differential diagnosis of exercise intolerance clinicians should include rip- pling muscle disease and/or caveolinopathy along with substrate use defects and mitochondrial myopathies. doi:10.1016/j.nmd.2007.06.174 G.P.8.10 Muscle imaging in familial asymptomatic hyperCKemia due to mutations in caveolin-3 gene Paradas, C. 1,* ; Gallano, P. 2 ; Gonzalez-Quereda, L. 2 ; De Luna, N. 3 ; Gonzalez, L. 4 ; Olive ´, M. 4 1 Hospital Universitario de Valme, Neurology, Sevilla, Spain; 2 Hospital de Sant Pau, Genetic, Barcelona, Spain; 3 Laboratorio de Neurologia Experi- mental, Hospital de Sant Pau, Neurology, Barcelona, Spain; 4 Instituto de Neuropatologia, IDIBELL, Hospital de Bellvitge, Neuropathology, Barce- lona, Spain Mutations in caveolin-3 gene have been associated with LGMD1C, rippling muscle disease, familial asymptomatic hyperCKemia, and distal myopathy. Muscle imaging studies have not been reported in patients suf- fering from familial asymptomatic hyperCKemia. To describe the pattern of muscle involvement on muscle MRI in two unrelated families suffering from asymptomatic hyperCKemia. Members of two unrelated families were evaluated for persistent elevation of CK levels. For each patient we performed a detailed clinical and EMG examination, CK level assess- ment, muscle biopsy, and muscle MRI of lower extremities. For molecular analysis, genomic DNA was analyzed by PCR and direct sequencing of CAV3 gene. None of the patients complained of muscle weakness or any other symptoms of myopathy. CK levels were 2-, 5- to 10-fold increased. EMG examination was normal, and muscle biopsy showed mild myopathic changes with reduced levels of caveolin-3. No abnormalities on muscle MRI were observed in patients under 30 years of age. However, asymmetrical involvement of the semimembranous, biceps femoris, and medial gastrocnemius were observed in patients over 40. Mutational anal- ysis identified two previously reported mutations (Val57Met and Thr78Met) in CAV3. To our knowledge this is the first description of mus- cle MRI abnormalities in patients suffering from familial asymptomatic hyperCKemia due to mutation in CAV3 gene. Our findings demonstrate subclinical involvement of posterior tight and leg muscles, which seems to be age-dependent. The present observations suggest that muscle imag- ing may be of help when evaluating patients with asymptomatic hyperC- Kemia and ordering appropriate molecular investigations, as previously reported in other muscle disorders. doi:10.1016/j.nmd.2007.06.175 G.P.8.11 The expression of caveolin-3 and its related limb girdle muscular dystrophy 1-c mutants in myoblasts: Physiological and pathological aspects Fanzani, A. 1,* ; Stoppani, E. 1 ; Musaro, A. 2 ; Giuliani, R. 1 ; Colombo, F. 1 ; Rossi, S. 1 ; Preti, A. 1 ; Marchesini, S. 1 1 University of Brescia, Department of Biomedical Sciences and Biotech- nology, Brescia, Italy; 2 CE-BEMM and Interuniversity Institute of Myol- ogy, University of Rome ‘‘La Sapienza’’, Department of Histology and Medical Embryology, Rome, Italy Caveolin-3 (Cav-3) is a muscle-specific membrane protein crucial for myoblast differentiation, as loss of the protein due to mutations within the gene causes an autosomal dominant form of limb girdle muscular dys- trophy 1-c (LGMD1-c). Here we show that along with p38 activity the PI3-kinase/AKT/mTOR pathway is required for proper Cav-3 up-regula- tion during muscle differentiation and hypertrophy, as revealed in C2C12 cells transfected with an activated form of AKT and in hypertrophic mus- cles of MLC/mIGF-1 transgenic mice. In contrast, Cav-3 expression was down-regulated in C2C12 myotubes exposed to atrophic stimuli, suggest- ing that Cav-3 expression is tightly regulated and causally linked to the maturation of muscle phenotype. Originally, two heterozygous mutations were identified within the human Cav-3 gene as responsible for LGMD- 1C, consisting of a 9-bp microdeletion (DTFT) and a missense mutation (P104L) which generate dominant negative proteins, leading to Cav-3 deg- radation. Indeed, we analysed the effects of the forced expression of Cav-3 and its LGMD1-c mutants on C2C12 differentiation. Both Cav-3 and P104L transfected myoblasts underwent myotube atrophy, whereas DTFT myoblasts exhibited abnormal hypertrophic myotubes. Our data suggest that the differentiation is severely impaired in both Cav-3 and P104L myo- blasts by reduced AKT activation, ultimately leading to increased expres- sion of atrophy-related genes; on the contrary, DTFT cells exhibited myotube hypertrophy by sustained AKT phosphorylation, confirming that different mutations within Cav-3 gene cause different cell behavior, although related to the same muscular dystrophy. Finally, the treatment of both Cav-3 and LGMD1-c myoblasts with trichostatin, an inhibitor of histone deacetylase, restored the activation of differentiation-related genes, suggesting that this molecule may represent a valid therapy for the treatment of limb-girdle muscular dystrophy. doi:10.1016/j.nmd.2007.06.176 G.P.8.12 Molecular characterization and clinical update on one of the earliest described families with severe childhood autosomal recessive muscular dys- trophy (SCARMD) Salih, M. 1,* ; Urtizberea, J.A. 2 ; Leturcq, F. 3 ; Mukhtar, M. 4 ; Anderson, L. 5 ; Bushby, K. 5 1 Division of Pediatric Neurology, Department of Pediatrics, Riyadh, Saudi Arabia; 2 Ho ˆ pital Marin, Hendaye, France; 3 Ho ˆ pital Cochin, Laboratoire de Biochimie Ge ´ne ´tique, Paris, France; 4 Institute of Endemic Diseases, Faculty of Medicine, University of Khartoum, Khartoum, Sudan; 5 Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, United Kingdom In the early 1980s, the phenotype of SCARMD (the severe form of limb girdle muscular dystrophy [LGMD]) was described in families from Sudan and Tunisia. Application of molecular genetic tools in the study of SCARMD in Tunisia, established that the majority of patients had gamma-sarcoglycanopathy (LGMD2C). The aim of the present study was to describe the molecular characterization and update the clinical fea- tures of one of the earliest described families with SCARMD. The Suda- nese kindred consisted of eight generations, when first studied in 1977, and extended by one generation since then. A total of 17 individuals died of the disease at a mean age of 21.65 + 9.96 years (range 12–39 years). The youn- gest and only surviving patient was seen at the age of 9 years and 4 months. Onset was at the age of 3 years and he was wheelchair-bound at 8 years and 8 months. Apart from proximal symmetrical muscle weak- ness and wasting, he showed tongue enlargement and calf muscle hyper- trophy. Serum creatine kinase was 9.5 times normal and histology of a muscle biopsy showed dystrophic features. Re-examining the stored mus- cle biopsy of one of the patients in the eighth generation revealed negative staining for the sarcoglycans alpha, beta, gamma and delta. Molecular analysis showed mutation in the beta-sarcoglycan gene (homozygous 2 bp deletion at 112 bp, changing Ser 38 to a stop codon in exon 2). Geno- mic DNA analysis of the youngest patient also showed a beta-sarcoglycan gene deletion (2 bases [AG] in exon 2, creating a stop codon in position 48). The parents were heterozygous for the mutation. The phenotypic dif- ferences reported in the 1980s between the Sudanese and Tunisian families seem to have been a reflection of the different sarcoglycans (beta versus gamma) involved in the pathogenesis of the disease. doi:10.1016/j.nmd.2007.06.177 Abstracts / Neuromuscular Disorders 17 (2007) 764–900 813