Inclusion Body Myopathy and Autosomal Recessive, Early Onset Myopathy via the MYH2 Gene

Inclusion body myopathy is a heterogeneous group of disorders characterized by muscle fibers with rimmed vacuoles and inclusions consisting of filaments with a diameter of 15 to 21 nm (Griggs et al. Ann Neurol 38:705-713, 1995). Dominantly inherited inclusion body myopathy (IMB3; OMIM 605637) was first described in a large Swedish family (Darin et al. Ann Neurol 44:242-248, 1998) and subsequently mutations in the myosin heavy chain IIa gene (MYH2; OMIM 160740) were shown to be causative (Martinsson et al. Proc Natl Acad SciUSA 97:14614-14619, 2000). IBM3 manifests itself as multiple congenital joint contractures, external opththalmoplegia, and weakness and atrophy of proximal muscles. Distribution of muscle weakness is similar to that of limb girdle and facioscapulohumeral muscular dystrophies (Martinsson et al. Am J Hum Genet 64:1420-1426, 1999). Contractures normalized during childhood in affected members of the Swedish family, and myopathy was mild in childhood and adolescence. Worsening muscle weakness along with elevated serum CpK levels were seen in affected individuals between 30 and 50 years of age. Muscle biopsies of affected children show mild changes including focal disorganization of myofilaments, variability in fiber size, and central placed nuclei. More significant pathology is seen in adult biopsies including dystrophic changes and rimmed vacuoles with cytoplasmic and nuclear inclusions containing filaments reminiscent of inclusion body myopathy (Tajsharghi et al. Neurol 58:780-786, 2002).

MYH2-related autosomal recessive early onset myopathy is a rare disorder caused by complete absence of skeletal muscle myosin heavy chain IIa protein (Tajsharghi et al. Brain 133:1451–1459, 2010).  This disorder has been described in only a small number of families (Tajsharghi et al., 2010). The key clinical features are pronounced ophthalmoplegia and generalized weakness.  Specific muscles affected by weakness include facial muscles, and neck and elbow flexors.  Age at onset was reported to be in early childhood, and intrafamilial variability in phenotypic expression is reported (Tajsharghi et al., 2010). In patients evaluated by EMG and muscle imaging, myopathic findings and moderate fatty degenerative changes in thigh and medial gastrocnemius muscles were observed (Tajsharghi et al., 2010). Muscle biopsies show internalized nuclei and fiber size variation. Serum CpK levels are normal.  The disease is non progressive.

Inclusion body myopathy due to MYH2 gene mutations (IBM3) is inherited as an autosomal dominant disorder. A similar disorder caused by GNE gene mutations and with autosomal recessive inheritance has also been reported (IBM2; OMIM 600737). 

Early onset myopathy due to MYH2 mutations is inherited as an autosomal recessive disorder.  MYH2-related autosomal recessive early onset myopathy results from null mutations of the MYH2 gene (Tajsharghi et al. Brain 133:1451–1459, 2010).

Inclusion Body Myopathy due to MYH2 mutations is a rare disorder; thus far a single family has been reported. At this time it is not possible to predict what portion of sporadic IBM is caused by MYH2 gene mutations. Autosomal recessive early onset myopathy due to MYH2 mutations is a rare disorder; thus far three families have been reported. Clinical sensitivity cannot be accurately predicted.

Thus far, no gross deletions or duplications have been reported in MYH2 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the MYH2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).