RYR1 mutations are the most common cause of congenital myopathies in general and also the most frequently encountered childhood myopathy excluding Duchenne muscular dystrophy [7]. RYR1 gene on chromosome 19q encodes a calcium-channel of the sarcoplasmic reticulum , which, along with sarcolemmal voltage-gated calcium channels (dihydropyridine receptor), is responsible for triggering muscle contraction after sarcolemmal depolarization and subsequent calcium release (excitation-contraction coupling) [8, 9]. Myopathies due to RYR1 mutations is thought to disrupt excitation-contraction coupling due to reduced calcium release [4].

RYR1 related myopathies (RYR1-RM) are both pathologically and phenotypically complex and diverse. Histopathological RYR1-RM subtypes include central core disease, multiminicore disease, centronuclear myopathy, core-rod myopathy, and congenital fiber-type disproportion [5, 10–15]. All these histologic types of RYR1-RM produce variable degree of muscle weakness. RYR1 mutations can lead to other conditions including malignant hyperthermia (MH) susceptibility, exertional heat stroke, rhabdomyolysis-myalgia syndrome, King Denborough syndrome, and atypical periodic paralysis [16–19]. RYR1-RM can be inherited as autosomal dominant and recessive traits [4, 5]. Heterozygous recessive mutations have also been described due to epigenetic silencing of the wild type allele without an additional mutation in the other allele [20]. For the purpose of this vignette, we will briefly discuss central core disease due to RYR1 mutations.

The most common phenotype encountered in patients with CCD is a nonprogressive, mild proximal limb-girdle weakness related to the dominant mutations in RYR1 . However, some patients with CCD can have a severe infantile presentation that results in respiratory failure and impaired ambulation [4]. Such patients typically have de novo dominant mutations [21]. Patients with RYR1-related minicore myopathy usually have a severe phenotype (axial weakness more common as well musculoskeletal complications) and are usually associated with recessive RYR1 mutations [4, 5]. Ophthalmoparesis is common in RYR1- related minicore disease and helps to clinically differentiate this from SEPN1-related minicore myopathy [22]. The patient presented in this case had a severe neonatal course with respiratory and feeding difficulty which fits with autosomal recessive inheritance and subsequently nonprogressive proximal muscle weakness which is commonly seen with CCD phenotype.

Serum creatinine kinase in CCD is usually normal or mildly elevated. EMG may show myopathic changes [5]. Muscle MRI shows selective involvement with sparing of certain muscle groups (rectus femoris, adductor longus, gracilis) in dominant RYR1-RM [23]; however, MRI findings are not consistent in recessively inherited cases. There is an overlap between CCD and MH susceptibility cases; patients with mutations at the N-terminal region have a higher probability of MH susceptibility [8]. Mutations are located in CCD hotspots including the C-terminal domain in 60% of RYR1-related CCD patients. Recessive mutations are found throughout the gene [4]. Patients with suspected RYR1-RM should have full RYR1 gene sequencing [8, 24]. Next generation sequencing techniques are very helpful in detecting mutations in patients with suspected congenital myopathies [3].

Currently, there are no specific treatments for core myopathies but several small molecules have been tried in some patients. Dantrolene , a muscle relaxant effective against MH has been reported to be effective in a single case [25]. Salbutamol (Albuterol) had been found to be effective in a small case series [26]. N-acetylcysteine by reducing oxidative stress could be potential therapeutic agent in RYR1-RM [27]. Rycals are drugs which help to stabilize excitation-contraction coupling and thus may be helpful in this condition [28]. Gene-based therapies may be helpful in some of the RYR1-RM. Using exon-skipping strategy , researchers were able to remove a pseudo-exon formed by one of the mutations from an individual with compound heterozygous state resulting in restoration of RYR1 expression and functional calcium release [29].

In the absence of a specific treatment, supportive management includes regular physical therapy and follow-up to detect respiratory failure, and orthopedic complications.