Myopathy, Proximal, And Ophthalmoplegia

A number sign (#) is used with this entry because of evidence that proximal myopathy and ophthalmoplegia (MYPOP) is caused by heterozygous, compound heterozygous, or homozygous mutation in the gene encoding myosin heavy chain IIa (MYHC2A, or MYH2; 160740) on chromosome 17p13.

Description

Proximal myopathy and ophthalmoplegia is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. MYPOP can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (summary by Lossos et al., 2005 and Tajsharghi et al., 2014).

Clinical Features

Autosomal Dominant Inheritance

Darin et al. (1998) described a multigeneration Swedish family with an apparently novel myopathy inherited as an autosomal dominant. The characteristic clinical features were congenital joint contractures, which normalized during early childhood, external ophthalmoplegia, and proximal muscle weakness. Muscle atrophy was most prominent in pectoralis and quadriceps muscles. The clinical course was nonprogressive in childhood, but most adults experienced deterioration of muscle function, starting from 30 to 50 years of age. The major histopathologic change in skeletal muscle in childhood was focal disorganization of myofilaments. In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments. These findings suggested that this myopathy should be classified as a variant of hereditary IBM.

D'Amico et al. (2013) reported a 12-year-old Italian girl with a congenital myopathy associated with external ophthalmoplegia. She presented soon after birth with severe respiratory distress necessitating ventilation, hypotonia, and myopathic facies with ptosis, ophthalmoplegia, and inability to swallow. She did not have joint contractures, and learned to walk at age 2 years; the swallowing problems resolved. At age 12 years, she had a myopathic face with ophthalmoplegia, arched palate, waddling/steppage gait, and mild scoliosis. The disorder was considered to be nonprogressive. Muscle biopsy showed rare and hypotrophic type 2 fibers and a predominance of type 1 fibers; inclusions were not noted.

Autosomal Recessive Inheritance

Lossos et al. (2005) reported 16 patients from 8 Arab families originating from the same consanguineous community with early-onset myopathy associated with external ophthalmoplegia. All patients reported normal early psychomotor development with vague onset of symptoms in childhood or as young adults. Features included limited eye movements, eye closure weakness without ptosis, and mild proximal limb-girdle muscle weakness also affecting the facial and neck flexor muscles. Most patients preferred not to engage in strenuous physical activity. Extraocular movements showed variable range limitation in the horizontal and vertical planes, always greatest in the upgaze. The disorder was slowly progressive, as older individuals were more affected. The patients had myopathic facies, nasal voice, and high-arched palate. Other more variable features included scapular winging, scoliosis, and intrinsic hand muscle weakness. Muscle biopsy mainly showed type 1 fiber predominance; some biopsies showed mild variation in fiber size, as well as increased internal nuclei, and core-like loss of oxidative enzyme activity in some patients. Necrosis, rimmed vacuoles, and ragged-red fibers were not observed; inclusions were not mentioned.

Tajsharghi et al. (2010) reported 5 patients from 3 unrelated families with autosomal recessive MYPOP. The patients had early onset of mild generalized muscle weakness, including facial weakness, and external ophthalmoplegia. There was little or no progression of symptoms, and the overall course was benign. Muscle biopsy from 1 patient in each family showed myopathic changes including variability of fiber size, internal nuclei, and increased connective and adipose tissue; inclusions were not noted in any of the biopsies. Biopsies from 2 patients showed type 1 fiber uniformity. Imaging studies of 2 patients showed predominant involvement of the semitendinosus, gracilis, vastus lateralis, and medial gastrocnemius muscle in the lower limbs.

Tajsharghi et al. (2014) reported 7 patients from 5 families with autosomal recessive proximal myopathy and ophthalmoplegia. All patients except 1 were adults at the time of the report. Common features included very slowly progressive ophthalmoplegia, usually without ptosis; proximal muscle weakness affecting the limbs, arms, and neck; and mild distal muscle weakness. All patients had onset of symptoms in childhood, although some first presented as adults. All were ambulatory and some had participated in sports as youths. Skeletal muscle biopsies showed type 1 fiber uniformity, variation in fiber size, internal nuclei, and either small type 2A fibers or lack of immunostaining for myosin IIa. None of the parents of the patients were affected.

Inheritance

The transmission pattern of myopathy with congenital joint contractures in the family reported by Darin et al. (1998) was consistent with autosomal dominant inheritance.

The transmission pattern of MYPOP in the families reported by Lossos et al. (2005) and Tajsharghi et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

Martinsson et al. (1999) performed a genomewide scan in the kindred reported by Darin et al. (1998) and demonstrated linkage to markers on 17p. The positions of cytogenetically localized flanking markers identified by linkage studies indicated that the disease locus, IBM3, maps in the region 17p13.1. Radiation hybrid analysis showed that the IBM3 locus is located in a 2-Mb chromosomal region and that the myosin heavy chain gene cluster, which consists of at least 6 genes, colocalizes to that region.

By genomewide linkage analysis of 8 Arab families with congenital myopathy with ophthalmoplegia, Lossos et al. (2005) found significant linkage to a 12-cM region on chromosome 17p13.1-p12 between markers D17S1812 and D17S947 (maximum 2-point lod score of 3.74).

Molecular Genetics

Heterozygous Mutations

Martinsson et al. (2000) reported that morphologic analysis of muscle biopsies from the family reported by Darin et al. (1998) indicated that type 2A fibers were frequently abnormal, whereas other fiber types appeared normal. This observation prompted them to investigate the MYHC2A gene, since MYHC2A is the major isoform in type 2A fibers. The complete genomic sequence of the gene was deduced by using an 'in silico' strategy, and the gene was subjected to a complete mutation scan in patients and controls. Martinsson et al. (2000) identified a missense mutation, glu706 to lys (160740.0001), in the highly conserved region of the motor domain, the so-called SH1 helix region. By conformational changes this region communicates activity at the nucleotide-binding site to the neck region, resulting in the lever arm swing. The authors concluded that a mutation in this region is likely to result in a dysfunctional myosin, compatible with the disorder in the family.

In an Italian girl with nonprogressive congenital myopathy and ophthalmoplegia, D'Amico et al. (2013) identified a heterozygous de novo missense mutation in the MYH2 gene (L1870P; 160740.0002). Functional studies of the variant were not performed.

Compound Heterozygous and Homozygous Mutations

In 5 patients from 3 unrelated families with MYPOP, Tajsharghi et al. (2010) identified compound heterozygous truncating mutations in the MYH2 gene (160740.0003-160740.0006). Western blot analysis of patient skeletal muscle showed complete absence of fast type 2A muscle fibers. All parents were clinically unaffected, suggesting that hemizygous complete loss of MYH2 expression does not lead to disease. Tajsharghi et al. (2010) commented on the unusually mild phenotype considering the complete loss of MYH2.

In 16 patients from 8 Arab families (Lossos et al., 2005) and 6 additional patients from the same highly consanguineous community with autosomal recessive MYPOP, Lossos et al. (2013) identified a homozygous truncating mutation in the MYH2 gene (160740.0007). Skeletal muscle biopsies showed no MYH2 transcript or protein, consistent with a complete loss of function.

In 7 patients from 5 families with autosomal recessive MYPOP, Tajsharghi et al. (2014) identified homozygous or compound heterozygous mutations in the MYH2 gene (see, e.g., 160740.0008 and 160740.0009). Five patients from 3 families were homozygous for missense mutations, 1 was compound heterozygous for a missense and a truncating mutation, and 1 was homozygous for a truncating mutation. The phenotype was not significantly different among the patients. None of the parents of the patients were affected, although Tajsharghi et al. (2014) noted that the parents may have had subclinical findings on muscle biopsy. Functional studies of the variants were not performed, but Tajsharghi et al. (2014) noted that paralogous mutations in other MYH genes (e.g., MYH3, 160720 and MYH7, 160760) had been identified in patients with other muscular disorders.