title: Congenital myopathies: Natural history of a large pediatric cohort.
abstract: OBJECTIVE
  To assess the natural history of congenital myopathies (CMs) due to different genotypes.
  
  
  METHODS
  Retrospective cross-sectional study based on case-note review of 125 patients affected by CM, followed at a single pediatric neuromuscular center, between 1984 and 2012.
  
  
  RESULTS
  Genetic characterization was achieved in 99 of 125 cases (79.2%), with RYR1 most frequently implicated (44/125). Neonatal/infantile onset was observed in 76%. At birth, 30.4% required respiratory support, and 25.2% nasogastric feeding. Twelve percent died, mainly within the first year, associated with mutations in ACTA1, MTM1, or KLHL40. All RYR1-mutated cases survived and did not require long-term ventilator support including those with severe neonatal onset; however, recessive cases were more likely to require gastrostomy insertion (p = 0.0028) compared with dominant cases. Independent ambulation was achieved in 74.1% of all patients; 62.9% were late walkers. Among ambulant patients, 9% eventually became wheelchair-dependent. Scoliosis of variable severity was reported in 40%, with 1/3 of (both ambulant and nonambulant) patients requiring surgery. Bulbar involvement was present in 46.4% and required gastrostomy placement in 28.8% (at a mean age of 2.7 years). Respiratory impairment of variable severity was a feature in 64.1%; approximately half of these patients required nocturnal noninvasive ventilation due to respiratory failure (at a mean age of 8.5 years).
  
  
  CONCLUSIONS
  We describe the long-term outcome of a large cohort of patients with CMs. While overall course is stable, we demonstrate a wide clinical spectrum with motor deterioration in a subset of cases. Severity in the neonatal/infantile period is critical for survival, with clear genotype-phenotype correlations that may inform future counseling.
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Irene
authors.initials: I
authors.lastname: Colombo
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Scoto
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Adnan Y
authors.initials: AY
authors.lastname: Manzur
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Robb
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Maggi
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Vasantha
authors.initials: V
authors.lastname: Gowda
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cullup
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Yau
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Rahul
authors.initials: R
authors.lastname: Phadke
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: From the Dubowitz Neuromuscular Centre and MRC Centre for Neuromuscular Disorders (I.C., M.S., A.Y.M., S.A.R., V.G., C.S., F.M.), University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK; Neuromuscular Unit (I.C.), Department of Neurological Sciences, IRCCS Foundation Cà Granda, Ospedale Maggiore Policlinico, Dino Ferrari Centre, Milan, University of Milan; Muscle Pathology and Neuroimmunology Unit (L.M.), Foundation IRCCS Neurological Institute C. Besta, Milan, Italy; DNA Laboratory (T.C., M.Y.), GSTS Pathology, Guy's Hospital, London; University College London Department of Neurology (R.P.), National Hospital for Neurology and Neurosurgery, London; Wolfson Centre for Inherited Neuromuscular Diseases RJAH (C.S.), Oswestry; Department of Paediatric Neurology (H.J.), Evelina Children's Hospital, London; Randall Division for Cell and Molecular Biophysics (H.J.), Muscle Signalling Section, King's College, London; and Clinical Neuroscience Division (H.J.), IoP, London, UK. f.muntoni@ucl.ac.uk.
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003241:Consanguinity; D003430:Cross-Sectional Studies; D003680:Deglutition Disorders / Q000209:etiology; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D051346:Mobility Limitation; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D017696:Myopathies, Nemaline / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000150:complications / Q000235:genetics / Q000473:pathology; D020512:Myopathy, Central Core / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012131:Respiratory Insufficiency / Q000209:etiology; D012189:Retrospective Studies; D012600:Scoliosis / Q000209:etiology; D055815:Young Adult
chemical_list: D009124:Muscle Proteins