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P.12.9 Electrophysiological characterization of novel CLCN1 mutations found in Korean patients with myotonia congenita
Abstracts / Neuromuscular Disorders 23 (2013) 738–852 ent aspects have been investigated by the members of the French CMS network: the difficulties to make a proper diagnosis, the course and long term prognosis, and the response to therapy, especially for the CMS that do not respond to cholinesterase inhibitors. CMS diagnosis was late in most cases due to confusion with other entities: congenital myopathies, due to the frequent myopathic presentation of patients including permanent weakness, atrophy, scoliosis, and biopsy often showing abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy); seronegative autoimmune myasthenia gravis when CMS was late onset; metabolic myopathy, with presence of lipidosis in muscle. We studied long term prognosis of CMS in a series of 81 patients recruited with the following mutated genes: CHRNA, CHRNE, DOK7, COLQ, RAPSN, AGRN, MUSK. Course pattern (progressive worsening, exacerbation, stability, improvement) could be variable along the life in one single patient. DOK7 patients had the most severe course with progressive worsening: among the 8 wheel-chair bound and ventilated, 6 were mutated for this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first line therapy for CMS patients, except for SlowChannel, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss CMS or RAPSN gene mutations. Ephedrine was given to 18 patients (8 DOK7, 5 COLQ, 4 AGRN, 1 RAPSN). Tolerance was good. Therapeutic response was encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient, allergic to Ephedrine. http://dx.doi:10.1016/j.nmd.2013.06.588
P.12.7 Swallowing evaluation in Escobar syndrome : A case report S. Serel 1, N. Demir 1, A.A. Karaduman 1, H. Kayy´han 2, H. Topaloglu 3 1 Hacettepe University, Physiotherapy and Rehabilitation, Ankara, Turkey; 2 Hacettepe University, Ergotherapy, Ankara, Turkey; 3 Hacettepe University, Pediatric Neurology, Ankara, Turkey Escobar syndrome is a rare disease characterized by multiple ptergia, skin webs and congenital anomalies like craniofacial defects, vertebral anomalies, cleft palate, kyphosis and scoliosis. Despite the passage of the disease is reported as an autosomal recessive, autosomal dominant and X-linked lethal multiple pterygium syndromes have also been reported in the literature. We aimed to discuss the swallowing physiology of a case who referred with swallowing disorders. Our case was 20 months old, male, 75 cm height and 10.5 kg weight and he fed by oral way. He was followed by 2.5 months with tracheostomy tube. He had pulmonary infection history once a month. Swallowing disorder was thought to be the cause of pulmonary infection so the swallowing evaluation was performed. Modified Barium Swallowing Evaluation was performed and the penetration aspiration scale (PAS) was used to define the aspiration severity. Delay in swallowing reflex (2–5 s) was determined. Silent aspiration was seen in liquid consistency with bottle feeding. The PAS score was 7. Oral intake with liquid thickener was recommended because swallowing evaluation showed that the cause of infections was liquid aspiration. Our results showed that swallowing disabilities should also be considered in this syndrome characterized by multiple congenital anomalies and necessary referral should be done in the early period. http://dx.doi:10.1016/j.nmd.2013.06.589
P.12.8 The results of aerobic exercise program in Escobar syndrome: A case report S. Subasi 1, I. Alemdaroglu 2, O. Yilmaz 1, A.A. Karaduman 1, E. Kilic 3 1 Hacettepe University, Physiotherapy and Rehabilitation, Ankara, Tur-
807
key; 2 Bezmialem Vakif University, Physiotherapy and Rehabilitation, Istanbul, Turkey; 3 Hacettepe University, Pediatrics Genetics, Ankara, Turkey Escobar Syndrome is an autosomal recessive malformation which is characterized with growth retardation, multiple pterygia (neck, fingers, antecubital, popliteal? and intercrural areas), craniofacial anomalies. There are limited studies about effects of physical therapy in Escobar Syndrome in literature. 13 years old girl with Escobar Syndrome is taken in 8 week exercise program. She has short stature, scoliosis, neck pterygia, flat expressionless face, small mouth and micrognathia. Myometer is used to evaluate strength of 10 muscle group in lower extremities. North Star Ambulation Assessment (NSAA) and Six Minute Walk Test (6MWT) were performed to evaluate ambulation and performance. Timed Performance Test (TPT) also was applied for 12 activities. Aerobic exercise using arm and leg ergometer and stretching exercises were done 3 days in a week supervised by physiotherapist. Evaluation parameters were repeated after physiotherapy. After exercise program, 10 m walk, rising from floor, 4 steps ascending durations were shorter and standing on right and left sides’ durations were longer. Hip, knee and elbow muscles’ strength were improved. NSAA score rose from 24 to 31 and 6MWT distance increased from 440 to 484. Improvements in performance after exercise training show us that physical therapy is proper treatment option in Escobar Syndrome. http://dx.doi:10.1016/j.nmd.2013.06.590
P.12.9 Electrophysiological characterization of novel CLCN1 mutations found in Korean patients with myotonia congenita J.H. Shin 1, Y.E. Park 2, K. Ha 3, I.S. So 3, D.S. Kim 1 1 Pusan National University Yangsan Hospital, Neurology, Yangsan, Republic of Korea; 2 Pusan National University Hospital, Neurology, Busan, Republic of Korea; 3 Seoul National University, Physiology, Seoul, Republic of Korea Myotonia congenita is the most common non-dystrophic channelopathy of the skeletal muscle. It is characterized by clinical myotonia on voluntary contraction, accompanied by warm-up alleviation with repeated movements. Mutations of the chloride channel gene (CLCN1) are responsible for the disease. Both autosomal dominant and recessive inheritance patterns are reported, while recessive cases are more frequent. We analyzed 38 Korean patients with myotonia congenita. Twelve mutations were found and 8 of them were novel. Patch clamp recording revealed significant difference between mutated genes and WT in current density, current–voltage curve, and open probability. Noteworthy of them were 2 peculiar mutations, R47W and A298T, found together as compound heterozygotes in 6 patients. To our best knowledge, they have not been reported to cause any disease phenotype and R47W is even listed in dbSNP as minor allele. R47W is coded from exon 1 and located at N-terminal; A298T is from exon 8, the hotspot of CLCN1 mutation and reside in domain V. By electrophysiologic techniques we could successfully show the pathogenicity of CLCN1 mutations in Korean patients with myotonia congenita. Mild electrophysiological abberation of R47W may explain the paucity of its homozygous patients despite its relatively high allele frequency. However, compound heterozygosity of R47W with A298T disclosed typical electrophysiologic abnormality in myotonia congenita. Further study on heterodimeric interaction of chloride channel protein is warranted to better understand its function and abnormalities. http://dx.doi:10.1016/j.nmd.2013.06.591
P.12.7 Swallowing evaluation in Escobar syndrome : A case report S. Serel 1, N. Demir 1, A.A. Karaduman 1, H. Kayy´han 2, H. Topaloglu 3 1 Hacettepe University, Physiotherapy and Rehabilitation, Ankara, Turkey; 2 Hacettepe University, Ergotherapy, Ankara, Turkey; 3 Hacettepe University, Pediatric Neurology, Ankara, Turkey Escobar syndrome is a rare disease characterized by multiple ptergia, skin webs and congenital anomalies like craniofacial defects, vertebral anomalies, cleft palate, kyphosis and scoliosis. Despite the passage of the disease is reported as an autosomal recessive, autosomal dominant and X-linked lethal multiple pterygium syndromes have also been reported in the literature. We aimed to discuss the swallowing physiology of a case who referred with swallowing disorders. Our case was 20 months old, male, 75 cm height and 10.5 kg weight and he fed by oral way. He was followed by 2.5 months with tracheostomy tube. He had pulmonary infection history once a month. Swallowing disorder was thought to be the cause of pulmonary infection so the swallowing evaluation was performed. Modified Barium Swallowing Evaluation was performed and the penetration aspiration scale (PAS) was used to define the aspiration severity. Delay in swallowing reflex (2–5 s) was determined. Silent aspiration was seen in liquid consistency with bottle feeding. The PAS score was 7. Oral intake with liquid thickener was recommended because swallowing evaluation showed that the cause of infections was liquid aspiration. Our results showed that swallowing disabilities should also be considered in this syndrome characterized by multiple congenital anomalies and necessary referral should be done in the early period. http://dx.doi:10.1016/j.nmd.2013.06.589
P.12.8 The results of aerobic exercise program in Escobar syndrome: A case report S. Subasi 1, I. Alemdaroglu 2, O. Yilmaz 1, A.A. Karaduman 1, E. Kilic 3 1 Hacettepe University, Physiotherapy and Rehabilitation, Ankara, Tur-
807
key; 2 Bezmialem Vakif University, Physiotherapy and Rehabilitation, Istanbul, Turkey; 3 Hacettepe University, Pediatrics Genetics, Ankara, Turkey Escobar Syndrome is an autosomal recessive malformation which is characterized with growth retardation, multiple pterygia (neck, fingers, antecubital, popliteal? and intercrural areas), craniofacial anomalies. There are limited studies about effects of physical therapy in Escobar Syndrome in literature. 13 years old girl with Escobar Syndrome is taken in 8 week exercise program. She has short stature, scoliosis, neck pterygia, flat expressionless face, small mouth and micrognathia. Myometer is used to evaluate strength of 10 muscle group in lower extremities. North Star Ambulation Assessment (NSAA) and Six Minute Walk Test (6MWT) were performed to evaluate ambulation and performance. Timed Performance Test (TPT) also was applied for 12 activities. Aerobic exercise using arm and leg ergometer and stretching exercises were done 3 days in a week supervised by physiotherapist. Evaluation parameters were repeated after physiotherapy. After exercise program, 10 m walk, rising from floor, 4 steps ascending durations were shorter and standing on right and left sides’ durations were longer. Hip, knee and elbow muscles’ strength were improved. NSAA score rose from 24 to 31 and 6MWT distance increased from 440 to 484. Improvements in performance after exercise training show us that physical therapy is proper treatment option in Escobar Syndrome. http://dx.doi:10.1016/j.nmd.2013.06.590
P.12.9 Electrophysiological characterization of novel CLCN1 mutations found in Korean patients with myotonia congenita J.H. Shin 1, Y.E. Park 2, K. Ha 3, I.S. So 3, D.S. Kim 1 1 Pusan National University Yangsan Hospital, Neurology, Yangsan, Republic of Korea; 2 Pusan National University Hospital, Neurology, Busan, Republic of Korea; 3 Seoul National University, Physiology, Seoul, Republic of Korea Myotonia congenita is the most common non-dystrophic channelopathy of the skeletal muscle. It is characterized by clinical myotonia on voluntary contraction, accompanied by warm-up alleviation with repeated movements. Mutations of the chloride channel gene (CLCN1) are responsible for the disease. Both autosomal dominant and recessive inheritance patterns are reported, while recessive cases are more frequent. We analyzed 38 Korean patients with myotonia congenita. Twelve mutations were found and 8 of them were novel. Patch clamp recording revealed significant difference between mutated genes and WT in current density, current–voltage curve, and open probability. Noteworthy of them were 2 peculiar mutations, R47W and A298T, found together as compound heterozygotes in 6 patients. To our best knowledge, they have not been reported to cause any disease phenotype and R47W is even listed in dbSNP as minor allele. R47W is coded from exon 1 and located at N-terminal; A298T is from exon 8, the hotspot of CLCN1 mutation and reside in domain V. By electrophysiologic techniques we could successfully show the pathogenicity of CLCN1 mutations in Korean patients with myotonia congenita. Mild electrophysiological abberation of R47W may explain the paucity of its homozygous patients despite its relatively high allele frequency. However, compound heterozygosity of R47W with A298T disclosed typical electrophysiologic abnormality in myotonia congenita. Further study on heterodimeric interaction of chloride channel protein is warranted to better understand its function and abnormalities. http://dx.doi:10.1016/j.nmd.2013.06.591