Myopathy, Centronuclear, 6, With Fiber-Type Disproportion

A number sign (#) is used with this entry because of evidence that centronuclear myopathy-6 with fiber-type disproportion (CNM6) is caused by homozygous mutation in the ZAK gene (609479) on chromosome 2q31.

Description

CNM6 is an autosomal recessive, slowly progressive congenital myopathy with onset in infancy or early childhood. Patients may be hypotonic at birth, but all show delayed motor development and walking difficulties due to muscle weakness mainly affecting the proximal lower and upper limbs. Other features include scapular winging, scoliosis, and mildly decreased respiratory vital capacity. The phenotype and muscle biopsy abnormalities are variable, although centralized nuclei and fiber-type disproportion appear to be a common finding on muscle biopsy.

For a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).

Clinical Features

Vasli et al. (2017) reported 6 patients from 3 unrelated consanguineous families with a slowly progressive congenital myopathy. Five of the patients were noted to be adults at the time of the report (age range, 26-37 years). One patient, a 27-year-old French man, presented at age 28 months with proximal weakness of the upper limbs and proximal and distal weakness in the lower limbs. He had winged scapulas, hyperlordosis, and increased fatigue. He could walk but was unable to run. EMG showed a myopathic pattern with decremental response to repetitive nerve stimulation; he showed a favorable therapeutic response to treatment with an anticholinesterase inhibitor. In another family, 2 French Canadian sisters were hypotonic with contractures at birth and showed motor delay with slowly progressive muscle weakness. One became wheelchair-bound after a car accident in her early thirties and subsequently died, whereas the other was still ambulant at age 33. This family had previously been reported by Tetreault et al. (2006) as family I. Both patients had joint hyperlaxity, which was also observed in unaffected family members. The third family, of Pakistani descent, contained 3 affected sibs who had hypotonia at birth followed by delayed walking, lower limb muscle weakness, and mild proximal upper limp weakness. They walked with a waddling gait, had scapular winging, scoliosis, and calf hypertrophy. They did not have contractures. All patients studied had mildly decreased respiratory vital capacity (decreased to 63-86%). None of the patients had facial weakness, swallowing difficulties, or cardiac involvement. Muscle biopsy, performed in 4 patients, tended to show increased fiber size variation, type 1 fiber predominance, rounded fibers, centralized nuclei, and rimmed vacuoles. Some patients had abnormal subsarcolemmal accumulation of mitochondria and sarcolemmal disorganization. Serum creatine kinase was normal or mildly increased.

Inheritance

The transmission pattern of CNM6 in the families reported by Vasli et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 patients from 3 unrelated consanguineous families with CNM6, Vasli et al. (2017) identified 3 different homozygous truncating mutations in the ZAK gene (609479.0003-609479.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. All mutations occurred in the N-terminal kinase domain, and analysis of patient cells showed that they resulted in nonsense-mediated mRNA decay, consistent with a loss of function. Muscle tissue from 1 of the patients showed differential expression of multiple genes, including upregulation of those involved in cell adhesion, extracellular matrix, glycosaminoglycan/carbohydrate binding, and muscle development, as well as downregulation of sarcomeric genes and those involved in gluconeogenesis.

History

Tetreault et al. (2006) linked the phenotype in 2 sisters of French Canadian descent (cases 11 and 12, family I in their report) to chromosome 3p23-p21 (combined with an unrelated family of French Canadian origin with a similar disorder yielded a multipoint lod score of 2.5). These sisters, who were later reported as family 2 in Vasli et al. (2017), had a mutation in the ZAK gene on chromosome 2q31, indicating that the original linkage analysis was incorrect.