Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene

Abstract

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.

Patients and 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.

Keywords: MUSCLE DISEASE; MYOPATHY; NEUROPATHOLOGY, MUSCLE.

Figure 1

Characterisation of the autosomal dominant (AD)-eccentric core disease patients with MYH7 mutation. (A) Pedigree of the family and segregation of the MYH7 heterozygous mutation (Het) in the affected individuals. (B) Chromatopherograms from the Sanger sequencing showing the c.5168T>C mutation. (C) MYH7 protein domains (myosin motor domain or globular head; IQ, calmodulin binding domain; myosin tail or rod domain; not to scale) and reported mutations in the tail domain linked to cardiomyopathy (blue), myosin storage disease (black) or Laing myopathy or related myopathies (green). Mutations in the motor domain that are all linked to cardiomyopathy are not displayed. The p.L1723P AD-central core disease mutation described in this study is in red. (D) Muscle biopsies findings: The patient is indicated in the upper right corner and the histoenzymological techniques in the bottom left corner. Cryostat sections with oxidative enzyme reactions demonstrated the presence of eccentric cores, with well-delimited borders, in type I muscle fibres (red arrows). Type I fibres size are slightly smaller than type II (white stars). Electron micrograph from patient P.III-2 shows widespread subsarcolemmal unstructured cores with compaction of myofibrils, sarcomeric disorganisation, Z-band streaming and lack of mitochondria.

Figure 2

Muscle MRI from P.II.2 performed at 70 years old showed a severe and selective involvement of the muscles of the anterior compartment of the thigh mainly in quadriceps (A) and anterior compartment of the legs predominantly in tibial anterior (B). Muscle MRI from P.III.3 performed at 36 years old showed a selective mild involvement of the anterior compartment of the legs mainly tibial anterior (D). Very mild abnormalities of the thigh were also noted (C).