A new MYH2 variant in an Italian patient expanding the clinical spectrum of MYH2-related myopathy

Abstract Background Myosin heavy chain (MyHC)-related congenital myopathies display variable age of onset and clinical manifestations depending on the mutated isoform. Cardiomyopathy, ophthalmoplegia and primarily proximal weakness may be part of the clinical picture. Case presentation A 57-year-old male patient with a history of arterial hypertension and hyperferritinemia (thalassemic trait) began to experience lower limb proximal weakness at the age of 23 years and he got progressively worse over the years when he also reported mild dyspnea, easy fatigability, fasciculations and a sort of discomfort in the posterior muscles of both thighs even at rest. He had no diplopia or dysphagia. Peculiar clinical features were bilateral exophthalmos, slight eyelid ptosis, limited ocular motility in all gaze directions, marked lower limb proximal weakness with posteromedial thigh hypotrophy and hypertrophic calves with increased consistency. Severe signs of both myopathic and neurogenic degeneration were seen at quadriceps skeletal muscle biopsy. Serum CK values were slightly elevated (less than 300 U/L). His parents are second-degree cousins and have normal serum CK levels, a proband’s first cousin had a diagnosis of muscular dystrophy and died at the age of 60 years, wheelchair bound. A 46-year-old sister is healthy. EMG showed signs of reinnervation in all muscles, myopathic signs being evident in the gastrocnemius muscles. Clear signs of fibro-adipose degeneration were observed at muscle MRI, more evidently so in the semitendinosus, rectus femoris, sartorius, gracilis and gastrocnemius muscles. Conclusions Genetic analysis revealed the new homozygous variant c.3901G > T in exon 29 of MYH2 gene (NM_017534), predicted to introduce the premature stop codon p.(Glu1301*), thus leading to a diagnosis of MYH2-related myopathy. This variant shows a clear genotype-phenotype correlation, as it leads to a near-complete loss of MyHC IIa expression and results in a recessive myopathy characterized by adult-onset progressive muscle weakness with ophthalmoplegia and myopathic changes consistent with biallelic truncating mutations.