C.P.1.02 Clinical and histopathological evolution of a calpain-3 deficiency presenting as congenital fiber type disproportion

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Abstracts / Neuromuscular Disorders 17 (2007) 764–900

Voit, T. 1; Cirak, S. 1; Abraham, S. 2; Karakesisoglou, I. 2; Parano, E. 3; Pavone, P. 3; Falsaperla, R. 3; Amthor, H. 1; Schroeder, J. 4; Muntoni, F. 5; Guicheney, P. 6; Nurnberg, P. 7; Noegel, A. 8; Herrmann, R. 1,* 1 University Hospital Essen, Department of Pediatrics and Pediatric Neurology, Essen, Germany; 2 University of Cologne, Centers of Biochemistry and Molecular Medicine Col, Cologne, Germany; 3 University of Catania, Institute of Neurological Sciences, Catania, Italy; 4 University of Aachen, Institute of Neuropathology, Aachen, Germany; 5 Imperial College London, Dubowitz Neuromuscular Unit, London, United Kingdom; 6 Universite´ Paris VI, Institut de Myologie, Paris, France; 7 University of Cologne, Cologne Center for Genomics, Cologne, Germany; 8 University of Cologne, Centers of Biochemistry and Molecular Medicine, Cologne, Germany The congenital muscular dystrophies are a heterogenous group of disorders. The main pathomechanisms identified to date are disruption of the mechanical link between a-dystroglycan and laminin a2 at the basement membrane, perturbation of the collagen VI network at the extracellular matrix or selenoprotein N mutations, an endoplasmic reticulum protein of unknown function. By excluding known candidate genes (LAMA2, Fukutin, POMGnT1) and employing a genome-wide linkage analysis we identified a single homozygous candidate region on chromosome 6q25 in a consanguineous family with a peculiar phenotype characterized by congenital muscular dystrophy with adducted thumbs, mental retardation and cerebellar hypoplasia (Voit et al., 2002). The candidate region harboured the giant, 147 exon gene Nesprin-1 encoding Enaptin (Syne-1), a multifunctional nuclear envelope scaffolding protein known to interact with lamin A/C and emerin, two other proteins underlying muscular dystrophies with contractures. Sequencing of Enaptin identified a homozygous premature stop mutation of Enaptin (Nesprin-1). Both parents were heterozygous for this mutation and healthy. In skeletal muscle the mutation leads to complete loss of C-terminal Enaptin expression at the nuclear envelope by immunofluorescence and vast reduction of a 1000 kDa band on Western blot. Further immunofluorescence data of Nesprin-1 expression in various muscle diseases will be presented. doi:10.1016/j.nmd.2007.06.245

POSTERS 15 CONGENITAL MYOPATHIES I C.P.1.01 Congenital fiber type disproportion and noncompaction cardiomyopathy in a patient Sampaolo, S. 1,*; Varone, A. 2; Diodato, D. 1; Limongelli, G. 3; Sannino, V. 1; Calabro`, P. 3; Calabro`, R. 3; Di Iorio, G. 1 1 Second University of Naples, Neurological Sciences, Napoli, Italy; 2 AORN Santobono-Pausilipon, Neurosciences, Napoli, Italy; 3 Second University of Naples, Cardiothoracic and Respiratory Sciences, Napoli, Italy We report the occurrence of congenital fiber type disproportion (CFTD) and noncompaction cardiomyopathy (NC) in a patient. A female infant born after an uneventful pregnancy and delivery, is the only child of a family with history of consanguinity and diabetes mellitus in the maternal line (her mother’s parents are first degree cousins), which was negative for neuromuscular diseases. From birth she manifested hypotonia, poor sucking and crying; Persistent Arterial Duct and Patent Oval Foramen diagnosed at birth, spontaneously resolved as shown by echocardiography at age 1 month. At age 17 months she was hospitalized because of body weight below the third percentile and hypoglycemia. Echocardiography demonstrated slight dilation (LVDd 38 mm) and prominent trabeculations of frontolateral, posterolateral and lower wall of the left ventricle, and reduced ejection fraction (40% of normal); the left atrium was enlarged (31.8 mm). ECG showed signs of LVH, prolonged QT (QT corrected for heart rate = 460 ms) and ST elevation. EEG and Brain MRI did not

disclose any abnormality. Neuromuscular examination revealed waddling gait, inability to stand-up from sitting position, slight degree weakness of facial and masticatory muscles, mild of glutei and ileopsoas, marked of quadriceps bilaterally; tendon reflexes were absent. Routine hemogram and blood biochemistry, including serum creatine kinase were normal. Electromyography demonstrated a myopathic pattern (low amplitude and short-duration motor units). Quadriceps muscle biopsy displayed predominance of type I fibers (76%) whose mean diameter was 30% smaller than that of type II fibres, which were hypertrophic for the age (mean diameter 35 lm). No further structural or histochemical abnormality was observed. These findings were compatible with the diagnosis of congenital fiber type disproportion. The association between CFTD and NC, never described so far, suggests that these clinical–pathological entities may share a pathogenic mechanism capable to affect the maturation of both skeletal and cardiac muscle. doi:10.1016/j.nmd.2007.06.246

C.P.1.02 Clinical and histopathological evolution of a calpain-3 deficiency presenting as congenital fiber type disproportion Vattemi, G. 1,*; Gualandi, F. 2; Tonin, P. 1; Rimessi, P. 2; Marini, M. 1; Filosto, M. 1; Ferlini, A. 2; Tomelleri, G. 1 1 University of Verona, Department of Neurological Sciences and Vision, Verona, Italy; 2 University of Ferrara, Dipartimento di Medicina Sperimentale e Diagnostica, Ferrara, Italy Congenital fiber type disproportion (CFTD) has a histopathological picture characterized by type 1 muscle fibers at least 12% smaller than the mean type 2 fiber diameter. The term is used when the clinical features suggest a congenital myopathy and other neuromuscular conditions have been ruled out. The lack of large case series and of the histopathological changes that occur with aging makes difficult our understanding of CFTD, particularly of its natural history. We describe the clinical and histopathological evolution of a male which had a muscle biopsy consistent with CFTD diagnosis at 4 years of age. He had difficulty in climbing stairs and mild increased level of serum creatine kinase. On clinical examination proximal limb and flexor muscles of the spine were weak and shortening of both achilles tendon was observed. During the following years, the weakness slowly worsened, proximal arm and leg muscles became atrophic, and the patient developed elbow and knee contractures. A second muscle biopsy, performed when the patient was 19 year old, showed dystrophic changes and an inversion in the size of fiber types; in addition, all type 1 fibers were lobulated. Immunohistochemistry for dystrophin, dystrophin-related proteins, caveolin-3, merosin, dysferlin, emerin and collagen VI was normal, while Western blot for calpain-3 showed a reduction of the protein expression. No mutations in the calpain-3 gene were detected. Our data suggest that calpain-3 deficiency should be included in the list of secondary causes of CFTD and expand the histopathological spectrum of calpain-3 deficiency. doi:10.1016/j.nmd.2007.06.247

C.P.1.03 TPM3 is a recurrent cause of congenital fibre type disproportion and is associated with a consistent phenotype Clarke, N. 1,*; Kolski, H. 2; Dye, D. 3; Lim, E. 3; Smith, R. 4; Patel, R. 5; Fahey, M. 6; Laing, N. 3; North, K. 1 1 Children’s Hospital at Westmead, University of Sydney, Institute for Neuromuscular Research, Sydney, Australia; 2 Stollery Children’s Hospital, University of Alberta Hospital, Department of Pediatrics, Edmonton, Canada; 3 University of Western Australia, QEII Medical Centre, Western Australian Institute for Medical Research, Perth, Australia; 4 University