Unveiling MYH2-related myopathy: Histological-genetic insights from a case series and systematic review

We report 13 unrelated patients and a systematic review of published cases through 30 October 2024, supplemented by HGMD Pro (2024.2) and LOVD (https://www.lovd.nl/) databases. In the case series, most patients (n = 11/13, 84.6%) exhibited clinical symptoms from early childhood to middle adulthood. The mean age of onset was 22.8 years (vs 7.73 years in literature review), likely because of absence of birth contractures, described in early reports. External ophthalmoparesis, though not a defining feature, should raise suspicion of MYH2-related myopathy in patients with a CPEO-like presentation and limb-girdle weakness. Notably, two patients presented with postural tremor of the upper limbs as their first symptom. Although rimmed vacuoles were a characteristic feature in initial reports of MYH2-related myopathy, they were absent in our case series. The most informative stain was ATPase, detecting the lack or reduction of type 2A fibres. Electron microscopy revealed additional features, such as the presence of cores associated with rods in one patient and pathological subsarcolemmal mitochondrial accumulations in 2 patients. Fifteen novel variants were identified amongst the 13 patients of this study, expanding the current genetic landscape for MYH2-related muscle diseases. The phenotypic and histological diversity observed can not be fully accounted for by genetic factors alone, suggesting the presence of additional contributing factors. This wide variability may lead to under-recognition of this disease, thus the importance of clinicians' awareness on the topic.