Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene

Background: Minicore myopathy (multi-minicore disease [MmD]) is a congenital myopathy characterized by multifocal areas with loss of oxidative activity on muscle biopsy. MmD is clinically heterogeneous and distinct phenotypes have been associated with recessive mutations in either the selenoprotein N ( SEPN1) or the skeletal muscle ryanodine receptor (RYR1) gene, also implicated in central core disease and malignant hyperthermia. External ophthalmoplegia is an additional finding in a subset of patients with MmD. Objective: To clinically and genetically examine families with MmD and external ophthalmoplegia. Methods: The authors investigated 11 affected individuals from 5 unrelated families. Clinical, histopathologic, and imaging studies were performed and RYR1 haplotyping and mutational analysis were carried out. Results: All patients had multiple cores involving the entire fiber diameter on longitudinal sections. Weakness and wasting in the shoulder girdle, scoliosis, moderate respiratory impairment, and feeding difficulties were prominent. In contrast to SEPN1-related myopathies, soleus was more severely affected than gastrocnemius on muscle MRI. Haplotyping suggested linkage to the RYR1 locus in informative families and mutational screening revealed four novel RYR1 mutations in three unrelated families; in addition, functional haploinsufficiency was found in one allele of two recessive cases. Conclusion: These findings expand the phenotypic spectrum associated with mutations in the skeletal muscle ryanodine receptor ( RYR1) gene. Recessive mutations of domains commonly affected in malignant hyperthermia appear to be particularly prevalent in multi-minicore disease with external ophthalmoplegia and might suggest a different patho-mechanism from that involved in central core disease.