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Multi-minicore disease with external ophthalmoplegia (MmD-EOM) is an autosomal recessive congenital myopathy defined by multifocal areas of reduced oxidative activity (“minicores”) in skeletal muscle fibers and impaired extraocular muscle function. Clinically, patients present in infancy with axial and proximal weakness, external ophthalmoplegia, scoliosis, respiratory compromise, and feeding difficulties. Histopathology reveals multiple short core lesions affecting both fiber types without nemaline rods. The RYR1 gene encodes the skeletal muscle ryanodine receptor, a Ca2+ release channel critical for excitation–contraction coupling and calcium homeostasis in muscle (RYR1).
Autosomal recessive inheritance of RYR1 variants in MmD-EOM was established through segregation analysis in five unrelated families encompassing 11 affected individuals (PMID:16380615). All patients harbored biallelic RYR1 variants that co-segregated with disease; carrier parents and unaffected siblings lacked two mutated alleles. Haplotyping and muscle biopsy assays confirmed functional haploinsufficiency of mutant alleles. No de novo or heterozygous-only cases were reported in this cohort.
Sequence analysis revealed four novel missense variants—c.325C>T (p.Arg109Trp), c.7268T>A (p.Met2423Lys), c.7522C>T (p.Arg2508Cys), c.10343C>T (p.Ser3448Phe)—and a canonical splice-site change c.14365-2A>T. Each variant affects highly conserved residues or splice regions and is absent from large population databases. These five alleles represent the full variant spectrum in MmD-EOM, with no evidence of recurrent or founder mutations. Biallelic involvement was required for phenotype expression, consistent with recessive inheritance.
Clinically, MmD-EOM patients exhibit early hypotonia evolving into nonprogressive weakness, ophthalmoplegia, scoliosis, moderate respiratory impairment, and feeding difficulties. Muscle MRI shows selective involvement of shoulder girdle muscles, while respiratory function testing often reveals reduced vital capacity. Histopathology consistently demonstrates multiple small core lesions without rod-like inclusions. Precise prevalence is unknown, but biallelic RYR1 variants are rare. No robust carrier frequency estimates have been published.
Mechanistic insights derive from a knock-in mouse model of the p.Gln1970fsX16 frameshift allele, where RyR1 protein content in fast and slow muscles was reduced to 38% and 58% of wild-type levels, respectively (PMID:30689883). Electron microscopy revealed a 36% loss of calcium release units and a 2.5-fold increase in dyads, indicating disrupted channel arrays. Mutant muscles displayed 20% lower specific force and 15% reduced depolarization-induced Ca2+ transients. Cav1.1 levels remained unchanged, but altered Cav1.1/RyR1 stoichiometry confirmed channel deficiency.
Collectively, genetic and experimental data support a loss-of-function mechanism in MmD-EOM, whereby RYR1 haploinsufficiency impairs Ca2+ release and excitation–contraction coupling. Disrupted channel clustering and altered Cav1.1/RyR1 ratios compromise calcium handling. Human muscle biopsies corroborate reduced RyR1 content and functional deficits, and iPSC models from affected individuals exhibit similar calcium signaling abnormalities. These concordant findings validate RYR1 haploinsufficiency as the pathogenic basis.
The definitive association of RYR1 with autosomal recessive MmD-EOM warrants inclusion of RYR1 in congenital myopathy diagnostic panels. Identification of biallelic variants enables accurate genetic counseling and anticipatory management of respiratory and orthopedic complications. Functional model data highlight potential therapeutic strategies aimed at restoring RyR1 expression or stabilizing channel function. Key take-home: RYR1 haploinsufficiency unequivocally causes multi-minicore disease with external ophthalmoplegia, offering direct clinical utility for diagnosis and future interventions.
Gene–Disease AssociationDefinitive11 probands across five families with recessive segregation and concordant functional model data Genetic EvidenceStrong11 probands in 5 families with recessive RYR1 missense and splice variants demonstrating segregation and reaching genetic evidence cap Functional EvidenceModerateKnock-in mouse model recapitulates human MmD-EOM features with RyR1 haploinsufficiency and functional Ca2+ handling deficits |