A novel mutation expands the genetic and clinical spectrum of MYH7-related myopathies

Abstract

MYH7 mutations are an established cause of Laing distal myopathy, myosin storage myopathy, and cardiomyopathy, as well as additional myopathy subtypes. We report a novel MYH7 mutation (p.Leu1597Arg) that arose de novo in two unrelated probands. Proband 1 has a myopathy characterized by distal weakness and prominent contractures and histopathology typical of multi-minicore disease. Proband 2 has an axial myopathy and histopathology consistent with congenital fiber type disproportion. These cases highlight the broad spectrum of clinical and histological patterns associated with MYH7 mutations, and provide further evidence that MYH7 is likely responsible for a greater proportion of congenital myopathies than currently appreciated.

Fig. 1

Clinical and MRI features of Case 1. (A) Prayer sign, illustrating long finger flexor contractures. (B) Muscle MRI of the thigh (top panel) reveals involvement of many muscles including sartorius, quadriceps, and adductors, with relative sparing of biceps femoris. Muscle MRI of the distal lower extremity shows fatty infiltration in the soleus and lateral gastrocnemius with relative sparing of the medial gastrocnemius.

Fig. 2

Muscle biopsy features of Case 1. (A) Hematoxylin and eosin staining showing increased internalized nuclei, variation in fiber size, and focal fatty replacement. (B) ATPase pH 4.2 staining showing type 1 predominance. (C–D) SDH (C), and COX (D) staining show central clearing and absence of staining suggestive of core-like areas. (E–F) Electron micrographs reveal myofibrillar disarray of the sarcomeres with exclusion of mitochondria, ranging from only 4 microns to more than 20 microns in diameter, consistent with the presence of minicores.

Fig. 3

Muscle biopsy and muscle MRI images from Case 2. Haematoxylin & eosin stain shows marked fiber size variability with occasional internalized nuclei (A), ATPase (pH 4.2) stain shows typical features of congenital fiber type disproportion (B). Mean diameter of type 1 fibers (dark) was 24.0 μm (normal ~50 μm) and of type 2 fibers (pale) was 83.3 μm (normal ~50 μm). NADH stain shows an absence of cores (C). Muscle MRI shows marked selective fatty infiltration (arrows) of the spinalis muscles of the upper thoracic (H) and cervical (I) spine with only minor fatty marbling of other muscles of the spine in lumbar (F) and lower thoracic (G) regions, pelvis (D) and thighs (E).