Recessive myopalladin mutations cause congenital cap myopathy with unusual rods

Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249 presented mutilple episodes of sudden stiffness usually after infection or orthopaedic surgery triggering episodes of rhabdomyolysis. When used Dantrolene, she was able to be partially relieved from these episodes. Genetic testing was negative SEPN1, TTN, RYR1. She was found with a homozygous new mutation in TNNT1 gene. Both parents are carrier of the same mutation. Only few case of non amish nemaline myopathy cases have been reported. We report the first French Canadian case with this interesting finding on muscle biopsy therefore expanding the clinical and pathological spectrum of TNNT1 gene. http://dx.doi.org/10.1016/j.nmd.2017.06.330

P.291 Recessive myopalladin mutations cause congenital cap myopathy with unusual rods E. Malfatti 1, X. Lornage 2, C. Chéraud 2, R. Schneider 2, V. Biancalana 2, J. Cuisset 3, M. Garibaldi 4, B. Eymard 5, M. Fardeau 1, A. Boland 6, J. Deleuze 6, J. Thompson 7, J. Böhm 2, N. Romero 1, J. Laporte 2 1 Unité de Morphologie Neuromusculaire, Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France; 2 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France; 3 Hôpital Roger-Salengro, Service de neuropédiatrie, Centre de Référence des Maladies Neuromusculaires, Lille, France; 4 Service de Neurologie, CHU de Nice, Nice, France; 5 Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Paris, France; 6 Centre National de Génotypage, Institut de Génomique, CEA, Evry, France; 7 Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Illkirch, France To identify the causative gene in three patients presenting progressive congenital myopathy and cap structures in skeletal muscle. Cap myopathy is a rare congenital myopathy characterized by the presence of peripherally-placed, well delimited structures resembling a cap in muscle fibres. Caps are mainly composed by thin filaments and segments of Z-disc. Although causative mutations in TPM2, TPM3, and ACTA1 genes have been associated with cap myopathy, an important number of patients remain without a molecular diagnosis precluding familial counselling and better patient health care. Clinical, histopathological and exome sequencing analyses were performed on three cap myopathy patients from two unrelated families. All patients, two males and one female, presented a consistent clinical phenotype characterized by neonatal hypotonia, retarded motor development and bone deformities including pectus excavatum, elongated face and high-arched palate. They successively developed severe facial weakness and progressive proximo-distal and axial muscle weakness without overt cardiomyopathy. One male patient lost ambulation in his late forties. Muscle biopsies revealed cap structures and atypical nemaline rods associated with type 1 fibers uniformity. Exome sequencing disclosed two different homozygous truncating mutations in the MYPN gene encoding for myopalladin (MYPN), a Z-disc protein implicated in sarcomere integrity. Mutations led to the truncation of the C-terminal part of MYPN responsible for the interaction with alpha-actinin. Immunostaining on frozen muscle sections with a MYPN N-terminal antibody showed strong labelling of caps and atypical rods suggesting aberrant aggregation of the truncated protein. Autosomal dominant mutations in MYPN gene have been reported in dilated, restrictive or hypertrophic cardiomyopathies (MIM#615248) without skeletal muscle involvement. Our findings demonstrate that recessive MYPN gene mutations cause cap myopathy. This suggests that MYPN is involved in two different diseases through different modes of inheritance. http://dx.doi.org/10.1016/j.nmd.2017.06.331

P.292 Novel homozygous recessive MYH2 variant associated with an autosomal dominant clinical pathological phenotype A. Findlay, M. Harms, A. Pestronk, C. Weihl Washington University in Saint Louis, Saint Louis, USA

S185

Mutations in MYH2 cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with congenital joint contractures that resolve with age, external opthalmoplegia, and later onset progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and intranuclear and cytoplasmic inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, a distinct phenotype occurs in patient’s with recessive MYH2 mutations. These patients also have severe opthalmoplegia but instead have a more mild and diffuse pattern of weakness that is early in onset and largely non-progressive. Muscle biopsy reveals small or absent type 2a fibers with no vacuole or inclusion pathology. We identified a patient with childhood onset opthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient’s disease course and histopathology is consistent with patients carrying dominant MYH2 mutations, whole exome sequencing revealed a novel c.737 G > A p.(Arg246Thr) homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies. http://dx.doi.org/10.1016/j.nmd.2017.06.332

P.293 Classic congenital myopathy with recessive mutations in genes encoding ion channels: clinical phenotype and good response to acetazolamide P. Munot 1, I. Zaharieva 2, L. Hartley 3, R. Phadke 2, C. Sewry 2, L. Feng 2, R. Sud 4, M. Hanna 4, E. Matthews 4, F. Muntoni 2 1 Great Ormond Street Hospital, London, UK; 2 UCL institute of Child Health, London, UK; 3 University Hospital of Wales, Cardiff, UK; 4 UCL institute of Neurology and National Hospital for Neurology and Neurosurgery Queen Square, London, UK We present data on 2 children with congenital myopathy due to mutations in genes encoding ion-channels. First, is a 10-year-old boy with neonatal hypotonia with lower limb contractures, bulbar and facial weakness, ophthalmoplegia, ptosis with maximal functional ability to sit independently. He uses NIV since the age of 7. He has periodic short-lived episodes where he loses head-control, develops slurred speech but remains conscious. Triggers include rest, hot weather, fasting, and illness. Exercise testing and CK were normal. Muscle MRI and biopsy showed changes compatible with congenital myopathy. Compound heterozygous mutations (p.Q1265H & p.E100K) were identified in CACNA1S gene using whole exome sequencing. p.E100K in isolation would predict a periodic paralysis phenotype. With acetazolamide, his periodic symptoms completely resolved and he gained some overall muscle strength over 1 year. Second, is a 16-year-old girl with neonatal-onset hypotonia, facial, axial and proximal weakness, hip, knee and ankle contractures with respiratory and feeding difficulties. She has ophthalmoplegia and uses NIV since the age of 6 and needed scoliosis surgery at 13. From the age of 12, she describes marked diurnal fluctuation in strength with short-lived episodic weakness during febrile illnesses, exertion and on hot days. She has significant fatigability. CK, stimulation SFEMG and exercise test were normal. Muscle biopsy and muscle MRI showed features of congenital myopathy. Compound heterozygous mutations were identified in SCN4A using whole exome sequencing. p.R1135C is reported previously with periodic paralysis. Treatment with salbutamol reduced fatigue. With acetazolamide, her periodic weakness and fluctuation in symptoms significantly improved. This report demonstrates the role of genetic evaluation in ion-channel related congenital myopathies. Mutations in specific regions of the channel may predict fluctuant symptoms and can help identify those who could be offered acetazolamide. These conditions present a diagnostic challenge as classical congenital myopathy mimics. http://dx.doi.org/10.1016/j.nmd.2017.06.333