De novo LMNA mutations cause a new form of congenital muscular dystrophy
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 wer...
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Published in | Annals of neurology Vol. 64; no. 2; pp. 177 - 186 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Wiley Subscription Services, Inc., A Wiley Company
01.08.2008
Willey-Liss |
Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | istex:D698009B639124E07A6017A2A87283D52B715EE7 GIS-Institut des Maladies Rares European Union Fifth Framework (Euro-laminopathies contract) - No. #018690; No. #RAS05018 NHMRC - No. 372104 Association Française contre les Myopathies (AFM) AFM rare disorder network program - No. 10722 ArticleID:ANA21417 Muscular Dystrophy Association of New South Wales, Australia ark:/67375/WNG-5229SQTW-L Institut National de la Santé et de la Recherche Médicale Muscular Dystrophy campaign Assistance Publique-Hôpitaux de Paris G.B. and B.E. contributed equally to this work. |
ISSN: | 0364-5134 1531-8249 |
DOI: | 10.1002/ana.21417 |