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Extreme Variability of Phenotype in Patients With an Identical Missense Mutation in the Lamin A/C Gene
From Congenital Onset With Severe Phenotype to Milder Classic Emery-Dreifuss Variant
Eugenio Mercuri, MD;
Maja Poppe, MD;
Ros Quinlivan, MD;
Sonia Messina, MD;
Maria Kinali, MD;
Laurence Demay;
John Bourke, MD;
Pascale Richard, MD;
Caroline Sewry, PhD;
Mike Pike, MD;
Gisèle Bonne, PhD;
Francesco Muntoni, MD;
Kate Bushby, MD
Arch Neurol. 2004;61:690-694.
Background Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, have been associated with 7 distinct pathologic conditions.
Objective To report 5 cases with the same missense mutation in exon 6 of the LMNA gene, resulting in an E358K substitution in the central rod domain.
Design Case report.
Setting Three muscle centers in England.
Patients Five patients with missense mutations of the LMNA gene.
Results All 5 individuals had muscle involvement, but the onset, severity, distribution of muscle weakness, and presence of associated features were highly variable. Three patients had humeroperoneal distribution of weakness and typical features of Emery-Dreifuss muscular dystrophy. Two other patients showed additional novel features. One had congenital onset and predominant axial weakness, with poor neck control and inability to sit independently at the age of 21 months. Another patient presented in childhood with an unusual pattern of muscle weakness, short stature, and midface hypoplasia with striking fat accumulation around the face and neck, in contrast to wasting of adipose tissue and muscle in the limbs. She developed both respiratory failure and cardiac arrhythmias in her late 20s.
Conclusion Our cases expand the clinical spectrum associated with mutations in the LMNA gene and further illustrate the overlapping phenotypes of the laminopathies.
From the Dubowitz Neuromuscular Centre, Hammersmith Hospital Imperial College, London, England (Drs Mercuri, Messina, Kinali, Sewry, and Muntoni); Institute of Human Genetics and Department of Cardiology, University of Newcastle Upon Tyne, Newcastle, England (Drs Poppe, Bourke, and Bushby); Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, England (Drs Quinlivan and Sewry); Cardiogénétique et Myogénétique, Service de Biochimie B, General Hospital Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France (Drs Demay and Richard); Department of Pediatrics, John Radcliffe Hospital, Oxford, England (Dr Pike); INSERM U582, Institut de Myologie, General Hospital Pitié-Salpétrière, Paris (Dr Bonne); Department of Child Neurology, Catholic University, Rome, Italy (Dr Mercuri); and Department of Neurosciences, Psychiatry and Anesthesiology, University of Messina, Messina, Italy (Dr Messina).
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