Nemaline Myopathy 11, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that nemaline myopathy-11 (NEM11) is caused by homozygous or compound heterozygous mutation in the MYPN gene (608517) on chromosome 10q21.

Description

NEM11 is an autosomal recessive congenital myopathy characterized by onset of slowly progressive muscle weakness in the first decade. Affected individuals present with gait difficulties due to proximal muscle weakness and atrophy mainly affecting the lower limbs and neck. Muscle biopsy shows nemaline bodies. Some patients may have mild cardiac or respiratory involvement, but they do not have respiratory failure (summary by Miyatake et al., 2017).

For a discussion of genetic heterogeneity of nemaline myopathy, see NEM3 (161800).

Clinical Features

Miyatake et al. (2017) reported 4 unrelated adult Japanese patients with a slowly progressive myopathy beginning in childhood. The first identified patient, born of consanguineous parents, had poor head control in infancy and showed proximal muscle weakness affecting the upper and lower limbs in childhood, resulting in poor athletic performance. The disorder progressed during her twenties and thirties, and she became wheelchair-bound at age 39. At age 40, she could not sit independently. Her vital capacity was decreased (about 40%), but she did not have respiratory failure. Additional features included narrow myopathic face, high-arched palate, pectus excavatum, and cardiac hypertrophy, which was diagnosed at age 12. She had generalized muscle weakness and atrophy with fatty replacement of muscles on imaging. She had a similarly affected sister, who was not available for study. The 3 other probands were identified from a cohort of 54 patients with nemaline myopathy. These 3 patients had onset of gait difficulties in the first decade, followed by slowly progressive muscle weakness mainly affecting the lower limbs and neck muscles. Two had facial muscle involvement, but none had ophthalmoplegia. One patient had diffuse cardiac hypokinesia with first-degree atrioventricular block and respiratory insufficiency. None had dysphagia and all had normal intelligence. Histologic examination of biopsied muscles from all 4 patients showed similar characteristics: mild to moderate variation in myofiber size, type 1 fiber predominance, and nemaline bodies with a granular shape. Electron microscopy confirmed the presence of cytoplasmic nemaline bodies; biopsies from 2 patients showed intranuclear nemaline bodies.

Inheritance

Miyatake et al. (2017) reported families with autosomal recessive transmission of NEM11.

Molecular Genetics

In a Japanese woman with NEM11, Miyatake et al. (2017) identified a homozygous truncating mutation in the MYPN gene (608517.0007). The mutation was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. Whole-exome sequencing of 54 families with nemaline myopathy identified 3 further probands (5.6%) with biallelic loss-of-function MYPN mutations (608517.0008-608517.0011). Immunostaining and Western blot analysis of patient muscle samples or myotubes showed undetectable MYPN protein, consistent with a loss of function. Patient muscle samples showed normal nebulin (NEB; 161650) and alpha-actinin (see 102573) localization, normal actin filament length, and absence of disorganized myofibrils.

Animal Model

Miyatake et al. (2017) found that mice homozygous for a nonsense mutation in the Mypn gene (Q526X, equivalent to human Q529X; 608517.0005) had no detectable Mypn protein in skeletal muscle. Skeletal muscle from homozygous mutant mice showed no apparent abnormalities on hematoxylin and eosin and modified Gomori staining. However, electron microscopic analysis showed mild Z-line streaming and small nemaline-like bodies, suggesting mild nemaline myopathy. Notably, homozygous mutant mice did not show muscle weakness.