Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy

Abstract

Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient's disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246His homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies.

Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype

“…Previous ultrastructural studies have shown small cytoplasmic inclusions consisting of 15 and 20 nm tubulofilaments, Z-band streaming [1,3,19], disarrangement of sarcoplasmic myofilaments [13,27], and nuclear filamentous inclusions [30]. Similarly to other MYH2-myopathy cases, which have shown selective reduction in the number and size of type 2A muscle fibers [2,5,13,28], occasionally even leading to the lack of type 2A fibers [26], our patient showed paucity and atrophy of type 2A fibers, and severe reduction in MyHC-IIA expression. The coexistent nonspecific chronic myopathic changes, also present in our patient's muscle biopsy, are not novel, except for the ring fibers.…”

“…Pathogenic MYH2 variants have tended to cluster either within key functional domains in the motor head, or in the coiled-coil tail region as truncations [ 5 ]. Here we describe an additional two MYH2 variants within the catalytic head and tail domains, being only the second report [ 30 ] of variants spanning both regions simultaneously.…”

“…Pathogenic autosomal recessive MYH2 variants have been shown to occur in other critical globular head domains (Table 1 ), including the SH1 helix domain [ 3 , 14 , 15 , 29 ], ATP binding Switch I [ 5 , 26 ], the ATP binding P-Loop domain [ 26 ], the IQ calmodulin binding motif for myosin light chain interactions [ 13 , 26 , 30 , 31 ], and the IQ motif with the actin binding domain [ 27 ]. Several recessive splice site changes produce exon skipping mutations in intervening sequences that scaffold the steric positioning of domains involving the actin binding site [ 27 , 36 ].…”

“…Far fewer mutations (Table 1 ), inherited as autosomal dominant or recessive traits, have been reported in the MYH 2 gene, encoding the MyHC-IIA isoform of fast-twitch type 2A muscle fibers [ 3 , 5 , 14 , 15 , 25 , 29 , 36 ]. Regardless of the genotype and pattern of inheritance, MYH2 -myopathy often manifests also with ophthalmoparesis, as a likely consequence of the high proportion of type 2A muscle fibers within extraocular muscles [ 1 , 2 , 10 , 31 ].…”

Dominantly inherited myosin IIa myopathy caused by aberrant splicing of MYH2

“…The first patients with recessive myosin IIa myopathy carried compound heterozygous or homozygous truncating variants in MYH2 [2]. Several additional cases have later been reported carrying either truncating or missense variants [3][4][5][6][7][8][9][10]. All described individuals so far have had external ophthalmoplegia and most have had ptosis and facial muscle weakness, in addition to usually proximal muscle weakness.…”