. Lipid metabolic abnormality such as increase of visceral fat or abnormal response to oral lipid absorption test is also described in DM1. The aim of this study was to elucidate the relation between liver functional impairment and glycolipid metabolic abnormality in DM1. Forty-two patients in DM1 without cholelithiasis (19 females and 23 males; the mean age, 46.7 years; the mean number of CTG repeat, 1125) were participated. Subjects had computed tomography (CT) examination to measure area of visceral fat (Vfat) and liver spleen ratio of CT density (LSR). Routine blood test was performed. Linear regression analysis was used to assess the association among Vfat, LSR, the number of CTG repeat, age, and results of blood test. According to the oral glucose tolerance test, patients were classified into diabetes (12 cases), impaired glucose tolerance (IGT, 18), and normal (NGT, 12). Similar parameters in each group were compared using non-parametric test. Forty-five percent of patients showed V-fad above 100 cm2. Nineteen percent had LSR less 0.9. High value of gamma GTP was observed in 81%, abnormal ALT was in 57%, and AST in 33%. The number of CTG repeat was significantly correlated to Vfat or gamma GTP. There was significant positive correlation between Vfat and gamma GTP, ALT or AST. Gamma GTP was significantly correlated to serum triglyceride or fasting plasma glucose. Vfat in diabetes group was significantly higher than that in IGT or NGT, although there was no significant difference for Vfat between IGT and NGT. Gamma GTP in IGT was significantly higher than that in NGT, and was lower than that in diabetes group. Liver functional impairment

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was relevant to glucose intolerance, visceral fat accumulation, and the number of CTG repeat in DM1. http://dx.doi:10.1016/j.nmd.2014.06.164

G.P.135 Dental and orthodontic aspects of myotonic dystrophy type 1 D. Nadaj, A. Lusakowska, D. Maciejak, A.M. Kaminska, M. Zadurska Medical University of Warsaw, Warsaw, Poland Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults with autosomal dominant inheritance and multisystemic involvements. The core features comprise progressive myopathy, often with a pronounced facial muscle atrophy and weakness. The aim of this study is to characterize dental and orthodontic aspects of this disease and to discuss possibles therapeutic strategies. The study concerned 16 patients, 6 women and 10 men, aged 13–63 years, with the genetically proved DM1. All patients were evaluated with clinical orthodontic and dental examination as well as a panoramic radiograph and lateral cephalogram. A general facial examination revealed: long face, frontal baldness, ptosis, hypomimia, temporal and masseter muscles weakness, atrophy and myotonia, large tongue in abnormal position at rest and tongue movements impairment due to myotonia, mouth breathing and gothic palate. An orthodontic examination showed class II malocclusion in 5 patients, class III malocclusion in 5 patients, anterior openbite in 7 patients, lateral crossbite in 3 patients and dental anomalies in 14 patients. A lateral cephalogram revealed abnormal development of the mandible (mandibular angle increase with posterior rotation of the condylar process and the open configuration of the jaws) in 11 patients. The majority of patients suffered from mastication difficulties, insufficient oral hygiene with multiple cavities and periodontal disease. All patients required a general dental treatment. Five patients required prosthetic treatment, two - orthodontic, surgical and prosthetic treatment, four - orthodontic and surgical treatment, two - orthodontic treatment. Two patients did not require orthodontic intervention. Progressive facial muscles weakness and myotonia result in malocclusions in patients with DM1. Orthodontic treatment requires multidisciplinary care to provide the most comprehensive treatment plan for DM1 patients. http://dx.doi:10.1016/j.nmd.2014.06.165

G.P.136 Muscle channelopathies: Clinical and genetic features in a large cohort of Italian patients L. Maggi 1, R. Brugnoni 2, L. Colleoni 1, D. Kapetis 1, A. Ardissone 1, A. Pini 3, G. Ricci 4, L. Vercelli 5, S. Ravaglia 6, I. Moroni 1, E. Pegoraro 7, M. Lo Monaco 8, V. Sansone 9, G. Meola 9, G. Siciliano 4, T. Mongini 5, M. Filosto 10, L. Morandi 2, R. Mantegazza 2, P. Bernasconi 2 1 Fondazione Istituto Neurologico, Milano, Italy; 2 Fondazione Istituto Neurologico “Carlo Besta”, Milano, Italy; 3 Neurological Sciences Institute, Bologna, Italy; 4 University of Pisa, Pisa, Italy; 5 University of Turin, Turin, Italy; 6 University of Pavia, Pavia, Italy; 7 University of Padova, Padova, Italy; 8 Catholic University, Rome, Italy; 9 University of Milan, Milano, Italy; 10 Spedali Civili, Brescia, Italy Skeletal muscle channelopathies are rare diseases, including non-dystrophic myotonia and periodic paralysis, which are associated with a great inter- and intrafamilial phenotypic variability, making challenging genotype-phenotype correlations. Hence studies on large

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populations of patients are needed. We included patients referred to Carlo Besta Neurological Institute molecular laboratory with a clinical diagnosis of periodic paralysis or nondystrophic myotonia and mutated in CLCN1, SCN4A, KCNJ2 or CACNA1S. We investigated 301 patients, among which 195 (64.3%) patients mutated in CLCN1 gene, 74 (24.6%) in SCN4A, 28 (9.3%) in CACNA1S and 4 (1.3%) in KCNJ2. We found 22 novel mutations: 8 in CLCN1 gene, 13 in SCN4A and 1 in CACNA1S. All the mutations detected in SCN4A, CACNA1S and KCNJ2 genes were missense, except for an unreported 9-nucleotide deletion in SCN4A. On the contrary CLCN1mutations were missense in 131/195 (67.2%) patients and remaining cases showed nonsense, splice site or deletion mutations. Our study confirms genetic heterogeneity of muscle channelopathies, although a relatively small number of mutations is responsible for most of the cases. http://dx.doi:10.1016/j.nmd.2014.06.166

G.P.137 Functional study of five new CLC-1 mutations causing myotonia congenita in Italian families P. Imbrici 1, J.F. Desaphy 1, R. Brugnoni 2, L. Colleoni 2, E. Canioni 2, D. Kapetis 2, C. Altamura 1, P. Bernasconi 2, L. Morandi 2, L. Maggi 2, R. Mantegazza 2, D. Conte 1 1 Universita` degli Studi di Bari, Bari, Italy; 2 Fondazione Istituto Neurologico, Milano, Italy Myotonia congenita is an inherited disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. It is caused by loss-of-function mutations of the muscle ClC-1 chloride channel. We report the functional characterization of five novel mutations found in patients with recessive and dominant myotonia congenita, selected among the largest cohort of Italian families reported to date, on the basis of the associated clinical phenotype and position in the protein 3D-structure. The mutations F484L, L198P and L520P resides within the channel pore and are inherited in a dominant manner. The mutations V640G and L628P occur in the C-terminal domain and show a recessive inheritance. Recombinant hClC-1 channel mutants were expressed in a mammalian cell line for patch-clamp studies of chloride current properties. The mutant channels F484L, L198P and V640G show a large current reduction at every tested potential. In addition, the mutations F484L and L198P induce a dramatic shift of activation voltage-dependence toward more positive potentials, resulting in nearly zero chloride current within physiological voltage range. These effects likely contribute to impaired muscle repolarization and explain the myotonia. Further experiments are required to clarify the dominant inheritance for mutations located outside the common hot-spot for dominant genetic variants, to address the mechanism of ATP modulation for the mutations close to the ATP binding sites, and to clarify genotype-phenotype correlations. Pharmacogenetics studies are also in progress. http://dx.doi:10.1016/j.nmd.2014.06.167

G.P.138 Late-onset non-thymomatous generalized myasthenia gravis S. Yildiz-Celik, H. Durmus, M. Hajibehzad, V. Yilmaz, P. Oflazer-Serdaroglu, Y. Parman, G. Saruhan-Direskeneli, F. Deyemeer Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey Findings in recent epidemiological studies have implied that the frequency of myasthenia gravis (MG) may be increasing in the elderly population. Published studies of late-onset MG have disclosed some of

its characteristics: males are more frequently affected, the thymus is more likely to be involuted, there is a different HLA profile and antistriatal muscle antibodies against titin/ryanodine receptors may be present. In our MG database, there were 95 generalized nonthymomatous MG patients with disease onset P50 years who first presented to our outpatient clinic during the 10 years between 2001 and 2010 and who were followed for at least 3 years. All patients were contacted by phone calls or letters. There was a marked male preponderance with male to female ratio of 1.7:1. Onset was with predominantly ocular symptoms (62%), followed by bulbar symptoms (23%) and weakness in the extremities (11%); two patients had neck weakness and 4 had mixed onset symptoms. Anti-acetylcholine receptor antibodies (AChR Ab) were present in 84%, 5% were anti-MuSK Ab positive and 11 % were double negative. Sixty-two percent had anti-titin antibodies. The disease was mild (MGFA 2) in approximately half of the patients (47%) while 6% were intubated. Fifty-seven percent (including all of the patients with MuSK MG) had MGFA postintervention status of complete stable remission/pharmacological remission/minimal manifestations at the last visit. A further 28 % were improved. The combination of prednisolone and azathioprine appeared to be superior to these agents used alone. In 15 mildly affected patients in whom azathioprine was combined with low dose prednisolone (<30 mg/day), 73% had pharmacological remission/minimal manifestations. Fifteen patients had thymectomy, but its effect could not be evaluated because of concomitant immunosuppressives. The thymus showed hyperplasia in only one-third. In this study group, LOMG appears to be a fairly benign disorder with good prognosis. http://dx.doi:10.1016/j.nmd.2014.06.168

G.P.139 Congenital myasthenic syndrome due to novel choline acetyltransferase (ChAT) gene mutations in Kadazandusun family from Borneo J.S. Tan, T. Ambang, A. Ahmad-Annuar, K.T. Wong, K.J. Goh University of Malaya, Kuala Lumpur, Malaysia Pathogenic mutations of the choline acetyltransferase (ChAT) gene alters its function and causes reduced synthesis of acetylcholine and its depletion in synaptic vesicles. This results in a rare presynaptic form of congenital myasthenic syndrome which presents at birth or in infancy characterised by apnoeic attacks. We present Kadazandusun family, an ethnic group native to Sabah, in north Borneo, with ChAT deficiency in which 5 of 6 siblings of non-consanguineous parents were affected. 2 died in their infancy from apnoeic atatacks while another sibling died at the age of 12 years from a severe apnoeic episode after an intercurrent infection. We reviewed 2 brothers, the eldest and the 4th at 24 and 18 years of age respectively, although both had presented in infancy with bilateral ptosis and limb weakness. The elder brother had episodes of apnoea and weakness on exposure to cold well water in their village. A congenital myasthenic syndrome was suspected and both brothers were treated on pyridostigmine after positive Tensilon tests and negative acetylcholine receptor antibody tests. On review, both had muscle weakness after moderate to severe exertion and repetitive nerve stimulation test of the abductor digiti minimi, which was normal at rest, showed sustained decremental response after prolonged 5 min stimulation at 10 Hz. Screening of the ChAT gene showed compound heterozygous mutation in both brothers, c.1069G>C and c.2263_2265delTCT in exons 6 and 15 respectively. Each parent was heterozygous for one of the mutations, which were not seen in any of 50 normal controls obtained from the native population of Sabah. In summary, we present a Kadazandusun family with ChAT deficiency congenital myasthenic syndrome, in which, 3 affected siblings died from apnoeic episodes, while another 2 survived to adulthood. This variable