G.B. and B.E. contributed equally to this work.
De novo LMNA mutations cause a new form of congenital muscular dystrophy
Version of Record online: 12 JUN 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 64, Issue 2, pages 177–186, August 2008
How to Cite
Quijano-Roy, S., Mbieleu, B., Bönnemann, C. G., Jeannet, P.-Y., Colomer, J., Clarke, N. F., Cuisset, J.-M., Roper, H., De Meirleir, L., D'Amico, A., Ben Yaou, R., Nascimento, A., Barois, A., Demay, L., Bertini, E., Ferreiro, A., Sewry, C. A., Romero, N. B., Ryan, M., Muntoni, F., Guicheney, P., Richard, P., Bonne, G. and Estournet, B. (2008), De novo LMNA mutations cause a new form of congenital muscular dystrophy. Ann Neurol., 64: 177–186. doi: 10.1002/ana.21417
- Issue online: 28 AUG 2008
- Version of Record online: 12 JUN 2008
- Manuscript Accepted: 4 APR 2008
- Manuscript Revised: 26 MAR 2008
- Manuscript Received: 24 DEC 2007
- Institut National de la Santé et de la Recherche Médicale
- Assistance Publique-Hôpitaux de Paris
- Association Française contre les Myopathies (AFM)
- GIS-Institut des Maladies Rares
- European Union Fifth Framework (Euro-laminopathies contract). Grant Numbers: #018690, #RAS05018
- AFM rare disorder network program. Grant Number: 10722
- Muscular Dystrophy campaign
- NHMRC. Grant Number: 372104
- Muscular Dystrophy Association of New South Wales, Australia
To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations.
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.
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.
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.