G.P.13.08 Benign phenotype in compound heterozygosity autosomal recessive central core disease: Case report

Abstracts / Neuromuscular Disorders 18 (2008) 724–833 By age of 47, his symptom gradually progressed to include left leg weakness and developed right foot drop at the age of 47. Neurological examination revealed prominent muscle atrophy and weakness in bilateral anterior tibial muscles with relative sparing of the gastrocnemius muscles. He could not walk on his heels but could still walk on his toes. Steppage gait was apparent. He did not have facial muscle weakness, ophthalmoplegia, or spinal rigidity. Serum CK level was normal at 200 IU/L. On muscle CT, both the soleus and tibialis anterior muscles were almost totally replaced by fat tissue, however the quadriceps femoris and gastrocnemius muscles were spared. The upper extremity muscles were normal. Muscle biopsy revealed moderate variation in fiber size on H&E. On NADH-TR, there were many fibers with multi-mini cores and central core-like structure. On longitudinal sections, these cores did not extend to the entire fiber length. On ATPase staining, type 1 fiber was atrophic. Multi-mini and central cores were present predominantly in type 1 fibers. Electron microscopy showed focal loss of striation. We screened RYR1, GNE, Myotilin and ZASP gene. We identified a heterozygous c.5869T>A (p.S1957A) in exon 36 of RYR1 gene. We report multi-minicore patient clinically presents distal myopathy with RYR1 mutation. This case report presents a new clinical form for multi-minicore disease. doi:10.1016/j.nmd.2008.06.291

G.P.13.07 Late-onset axial myopathy with cores due to a novel dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene H. Jungbluth 1; S. Lillis 2; H. Zhou 3; S. Abbs 2; M. Swash 4; F. Muntoni 3 1 Evelina Children’s Hospital Guy’s & St. Thomas’ NHS Foundation Trust, Department of Paediatric Neurology, London, United Kingdom; 2 Guy’s & St. Thomas’ NHS Foundation Trust, Diagnostics Genetics Laboratory, London, United Kingdom; 3 UCL Institute of Child Health, Dubowitz Neuromuscular Centre, London, United Kingdom; 4 Royal London Hospital, Department of Neurology, London, United Kingdom Mutations in the skeletal muscle ryanodine receptor (RYR1) gene have been associated with a wide range of phenotypes including the malignant hyperthermia susceptibility (MHS) trait and various congenital myopathies such as Central Core Disease (CCD) and specific subgroups of Multi-minicore Disease (MmD) and centronuclear myopathy (CNM). The ‘‘core myopathies” – CCD and MmD – associated with dominant and recessive RYR1 mutations, respectively, are usually characterized by onset in infancy or childhood and predominant proximal weakness pronounced in the hip girdle. Here we report a previously healthy patient with weakness almost exclusively affecting trunk extension and associated camptocormia presenting from the 7th decade of life; prominent involvement of the spine extensors was confirmed on MRI demonstrating marked increase in signal intensity suggestive of fatty infiltration. Muscle biopsy obtained from the left quadriceps showed marked variability in fibre size, increase in internal nuclei, marked type 1 predominance and multiple, well-defined central and eccentric cores suggestive of RYR1 involvement; sequencing of the entire RYR1 coding sequence revealed a novel heterozygous missense mutation (c.119G>T;p.Gly40Val) affecting the RYR1 N-terminus previously predominantly associated with MHS-related mutations. Camptocormia, an abnormal posture characterized by forward bending of the trunk with or without lumbar weakness, has been associated with a wide range of neuromuscular and neurological conditions. This report expands the clinical and radiological spectrum associated with RYR1 mutations and emphasizes that MHS-related RYR1 mutations may give rise to more overt neuromuscular symptoms later in life, with clinical symptoms unlike those associated with typical CCD due to C-terminal hotspot mutations. The late manifestation of this genetic defect remains unaccounted for but may reflect a synergistic effect of the specific mutation and the ageing process on the calcium release unit (CRU). Genetically

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determined congenital myopathies may be underreported in the elderly as presentation of these conditions in late-adulthood is not commonly expected. doi:10.1016/j.nmd.2008.06.292

G.P.13.08 Benign phenotype in compound heterozygosity autosomal recessive central core disease: Case report L.J.M. Negra˜o 1; A. Matos 1; O. Rebelo 1; A. Geraldo 1; R. Santos 2 1 Hospitais da Universidade de Coimbra, Neurology, Coimbra, Saint Helena, Portugal; 2 Instituto de Gene´tica Me´dica, Gene´tica Molecular, POrto, Portugal Central core disease (CCD) is a congenital myopathy associated to ryanodine receptor (RYR1) gene mutations. This gene was mapped to chromosome 19q13 and encodes a 5037 amino-acid protein located in the junctional terminal cisternae of the sarcoplasmic reticulum membrane. There is a broad range of clinical severity and the majority of patients are symptomatic at birth or childhood. Most of the CCD cases have an autosomal dominant inheritance. Autosomal recessive (AR) inheritance has been rarely reported and compound heterozygosity AR is even rarer, with only three families identified. We report a 50 year old caucasian male patient, born of a non-consanguineous marriage, who, at the end of his third decade of life, started complaining of fatigability while doing recreational sport activity, which forced him to rest a few minutes, after which he was able to resume a less intensive physical activity. Neurological examination was normal without detectable muscle weakness or skeletal deformities. The laboratory examination revealed elevated CK levels (5 upper limit of normal), with normal EMG and cardiovascular system evaluation. The muscle biopsy showed myopathic changes and in type 1 fibers cores extending almost along the full length of the fiber longitudinal axis. In the semithin sections from the material included in Epon it was observed irregularity of the sarcomeres inside the cores. T2 weighted pelvic and thigh muscles MRI showed mild fat infiltration of the biceps femoris and semimembranosus muscles. Genetic testing of the RYR1 detected the mutations c.7361G>A (p.Arg2454His) in exon 46 and c.14468C>T (p.Thr4823Met) in exon 100, both in heterozygosity. In conclusion, this clinical case shows that compound heterozygosity autosomal recessive CCD may present in adult life with a benign phenotype, compatible with a normal professional and social life. doi:10.1016/j.nmd.2008.06.293

G.P.13.09 Identification of a point mutation in the skeletal muscle ryanodine receptor gene associated in the homozygous state to central core disease G. Melli 1; L. Colleoni 1; P. Bernasconi 1; S. Romaggi 1; V. Tegazzin 2; R. Mantegazza 1; L. Morandi 3 1 Fondazione Istituto Neurologico ‘‘Carlo Besta”, Neurology IV, Milan, Italy; 2 S Antonio University Hospital, Department of Anaesthesia, Padova, Italy; 3 Fondazione Istituto Neurologico, Neuromuscular Diseases and Neuroimmunology, Milan, Italy Central core disease (CCD) is a rare congenital myopathy with hypotonia and proximal muscle weakness. Muscle biopsy is characterized by core areas lacking mitochondria and oxidative enzyme activity. CCD can be caused by mutations of the ryanodine receptor (RYR1) gene, which encodes the sarcoplasmic reticulum Ca2+-release channel. Malignant hyperthermia (MH), a pharmacogenetic disorder of skeletal muscle, is also associated with RYR1 mutations. We describe a family in which the parents are consanguineous and clinically asymptomatic, while the two daughters are both affected by congenital myopathy and severe muscle