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Gene & Protein in Disease Clinical findings of RYR1 mutation

in different forms, i.e., classic, progressive, antenatal, Ca release. However, variants in the N-terminal region
2+
and ophthalmoplegic. In the most common classic form, increase Ca release by stabilizing the closed state. 16,17
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the baby is “floppy” (hypotonic) and may experience RYR1 variants can be associated with either MH or CCD,
feeding problems in the early stages of their lives. The with some variants being associated with both disorders.
progressive form of multiminicore disease with hand However, this has not yet been fully elucidated.
involvement results in joint laxity and muscle weakness Congenital myopathies are divided into the following five
in the arms and hands. Antenatal arthrogryposis is subgroups according to the major morphological features
characterized by distinctive facial features and rigid joints. observed in muscle biopsy specimens: core, nemaline,
The ophthalmoplegic form is characterized by external centronuclear, myosin storage, and congenital fiber-type
ophthalmoplegia, causing abnormal eye movements, disproportion myopathies. Core myopathies, located at the
drooping eyelids (ptosis), and weakness of the proximal center or periphery of muscle fibers, are minicore areas of
muscles. In our patient, moderate proximal muscle myofibrillar disruption without mitochondria. In CCD,
5,12
weakness, delayed motor development, feeding problems, there are typically large and centrally located nuclei in the
and a homozygous c.115G>A variant in RYR1 supported muscle fibers. In multiminicore myopathy, multiple focal
the diagnosis of a classic form of multiminicore disease. areas devoid of oxidative enzyme activity are observed.
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The deceased brother was believed to have multiminicore Our study’s family refused to undergo muscle biopsy
disease due to the presence of a homozygous c.115G>A because they deemed it an invasive procedure, making it
variant in RYR1, hypotonicity, dysphagia, and breathing a limitation of this study. However, the 4-year-old patient’s
difficulty due to bulbar involvement.
clinical picture can be explained by the current molecular
CCD (MIM 117000) mainly presents during infancy or findings.
childhood and sometimes in older individuals. It affects The study results show that pathogenic variants of
the proximal muscles of the lower extremities and causes RYR1 lead to four distinct types of channel defects.
generalized joint laxity and scoliosis symptoms. The same Excitation–contraction coupling in the transverse tubules
variants in RYR1 result in a wide range of phenotypes, and SR membrane occurs in a macromolecular complex
from mild to very severe, even within the same family. composed of RYR1, the dihydropyridine receptor
Patients with N-terminal variants of RYR1 may exhibit (DHPR), and calsequestrin. The first class of these variants
lighter phenotypes. Muscle weakness, congenital hip
8,13
dislocation, generalized joint laxity, and scoliosis are more makes the channels sensitive to activation due to electrical
and pharmacological stimuli, resulting in the clinical
common and severe. Bulbar, respiratory, and cardiac presentation of MH. The second class causes depletion
involvement is uncommon. The heterozygous c.115G>A of Ca from intracellular SR deposits, resulting in CCD.
1
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variant of RYR1 was found in our patient’s mother, father, The third class, associated with some types of CCD,
and sister near the N-terminal region. However, it did results in excitation–contraction uncoupling. Activation
not produce any clinical symptoms, indicating that this 2+
heterozygous form is not associated with CCD. of the voltage-sensing DHPR fails to induce Ca release
from the SR. The fourth class is the reduced expression
MH susceptibility 1 (MIM 145600) is an autosomal of mutant RYR1 channels in SR membranes, which is
dominant skeletal muscle disease. Exposure to certain distinct from recessive RYR1 mutations. Thus, each
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volatile anesthetic agents, such as halothane, or RYR1 gene variant affects calcium balance differently.
depolarizing muscle relaxants, such as succinylcholine, However, functional or protein expression studies in
can cause an MH crisis, resulting in muscle rigidity, these young patients are lacking. Thus, a mutation-
hyperthermia, arrhythmias, respiratory and metabolic specific effect cannot be demonstrated. The identified
acidosis, and rhabdomyolysis. Although the child’s variants and the resultant clinical findings demonstrated
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mother was exposed to anesthetic agents several times, an a genotype–phenotype relationship in RYR1, highlighting
MH crisis was not observed. However, we cannot conclude its important neuromuscular features in the clinical
that this RYR1 gene variant will not lead to anesthesia- presentation of congenital myopathy.
related deaths, as we cannot predict which anesthetic agent
will be used. 4. Conclusion
Gain-of-function mutations in RYR1 cause MH Our case report illustrates the clinical presentation
susceptibility due to increased Ca release from the SR. of multiminicore disease caused by the c.115 G>A
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Furthermore, mutations that cause CCD are typically homozygous variant of RYR1. The clinical differences
associated with a loss of function. RYR1 variants in between patients with the homozygous and heterozygous
15
the central region of the protein increase Ca -induced variants shed light on the genotype–phenotype correlation.
2+
Volume 4 Issue 1 (2025) 4 doi: 10.36922/gpd.4748