Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report

Abstract

Background: Defects of the slow myosin heavy chain isoform coding MYH7 gene primarily cause skeletal myopathies including Laing Distal Myopathy, Myosin Storage Myopathy and are also responsible for cardiomyopathies. Scapuloperoneal and limb-girdle muscle weakness, congenital fiber type disproportion, multi-minicore disease were also reported in connection of MYH7. Pathogeneses of the defects in the head and proximal rod region of the protein are well described. However, the C-terminal mutations of the MYH7 gene are less known. Moreover, only two articles describe the phenotypic impact of the elongated mature protein product caused by termination signal loss.

Case presentation: Here we present a male patient with an unusual phenotypic variant of early-onset and predominant involvement of neck muscles with muscle biopsy indicating myopathy and sarcoplasmic storage material. Cardiomyopathic involvements could not be observed. Sequencing of MYH7 gene revealed a stop-loss mutation on the 3-prime end of the rod region, which causes the elongation of the mature protein.

Conclusions: The elongated protein likely disrupts the functions of the sarcomere by multiple functional abnormalities. This elongation could also affect the thick filament degradation leading to protein deposition and accumulation in the sarcomere, resulting in the severe myopathy of certain axial muscles. The phenotypic expression of the detected novel MYH7 genotype could strengthen and further expand our knowledge about mutations affecting the structure of MyHCI by termination signal loss in the MYH7 gene.

Keywords: Axial muscle atrophy; Case report; MYH7; Myosin storage myopathy; Stop loss mutation.

Fig. 1

Relevant history of the patient organized into a timeline

Fig. 2

Axial MRI of the thigh (a) and the calf (b). a. T1 fatsat image shows fatty degeneration of muscles in the posterior compartment (dark, arrow). b. T1 image shows degeneration of anterior tibial muscles (arrow) and fatty infiltration of medial gastrocnemius muscles

Fig. 3

Muscle biopsy results. Myopathic changes: increased fiber-size variation, internal nuclei, endomysial fibrosis (a). Subsarcolemmal storage material staining bright on HE (a) and with modified Gomori (b), dark on NADH (c). The storage material beneath the sarcolemma is clearly visible on the electron microscopic (EM) image (d). An atrophic fiber is almost completely filled with granular storage material (e). Structural alterations of fibers: dysorganized sarcomers and abnormal electrondense bodies (f), „core-like” appearance of fibers with NADH (c) and core structures on EM (g). Original magnifications: A: 80×, B: 160×, C: 80×, D: 10.000×, E: 7.500×, F: 20.000×, G: 15.000×

Fig. 4

Electropherogram of the involved sequence fragment of MYH7. The result of forward sequencing (a). The result of reverse sequencing (b). The detected mutation and the two variations c.5805G > A, c.5807A > T and c.5808 + 1C > A are highlighted with rectangles in the nucleotide sequence and corresponding peaks are also underlined