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 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.


CONCLUSIONS
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).
Quijano-Roy
Susana
S
Assistance Publique-Hôpitaux de Paris, Service de Pédiatrie, Hôpital Universitaire Raymond Poincaré, Centre National de Référence des Maladies Neuromusculaires Garches-Necker-Mondor-Hendaye, Garches, France. susana.quijano-roy@rpc.aphp.fr
Mbieleu
Blaise
B
Bönnemann
Carsten G
CG
Jeannet
Pierre-Yves
PY
Colomer
Jaume
J
Clarke
Nigel F
NF
Cuisset
Jean-Marie
JM
Roper
Helen
H
De Meirleir
Linda
L
D'Amico
Adele
A
Ben Yaou
Rabah
R
Nascimento
Andrés
A
Barois
Annie
A
Demay
Laurence
L
Bertini
Enrico
E
Ferreiro
Ana
A
Sewry
Caroline A
CA
Romero
Norma B
NB
Ryan
Monique
M
Muntoni
Francesco
F
Guicheney
Pascale
P
Richard
Pascale
P
Bonne
Gisèle
G
Estournet
Brigitte
B
D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics* / Q000473:pathology*; D009154:Mutation / Q000235:genetics*
D005819:Genetic Markers; C494847:LMNA protein, human; D034904:Lamin Type A