progressive muscle weakness beginning from late teens to adult ages; all of them were still ambulant (age range, 32–61, male:female, 3:3). There were mild to moderate facial weekness and high palate in all of them. None had ptosis or ophthalmoplegia. The clinical evaluation of patients revealed both proximal and distal weakness of different severity. In general, the more affected muscles were deltoids, biceps and finger extensors in the upper limbs. Hip extensors, knee flexors and ankle dorsiflexors were relatively more affected in the lower limbs. Muscle MRI of lower extremities showed similar pattern in 5 patients with AD inheritance. The posterior compartment of tigh muscles were more affected with relative sparing of sartorius and gracilis muscles. The lower leg MRI revealed prominent involvement of soleus, gastrocnemius and tibialis anterior muscles with sparing of tibialis posteriors. The patient with AR inheritance showed differ- ent MRI findings. The anterior compartment of thigh muscles were more affected. Muscle MRI findings may be helpful for selection of appropriate genetic testing in CNM patients with broad phenotypical and genetic spectrum. doi:10.1016/j.nmd.2011.06.933 P3.40 Myopathy in a woman and her daughter associated with a novel MTM1 mutation C. Hedberg a , C. Lindberg b , M. Ma ´the ´ c , A.R. Moslemi a , A. Oldfors a a Institute of Biomedicine, Department of Pathology, Gothenburg, Swe- den; b Institute of Neuroscience and Physiology, Department of Neurology, Sahlgrenska Academy, Gothenburg, Sweden; c Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden X-linked recessive myotubular myopathy (XLMTM) is due to mutations in MTM1, which encodes a phosphatase called myotubula- rin. The disease usually affects boys and frequently presents with severe neonatal onset of hypotonia and muscle weakness. Female heterozy- gous carriers may manifest muscle weakness possibly due skewed X- inactivation. We have investigated a woman and her daughter with an early onset, slowly progressive myopathy. The proband had mild leg weakness since childhood and onset of upper extremity weakness at age 20. She has slowly lost muscle strength and was at age 72 wheelchair bound and had impaired vital capacity. Her daughter was first seen at age 43, when she had mild to moderate facial, neck flexor and handgrip weakness. They both had spontaneous muscle fibre activ- ity and signs of myopathy on EMG. Muscle biopsy showed in both cases severe atrophy with marked fatty replacement. Frequent fibers with internalized nuclei were present but no typical features of centro- nuclear myopathy. There were also many fibers with deep invagin- ations of the plasma membrane. The presence of frequent “necklace- fibers” provided clues to correct genetic diagnosis. Both patients had a novel heterozygous splice site mutation in the exon 9 donor site (c.867+ 1 G>T). Analysis of MTM1 cDNA revealed that the mutation resulted in aberrant splicing with variable skipping of exon 9 and exon 9–11. The allele without the splice site mutation was virtually not expressed in the woman or in her daughter, but we did not obtain evi- dence of skewed X-chromosome inactivation. In this study we demon- strate that manifesting carriers of MTM1 mutations without centronuclear myopathy may be identified by the presence of “necklace fibers”. Other factors than skewed X-inactivation may cause allele inac- tivation and manifestation of severe myopathy in heterozygous carriers of pathogenic MTM1 mutations. doi:10.1016/j.nmd.2011.06.934 P3.41 Clinical and genetic findings in a large cohort of patients with congenital myopathies due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene A. Klein a , S. Lillis b , I. Oprea c , M. Scoto c , S. Robb c , A. Manzur c , V. Straub d , H. Roper e , P.Y. Jeannet f , H. Kingston g , U.B. Jensen h , E. Wraige i , N. Trump b , W. Rakowicz j , M. Roberts k , C. Longman l , H. Lochmuller d , K. Bushby d , M.I. Hughes m , S. Abbs b , H. Jungbluth i , F. Muntoni c a University Children’s Hospital, Zurich, Switzerland; b Guy’s Hospital, DNA Laboratory, GSTS Pathology, London, United Kingdom; c Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom; d International Centre for Life, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom; e Birmingham Heartlands Hospital, Birmingham, United King- dom; f University Hospital Lausanne, Lausanne, Switzerland; g Cenrtal Manchester University Hospitals, Manchester, United Kingdom; h Institute for Human Genetics, Aarhus, Denmark; i Evelina Children’s Hospital, Guy’s and St. Thomas’ Hospital, London, United Kingdom; j Imperial College, London, United Kingdom; k University of South Manchester, Manchester, United Kingdom; l Ferguson Smith Centre for Clinical Genet- ics, Yorkhill Hospital, Glasgow, United Kingdom; m Royal Manchester Children’s Hospital, Manchester, United Kingdom RYR1 mutations are the most common cause of structural congenital myopathies and may exhibit both dominant and recessive inheritance. His- topathological findings are variable and include central cores, multi-mini- cores, type 1 predominance/ uniformity, fibre type disproportion, increased internal nucleation and fatty and connective tissue. Until recently, diagnostic RYR1 sequencing was limited to mutational hotspots due to the large size of the gene. Since the introduction of full RYR1 sequencing in 2007 we have detected pathogenic mutations in 77 families: 39 had dominant inheritance and 38 recessive inheritance. In some cases with presumably recessive inheritance, only one heterozygous mutation inherited from an asymptomatic parent was identified. Of 28 dominant mutations, 6 were novel; 37 of the 59 recessive mutations were also novel. Dominant mutations were more frequently in recognized hotspot regions, while recessive mutations were distributed throughout the coding sequence. Dominant mutations were predominantly missense, whereas recessive mutations included many nonsense and splice mutations expected to result in reduced RyR1 protein. There was wide clinical variability in patients with both dominant and recessive inheritance. As a group, those with dom- inant mutations were generally more mildly affected than those with reces- sive inheritance, who had earlier onset and were weaker with more functional limitations. Extraocular muscle involvement was almost exclu- sively observed in the recessive group. Bulbar involvement was also more prominent in this group, resulting in a larger number requiring gastrostomy insertion. In conclusion, genomic sequencing of the entire RYR1 leads to the detection of many novel mutations, but may miss large genetic rear- rangements in some cases. Assigning pathogenicity to novel mutations is often difficult and interpretation of genetic results in the context of clinical, histological and, increasingly, muscle MRI findings is essential. doi:10.1016/j.nmd.2011.06.935 P3.42 Mutation in the ryanodine receptor (RYR1) gene in a family with slowly progressive axial muscular dystrophy T. Torbergsen a , B. Karime b , S. Løseth a a University Hospital of North Norway, Neurology, Tromsø, Nor- way; b National Hospital, Neurology, Oslo, Norway The proband is a 31 years old male patient with a slowly progressive proximal muscular dystrophy. At school age his teacher found it strange 694 Abstracts / Neuromuscular Disorders 21 (2011) 639–751