Novel mutations widen the phenotypic spectrum of slow skeletal/β-cardiac myosin (MYH7) distal myopathy

Abstract

Laing early onset distal myopathy and myosin storage myopathy are caused by mutations of slow skeletal/β-cardiac myosin heavy chain encoded by the gene MYH7, as is a common form of familial hypertrophic/dilated cardiomyopathy. The mechanisms by which different phenotypes are produced by mutations in MYH7, even in the same region of the gene, are not known. To explore the clinical spectrum and pathobiology, we screened the MYH7 gene in 88 patients from 21 previously unpublished families presenting with distal or generalized skeletal muscle weakness, with or without cardiac involvement. Twelve novel mutations have been identified in thirteen families. In one of these families, the father of the proband was found to be a mosaic for the MYH7 mutation. In eight cases, de novo mutation appeared to have occurred, which was proven in four. The presenting complaint was footdrop, sometimes leading to delayed walking or tripping, in members of 17 families (81%), with other presentations including cardiomyopathy in infancy, generalized floppiness, and scoliosis. Cardiac involvement as well as skeletal muscle weakness was identified in nine of 21 families. Spinal involvement such as scoliosis or rigidity was identified in 12 (57%). This report widens the clinical and pathological phenotypes, and the genetics of MYH7 mutations leading to skeletal muscle diseases.

Keywords: Laing distal myopathy; MPD1; MYH7.

Figure 1

Weakness of the long finger extensors without involvement of the thenar eminence is typical of MPD1, but may not occur until years after the weakness of the ankle and toe dorsiflexors has occurred. Rarely finger extension weakness does not develop at all. 1a – 17 year old female 1b – 65 year old man 1c – 28 year old man

Figure 2. Myosin immunohistochemistry with double staining method

2a - Biopsy from a Finnish patient with the p.Glu1508del mutation shows the earlier stages of pathology: practically all type 1 fibres (brown) are small as is seen in Congenital Fibre Type Disproportion. Almost all fast IIa (red) fibres are normal-sized and there are no light blue IIx fast fibres in this tibialis anterior biopsy. 2b - Biopsy from a Finnish patient with the p.Lys1617del mutation illustrates more advanced pathology with extensive fibrosis and fat and almost SMA-like large group atrophies. All type1 fibres (brown) have variable degrees of reddish indicating hybrid fibres (arrows) expressing also fast IIa myosin (red). There are also atrophic fast type IIa and IIx (light blue) fibres which do not express slow myosin at all.

Figure 3

A schematic of the MYH7 gene, indicating the position of gene mutations causing hypertrophic or dilated cardiomyopathy, myosin storage myopathy or Laing distal myopathy, as well as mutations described in this review.