Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene.
BACKGROUND
Autosomal dominant (AD) central core disease (CCD) is a congenital myopathy characterised by the presence of cores in the muscle fibres which correspond to broad areas of myofibrils disorganisation, Z-line streaming and lack of mitochondria. Heterozygous mutations in the RYR1 gene were observed in the large majority of AD-CCD families; however, this gene was excluded in some of AD-CCD families.


OBJECTIVE
To enlarge the genetic spectrum of AD-CCD demonstrating mutations in an additional gene.


METHODS
Four affected AD family members over three generations, three of whom were alive and participate in the study: the mother and two of three siblings. The symptoms began during the early childhood with mild delayed motor development. Later they developed mainly tibialis anterior weakness, hypertrophy of calves and significant weakness (amyotrophic) of quadriceps. No cardiac or ocular involvement was noted.


RESULTS
The muscle biopsies sections showed a particular pattern: eccentric cores in type 1 fibres, associated with type 1 predominance. Most cores have abrupt borders. Electron microscopy confirmed the presence of both unstructured and structured cores. Exome sequencing analysis identified a novel heterozygous missense mutation p.Leu1723Pro in MYH7 segregating with the disease and affecting a conserved residue in the myosin tail domain.


CONCLUSIONS
We describe MYH7 as an additional causative gene for AD-CCD. These findings have important implications for diagnosis and future investigations of AD-congenital myopathies with cores, without cardiomyopathy, but presenting a particular involvement of distal and quadriceps muscles.
Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France Inserm, U974, Paris, France University Pierre et Marie Curie- Paris 6, UM 76, CNRS, UMR 7215, Myology Institute, IFR14, Paris, France Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Norma B
NB
Romero
Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France Inserm, U964, Illkirch, France CNRS, UMR7104, Illkirch, France Université de Strasbourg, Illkirch, France Collège de France, chaire de génétique humaine, Illkirch, France.
Ting
T
Xie
Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France Inserm, U974, Paris, France University Pierre et Marie Curie- Paris 6, UM 76, CNRS, UMR 7215, Myology Institute, IFR14, Paris, France Centre de référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France Department of Neurological, Neurosurgical, and Behavioral Sciences, University of Siena, Siena, Italy.
Edoardo
E
Malfatti
Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France Inserm, U964, Illkirch, France CNRS, UMR7104, Illkirch, France Université de Strasbourg, Illkirch, France Collège de France, chaire de génétique humaine, Illkirch, France.
Ursula
U
Schaeffer
Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France Inserm, U964, Illkirch, France CNRS, UMR7104, Illkirch, France Université de Strasbourg, Illkirch, France Collège de France, chaire de génétique humaine, Illkirch, France.
Johann
J
Böhm
BGI-Shenzhen, Shenzhen, China.
Bin
B
Wu
BGI-Shenzhen, Shenzhen, China.
Fengping
F
Xu
Service de Neurologie and Pôle Imagerie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
Samy
S
Boucebci
Service de Neurologie and Pôle Imagerie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
Stéphane
S
Mathis
Service de Neurologie and Pôle Imagerie, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.
Jean-Philippe
JP
Neau
Laboraroire de Biochimie et Génétique moléculaire, IBP, CHU Grenoble, Grenoble, France.
Nicole
N
Monnier
Neuromuscular Morphology Unit, Myology Institute, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France University Pierre et Marie Curie- Paris 6, UM 76, CNRS, UMR 7215, Myology Institute, IFR14, Paris, France.
Michel
M
Fardeau
Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France Inserm, U964, Illkirch, France CNRS, UMR7104, Illkirch, France Université de Strasbourg, Illkirch, France Collège de France, chaire de génétique humaine, Illkirch, France.
Jocelyn
J
Laporte
D000328:Adult; D000368:Aged; D024722:Cardiac Myosins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D018657:Muscle Fibers, Slow-Twitch / Q000000981:diagnostic imaging / Q000473:pathology / Q000648:ultrastructure; D020125:Mutation, Missense / Q000235:genetics*; D020512:Myopathy, Central Core / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics*; D010375:Pedigree; D011859:Radiography
C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains
MUSCLE DISEASE; MYOPATHY; NEUROPATHOLOGY, MUSCLE