Myopathy, Myofibrillar, 7

A number sign (#) is used with this entry because of evidence that myofibrillar myopathy-7 (MFM7) is caused by homozygous mutation in the KY gene (605739) on chromosome 3q22.

Description

Myofibrillar myopathy-7 is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness primary affecting the lower limbs and associated with joint contractures (summary by Straussberg et al., 2016).

For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

Clinical Features

Straussberg et al. (2016) reported 2 adult brothers, born of consanguineous Israeli Arab parents, with onset of a slowly progressive myopathy from infancy. The lower limbs were primarily affected with weakness and muscle atrophy; upper limb involvement became apparent later, and both patients had atrophy of the lateral tongue margins. Other features included congenital bilateral equinovarus foot deformity, Achilles tendon contractures, elbow contractures, mild facial weakness, and kyphosis with rigid spine. The younger brother had intellectual disability and behavioral disorders, whereas the older brother had normal cognitive and speech development. Muscle biopsy showed myopathic changes with fiber-size variation, rounded, atrophied, and necrotic fibers, internalized nuclei, and occasional myophagocytosis. Electron microscopy showed unstructured core targetoid defects with streaming and thickening of the Z discs, as well as an enlarged endoplasmic reticulum, consistent with myofibrillar derangement.

Hedberg-Oldfors et al. (2016) reported a 7.5-year-old girl, born of consanguineous Kurdish parents, with MFM7. After normal early psychomotor development, she presented around 3 years of age with walking difficulties due to muscle weakness and atrophy of the lower limbs and progressive equinus contractures of the feet. Achilles tendon elongation surgery at age 6.5 years resulted in improvement in her walking abilities; there was no progression of symptoms from 6.5 to 7.5 years of age. She was not able to walk on her heels, but could walk on her toes and run. She also had slightly increased lumbar lordosis, weak reflexes, and limited movement of the shoulders, elbows, hips, and ankles. Muscle imaging showed muscle atrophy and fatty replacement of the posterior calf muscles. Muscle biopsy showed increased variability of fiber size affecting type 1 and type 2 fibers, internalized nuclei, and small fibers. There was variable myofibrillar ATPase activity, and electron microscopy showed abnormal sarcomeres with Z-line thickening and formation of small nemaline rods. Cognitive function, fine motor skills, and respiratory and heart function were all normal.

Inheritance

The transmission pattern of MFM7 in the family reported by Straussberg et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 brothers, born of consanguineous Arab Israeli parents, with MFM7, Straussberg et al. (2016) identified a homozygous truncating mutation in the KY gene (Y135X; 605739.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Immunostaining showed absence of the KY protein in patient muscle, consistent with a loss of function.

In a 7.5-year-old girl, born of consanguineous Kurdish parents, with MFM7, Hedberg-Oldfors et al. (2016) identified a homozygous frameshift mutation in the KY gene (605739.0002). The mutation was found by whole-exome sequencing and segregated with the disorder in the family.

Animal Model

The kyphoscoliosis (ky) mouse mutant exhibits a primary degenerative myopathy preceding chronic thoracolumbar kyphoscoliosis. The histopathology of the ky mutant suggests that ky protein activity is crucial for normal muscle growth and function as well as the maturation and stabilization of the neuromuscular junction. Muscle hypertrophy in response to increasing demand is deficient in the ky mutant, whereas adaptive fiber type shifts take place (Blanco et al., 2001).