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De novo LMNA mutations cause a new form of congenital muscular dystrophy

Authors

  • Susana Quijano-Roy MD, PhD,

    Corresponding author
    1. Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Universitaire Raymond Poincaré, Centre National de Référence des Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye, Garches
    2. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    3. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
    • Service de Pédiatrie, Hôpital Raymond Poincaré, 92380 Garches, France
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  • Blaise Mbieleu MD,

    1. Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Universitaire Raymond Poincaré, Centre National de Référence des Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye, Garches
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  • Carsten G. Bönnemann MD, PhD,

    1. Division of Neurology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA
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  • Pierre-Yves Jeannet MD, PhD,

    1. Service de Pédiatrie, Unité de Neuropédiatrie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
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  • Jaume Colomer MD,

    1. Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain
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  • Nigel F. Clarke MD, PhD,

    1. Institute for Neuromuscular Research, Children's Hospital at Westmead, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia
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  • Jean-Marie Cuisset MD,

    1. Service de Neurologie Pédiatrique, Hôpital Roger-Salengro, Centre National de Référence des Maladies Neuromusculaires, Centre Hospitalier Régional Universitaire de Lille, Lille, France
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  • Helen Roper MD,

    1. Department of Child Health, Birmingham Heartlands Hospital, Birmingham, United Kingdom
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  • Linda De Meirleir MD,

    1. Pediatric Neurology Department, Free University of Brussels, Brussels, Belgium
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  • Adele D'Amico MD, PhD,

    1. Unit of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy
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  • Rabah Ben Yaou MD,

    1. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    2. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
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  • Andrés Nascimento MD,

    1. Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain
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  • Annie Barois MD, PhD,

    1. Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Universitaire Raymond Poincaré, Centre National de Référence des Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye, Garches
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  • Laurence Demay,

    1. Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France
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  • Enrico Bertini MD, PhD,

    1. Unit of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy
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  • Ana Ferreiro MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    2. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
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  • Caroline A. Sewry MD, PhD,

    1. Wolfson Centre for Inherited Neuromuscular Diseases, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry
    2. Dubowitz Neuromuscular Centre. UCL Institute of Child Health and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom
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  • Norma B. Romero MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    2. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
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  • Monique Ryan MD, PhD,

    1. Neurosciences Department, Royal Children's Hospital, Parkville, Victoria, Australia
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  • Francesco Muntoni MD, PhD,

    1. Dubowitz Neuromuscular Centre. UCL Institute of Child Health and Great Ormond Street Hospital for Children (GOSH), London, United Kingdom
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  • Pascale Guicheney PhD,

    1. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    2. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France
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  • Pascale Richard MD, PhD,

    1. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    2. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France
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  • Gisèle Bonne PhD,

    1. Institut National de la Sante et de la Recherche Médicale (INSERM) U582, Institut de Myologie
    2. Université Pierre et Marie Curie-Paris6, Unité Mixte de Recherche S582, Institut Fédératif de Recherche, Paris, France
    3. Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France
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    • G.B. and B.E. contributed equally to this work.

  • Brigitte Estournet MD, PhD

    1. Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Universitaire Raymond Poincaré, Centre National de Référence des Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye, Garches
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    • G.B. and B.E. contributed equally to this work.


Abstract

Objective

To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations.

Methods

Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients.

Results

The 15 patients presented with muscle weakness in the first year of life, and all had de novo heterozygous LMNA mutations. Three of them had severe early-onset disease, no motor development, and the rest experienced development of a “dropped head” syndrome phenotype. Despite variable severity, there was a consistent clinical pattern. Patients typically presented with selective axial weakness and wasting of the cervicoaxial muscles. Limb involvement was predominantly proximal in upper extremities and distal in lower extremities. Talipes feet and a rigid spine with thoracic lordosis developed early. Proximal contractures appeared later, most often in lower limbs, sparing the elbows. Ten children required ventilatory support, three continuously through tracheotomy. Cardiac arrhythmias were observed in four of the oldest patients but were symptomatic only in one. Creatine kinase levels were mild to moderately increased. Muscle biopsies showed dystrophic changes in nine children and nonspecific myopathic changes in the remaining. Markedly atrophic fibers were common, most often type 1, and a few patients showed positive inflammatory markers.

Interpretation

The LMNA mutations identified appear to correlate with a relatively severe phenotype. Our results further broaden the spectrum of laminopathies and define a new disease entity that we suggest is best classified as a congenital muscular dystrophy (LMNA-related congenital muscular dystrophy, or L-CMD). Ann Neurol 2008.

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