Novel compound heterozygous mutations in PLEC gene causing epidermolysis bullosa simplex with muscular dystrophy, case series of two affected sisters

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Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249

myopathy/movement disorder, elevated CK and central nervous system involvement. http://dx.doi.org/10.1016/j.nmd.2017.06.074

P.45 Complications of advanced Fukuyama congenital muscular dystrophy from a nationwide registry K. Ishigaki 1, C. Ihara 2, T. Sato 1, M. Shichiji 1, T. Murakami 1, K. Ishiguro 1, M. Mori-Yoshimura 3, H. Kaiya 2, M. Osawa 1, S. Nagata 1 1 Tokyo Women’s Medical University, Tokyo, Japan; 2 The Japan Muscular Dystrophy Association, Tokyo, Japan; 3 National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan Fukuyama congenital muscular dystrophy (FCMD), the most common CMD in Japan, features cortical migration defects. Most patients die of respiratory dysfunction, congestive heart failure and suffocation or aspiration pneumonia around age 20 years. In 2013, the Japan muscular dystrophy association developed an FCMD patient registry of FCMD. From October 2011 through September 2013, 207 Japanese FCMD patients (104 boys; 103 girls) in total were registered (0–42 years). A homozygous founder 3-kb insertion mutation in the FKTN gene was present in 80% of registrants, while 20% had a compound heterozygous mutation. We retrospectively analyzed complications and clinical care based on the registry database, focusing especially on 16 advanced patients over age 20 years. All advanced FCMD patients without complications had a homozygous founder mutation and higher maximum motor development. Thirty-four patients (16%) overall and 11 advanced patients (69%) needed respiratory support. After age 15 years, the percentage of patients needing respiratory support increased with age. Five advanced patients without respiratory dysfunction maintained their weight. Twenty-six patients (13%) in total were frequently treated for cardiac dysfunction (ACE inhibitors, beta-blockers, diuretics). Over age 15 years, 50% of patients showed cardiac dysfunction but this percentage did not change with age. Seven advanced patients without cardiac dysfunction tended to be underweight, despite respiratory dysfunction. Dysphagia was frequent among FCMD patients affecting 46 patients (22%) overall. Over age 20 years, 12/16 patients (75%) had dysphagia, though only 33% underwent gastrostomy. Four advanced patients without dysphagia tended to show higher intelligence and better speech development. Analysis of the tendencies for developing complications in advanced patients requires an information campaign to highlight the importance of the registry for older patients. http://dx.doi.org/10.1016/j.nmd.2017.06.075

P.46 A case of epidermolysis bullosa simplex and muscular dystrophy with myasthenic symptoms caused by two novel PLEC mutations J. Lee, H. Shin, Y. Choi Yonsei University College of Medicine, Seoul, Republic of Korea Mutations in plectin were identified as a cause of muscular dystrophy, myasthenic syndrome, and epidermolysis bullosa simplex. We report a case of epidermolysis bullosa simplex and muscular dystrophy with myasthenic symptoms caused by two novel PLEC mutations. A 17-year-old male visited to our hospital due to extraocular muscle (EOM) weakness, bilateral ptosis, chronic fatigue, and upper arm weakness since 7 years old. He didn’t have any medical or surgical illness and there are no patients with neuromuscular disease in his family. After birth, he had mild mastication difficulty and tendency of skin blister on recurrent frictional area, mainly bilateral feet. At the age of 7, medial rectus palsy of left eye was developed and one year after, he suffered left ptosis with fatigability. At the age of 16, when he operated his eyes due to bilateral severe ptosis, he was diagnosed as muscular dystrophy with elevated serum creatine kinase, myopathic change on electrodiagnostic study and muscle biopsy. One year after, he visited our hospital. On physical and neurologic

examination, she presented multiple skin blister of bilateral feet, severe bilateral EOM weakness of all directions, bilateral ptosis, mild facial diplegia, moderate neck flexion weakness (MRC GIII), and upper arm weakness. Vital capacity on sitting position was 1960 mL, 45.3% of predicted values. Serum creatine kinase level was 2224 (35–232) IU and acetylcholine receptor binding antibody was below 0.001 (negative). Muscle MRI showed mild fatty atrophy of tongue, biceps, tongue, and paraspinal muscles on multiple levels. We performed whole exome sequencing and found two novel mutations of PLEC gene (c.11986_12005del [Q3996Sfs*2], c.11753C > T [p.S3918L]), followed by confirmation of decreased expression of plectin by immunohistochemistry. We confirmed the presence of muscular dystrophy with myasthenic symptoms caused by PLEC mutation in Korean population, and reported two novel mutations in PLEC gene. http://dx.doi.org/10.1016/j.nmd.2017.06.076

P.47 Congenital centronuclear myopathy and epidermolysis bullosa due to two novel mutations in the plectin gene M. Walter 1, P. Reilich 1, S. Krause 1, A. Abicht 2, B. Schoser 1 1 Friedrich-Baur-Institute, Munich, Germany; 2 Friedrich-Baur-Institute and MGZ Munich, Munich, Germany We report on a Turkish patient with congenital myopathy with a fiber type disproportion and central myonuclei comparable to a centronuclear myopathy and skin blistering (epidermolysis bullosa simplex, EBS) due to a novel homozygous mutation in the plectin gene, a cytoskeleton-membrane anchorage protein. So far, EBS has only been described to be associated with congenital or limb girdle muscular dystrophy, myasthenic syndrome, or pyloric atresia. A clubfoot and hypotonia were noted directly at birth, skin blistering was identified shortly after cast treatment of the foot malposition. Motor milestones were only mildly delayed; walking was possible with 18 months of age. The parents are first grade cousins; the patient has no siblings. There are no other affected family members, offspring of the parents siblings are reported healthy. Clinical examination at age 25 revealed bilateral ptosis, normal eye movement, long facial bones, high palate, scoliosis, rigid neck and spine, severe contractures of elbow, wrist, knee and ankle joints, scapular winging, slim muscles, and a cachectic phenotype with an BMI of 15.7. Serum CK was elevated with 1500 U/ml, EMG revealed myopathic changes, repetitive stimulation showed a 12% decrement. Lung function showed respiratory involvement with vital capacity 50% of predicted, heart ultrasound was normal. Multigene panel diagnostics for congenital and distal myopathies (55 genes) revealed a homozygous missense mutation in the plectin gene c.8306C > G (p.Pro2769Arg). Even though plectinopathy represents a rare condition, testing should be included into the diagnostic work-up of congenital myopathies with or even without skin blistering. http://dx.doi.org/10.1016/j.nmd.2017.06.077

P.48 Novel compound heterozygous mutations in PLEC gene causing epidermolysis bullosa simplex with muscular dystrophy, case series of two affected sisters I. Lee 1, A. Hurst 1, B. Wong 2, C. Tian 2 1 University of Alabama at Birmingham, Birmingham, USA; 2 Cincinnati Children’s Hospital Medical Center, Cincinnati, USA Epidermolysis bullosa simplex with muscular dystrophy (EBSMD) is a rare clinical entity characterized by childhood onset of progressive muscular dystrophy and blistering skin changes. It is caused by homozygous or compound heterozygous mutations in the plectin gene (PLEC). Genetic defects have been reported in a limited number of patients. The precise phenotypegenotype correlations have yet to be defined. Here we describe two affected

Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249 sisters with detailed clinical presentation, exam findings including timed motor function tests, MRI images and results, and confirmed novel PLEC compound heterozygous mutations. CASE SERIES: #1 Five-year-old female born premature at 25 weeks was evaluated for motor delay. Epidermolysis bullosa (EB) was diagnosed at age 5 months with recurrent skin blisters. She sat alone at 18 months, walked at 2 years of age and never could jump with both feet. Physical exam revealed small stature and dysmorphic findings including micrognathia, high-arched palate, poor dentition with erosions, hand and foot blisters and nail deformation. Neurological examination showed generalized muscle weakness, decreased reflexes and delayed time-with-sit-to-stand, 30-feet-run, and 4-steps-climbing. CPK was elevated at 519 unit/L. Muscle MRI showed asymmetric atrophy of the quadriceps muscles, mild fatty infiltration in the quadriceps and gluteus maximus muscles and subtle increased T2 signal in the quadriceps muscles bilaterally. Genetic testing confirmed heterozygous mutations in PLEC (c.11912delA and c.6276dupA) causing frame shift stacking leading to premature stop codons. #2 Three-year-old sister was also diagnosed with EB was found to have same heterozygous PLEC mutations. She had delayed motor development and elevated CPK level. Muscle MRI was unremarkable. We presented clinical evidence that the novel compound heterozygous PLEC mutations are pathogenic for EBSMD. http://dx.doi.org/10.1016/j.nmd.2017.06.078

DMD/BMD: HEART, BRAIN AND LUNGS P.49 Duchenne muscular dystrophy patients with chest pain require cardiac evaluation: A report of eight DMD patients presenting with chest pain, marked troponin elevation, and worsening cardiomyopathy P. Johnston, K. Hor, L. Cripe, C. Stiver Nationwide Children’s Hospital, Columbus, USA Improved neuromuscular and respiratory therapies including nocturnal ventilation have altered the natural history of Duchenne muscular dystrophy(DMD) such that the most common cause of mortality is progressive cardiomyopathy. Cardiac magnetic resonance imaging (CMR) demonstrates a characteristic subepicardial late gadolinium enhancement (LGE) preferring the lateral left ventricular wall. LGE typically precedes systolic dysfunction. Despite imaging evidence of progressive cardiomyopathy, traditional myocardial injury biomakers such as troponin I are normal when checked randomly in DMD patients. We report a series of eight patients who presented to our institution with chest pain and acute troponin elevation. Of our eight patients, six presented with a primary chest pain complaint, while two presented with a presumably secondary myocardial injury in the context of an illness requiring hospitalization. In general, electrocardiograms (EKGs) showed diffuse ST segment elevation with low voltage QRS waves in V4-V6. Baseline EKGs on all patients demonstrate normal baseline ST segments. The mean peak troponin level documented is 46 ng/mL. These levels normalized without specific intervention within about 100 hours. CMR was performed on all but one patient, demonstrating increased LGE and new or worsened systolic dysfunction. In longitudinal assessment, left ventricular systolic function remained lower following the event(48.4 + /- 9.0 versus 61.8 + /- 4.6) whereas right ventricular systolic function appeared to be more preserved and/or recover. The etiology of these events is unknown. Normal coronary angiography was demonstrated by cardiac catheterization in 2/8 patients and CT angioraphy in 2/8. Viral studies were obtained routinely; no viral studies were positive including nasopharyngeal and blood PCR. Acute chest pain with dramatic troponin elevation occurs in DMD boys marking myocardial injury. These epidoses may represent a component of the diseases cardiac natural history. Further investigation should define the etiology and scope of these events. http://dx.doi.org/10.1016/j.nmd.2017.06.079

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P.50 Adolescence with Duchenne and Becker muscular dystrophy: a cardiac magnetic resonance comparison study P. Johnston, K. Hor, L. Cripe Nationwide Children’s Hospital, Columbus, USA Duchenne muscular dystrophy (DMD) is the most common neuromuscular disease with high prevalence of DMD-associated heart disease as defined by late gadolinium enhancement (LGE) indicative of myocardial fibrosis and ventricular dysfunction by ejection fraction (EF) that is progressive. The use of cardiac magnetic resonance imaging (CMR) is standard at our institution for DMD patients when sedation is no longer required. LGE by CMR occurs early in DMD patients and is an established marker of myocardial fibrosis preceding systolic dysfunction. In contrast, patients with Becker muscular dystrophy (BMD) are assumed to have a milder cardiac phenotype and undergo later and less frequent CMR evaluation. As such, it is less well characterized with reports of LGE and dysfunction in the third decade of life. We hypothesize that BMD patients will demonstrate high prevalence of LGE and EF abnormality (EF < 55%) in late adolescence similar to DMD patients. We reviewed our CMR database for BMD and age-matched DMD patients with complete CMR studies blinded to the patients CMR findings. Of the DMD patients, 24/31(77%) were LGE positive compared to 10/22(45%) of BMD patients with no difference in age. The mean age for LGE positive versus negative BMD patients was 22.7 ± 6.4 and 15.7 ± 4.8 years respectively. The youngest LGE positive BMD patient was 15.7 years of age. Of those with positive LGE, 13/24 (52%) of DMD had abnormal LVEF while 6/10 (60%) of BMD had abnormal LVEF. LGE positive BMD patients trended toward a lower LVEF of 50.3 ± 8.4% versus 59.9 ± 4.6% for LGE negative patients. This study demonstrates a high prevalence of LGE and ventricular dysfunction in BMD patients by late adolescence. Although BMD patients have been reported to have milder cardiac disease, a substantial percentage of these adolescent BMD patients have LGE and ventricular dysfunction. Further work should characterize the natural history of BMD cardiomyopathy with an emphasis on predicting fibrosis progressiona and ventricular dysfunction. http://dx.doi.org/10.1016/j.nmd.2017.06.080

P.51 Quantitative cardiac NMR imaging in a large cohort of patients with Becker muscular dystrophy B. Marty 1, M. Toussaint 1, R. Gilles 2, P. Carlier 1, K. Wahbi 1 1 Institute of Myology, Paris, France; 2 Chwapi, Tournai, Belgium Becker muscular dystrophy (BMD) is a genetic disease caused by an X-linked recessive mutation leading to a defective dystrophin expression, with a relatively mild clinical course. Myocardial involvement is frequent, eventually progressing to a dilated cardiomyopathy. The purpose of this study was to evaluate myocardial structural and functional alterations in adult BMD patients using quantitative cardiac NMR (CMR) imaging. 86 BMD patients and 22 age-matched volunteers underwent CMR imaging at 3T (Siemens PRISMA, Siemens Healthcare). Left ventricular T1 maps pre- and post-gadoliniumDOTA (GdCA) injection were acquired with a modified look-locker sequence (MOLLI), from which extracellular volume fraction values (ECV) were derived. T2 maps were generated with a T2 prepared TrueFISP sequence. Myocardial T1 and T2 values were sorted according to the classification of the AHA segmentation. Standard cine imaging was also performed to evaluate the left ventricular function with software Segment®. Mean left ventricular ejection fraction (LVEF) was slightly but significantly lower in the BMD group (62 ± 12% VS 70 ± 6%) and was not correlated with age (R = 0.09, p > 0.05). Around 15% of the patients presented a LVEF below 50%. Post-GdCA T1 values were significantly lower in the antero-lateral region compared to the other segments (p < 0.05). On the contrary, pre-GdCA T1 values were increased in this region (p < 0.05), and a slight but not significant increase in T2 values was also observed at the same location. ECV was correlated with pre GdCA T1 values (R = 0.70, p < 0.05), T2 values (R = 0.74, p < 0.05) as well as LVEF