Table 1.

Major subtypes of RyR1-related congenital myopathies.

	Causative Gene (S) *	Inheritance	Histological Features	Clinical Features
Central Core Disease (CCD)	RyR1 > 90% CACNA1S	AD or AR	✓Centrally located, well-demarcated cores, spanning the whole fiber axis Predominance in type 1 fibers Increased central nuclei [133]	✓Infantile non-progressive hypotonia and motor development delay Mild proximal muscle weakness Respiratory distress High arched palate Craniofacial dysmorphism
Multiminicore Disease (MMD)	RyR1 CACNA1S	AR	✓Numerous cores in a limited area on longitudinal section Multiple internally located nuclei Predominance in type 1 fibers [133,134,135,136]	✓Axial muscle weakness, scoliosis, respiratory insufficiency, and limb joint hyperlaxity Ophthalmoplegia Arthrogryposis Hand amyotrophy
Centronuclear Myopathy (CNM)	RyR1~12%	AR	✓Centralized and internalized nuclei Peripheral halos depleted of oxidative activity Cores [133,134,135,136]	✓Non-progressive proximal muscle weakness Non-progressive hypotonia
Congenital Fibre Type Disproportion (CFTD)	RyR1~20%	AR	✓Fiber size disproportion (35–40% of type 1 fibers are smaller in size than type 2 fibers) Age-related development of rods, cores, and central nuclei [133,134,135,136]	✓Static or slowly progressive muscle weakness Respiratory and proximal axial weakness Ophthalmoplegia Dysphagia Facial muscle weakness
Dusty Core Disease (DUCD)	RyR1	AR	✓Irregularly sized/shaped “Dusty” cores (reddish-purple granular material deposition) spanning 10 to 50 sarcomeres Myofibrillar disorganization [133,134,135,136]	✓Ocular involvement (eyelid ptosis, ophthalmoplegia)
Core Rod Myopathy (CRM)	RyR1	AD or AR	✓Nemaline bodies (rods), clustered or widely distributed along the fibers Central cores [133,134,135,136]	✓Non-specific clinical features, including: hypotonia, muscle weakness, scoliosis, and respiratory insufficiency
Malignant Hyperthermia (MH)	RyR1 CACNA1S STAC3	AD	✓No histological features can be found in muscle fibers from MH patients [119]	✓Uncontrolled contractures and muscle rigidity Hyperthermia Hyperkalemia Hypermetabolism Cardiac arrhythmia

* Mutations in additional genes are known to be causative for the listed congenital myopathies. See Refs. [119,133,134,135,136]. Autosomal-dominant (AD), autosomal-recessive (AR).