J Clin Neurol.  2018 Jan;14(1):58-65. 10.3988/jcn.2018.14.1.58.

Clinical and Pathologic Findings of Korean Patients with RYR1-Related Congenital Myopathy

• Jeong HN
• Park HJ
• Lee JH
• Shin HY
• Kim SH
• Kim SM
• Choi YC

• KMID: 2399600
• DOI: http://doi.org/10.3988/jcn.2018.14.1.58

Abstract

BACKGROUND AND PURPOSE
This study was designed to investigate clinical and pathologic characteristics of five Korean patients with RYR1-related congenital myopathy (CM).
METHODS
Five patients from unrelated families were diagnosed with RYR1-related CM via direct or targeted sequencing of RYR1. Their clinical, mutational, and pathologic findings were then analyzed.
RESULTS
Seven different mutations were identified, including two novel mutations: c.5915A>T and c.12250C>T. All of the patients presented at infancy with proximal dominant weakness and delayed motor milestones. Other clinical findings were scoliosis in three patients, winged scapula in two, hip dislocation in one, and pectus excavatum in one. Ophthalmoplegia was observed in one patient with a novel recessive mutation. Two of three muscle specimens revealed a myopathic pattern with core.
CONCLUSIONS
We have identified a novel compound heterozygous RYR1 mutation and demonstrated clinical and pathologic findings in five Korean patients with RYR1-related CM.

Keyword

myopathy; RYR1; ryanodine receptor 1; central core disease

MeSH Terms

Funnel Chest
Hip Dislocation
Humans
Muscular Diseases*
Myopathy, Central Core
Ophthalmoplegia
Ryanodine Receptor Calcium Release Channel
Scapula
Scoliosis
Ryanodine Receptor Calcium Release Channel

Figure

• 

  Fig. 1 Pedigrees of the five patients with RYR1-related congenital myopathies.

• 

  Fig. 2 Radiologic findings of three patients with RYR1 mutations. Whole-spine-bending X-ray of patient ID37 showed severe scoliosis at 7 years old (A). Scoliosis was also observed in a whole-spine X-ray of patient ID45 at 33 years old (B). Muscle CT fat-scan imaging of patient ID185 at 23 years old (C) revealed fatty infiltration in the lumbar paraspinal and gluteus maximus muscles. The posterior compartments of the thigh, rectus femoris, and adductor longus were spared, while the most-affected muscle in the calf was the soleus.

• 

  Fig. 3 Pathologic findings of three patients with RYR1 mutations. Hematoxylin and eosin staining demonstrated wide variations in fiber size, degenerative fibers, and increased interstitial fibrosis (A: ID37, ×400, B: ID185, ×200, C: ID131, ×400). Two muscle specimens exhibited well-demarcated (D) and ill-defined (E) central cores on nicotinamide adenine dinucleotide-tetrazolium reductase staining (D: ID37, ×400, E: ID185, ×200). Modified Gomori trichrome staining did not demonstrate any rimmed vacuoles, nemaline rods, ragged red fibers, or other granular materials (F: ID37, ×400).

• 

  Fig. 4 Locations of RYR1 mutations and phenotypes in the reported Korean patients. Schematic representation of the RYR1 protein. SPRY domains are protein-protein interaction motifs which are first identified in tyrosine kinase spore lysis A and mammalian RyRs. ‡ Variants found in a cis arrangement, *, †, §, ¶ Variants that are compound heterozygous mutations, ◆Variants found in our patients with RYR1-related congenital myopathy. CCD: central core disease, MH: malignant hyperthermia.

Reference

1. Sewry CA, Jimenez-Mallebrera C, Muntoni F. Congenital myopathies. Curr Opin Neurol. 2008; 21:569–575. PMID: 18769251.

2. Choi YC. Congenital dystrophies and myopathies. In : Lisak RP, Truong D, Carroll WM, Bhidayasiri R, editors. International Neurology. 2nd ed. Hoboken (NJ): John Wiley & Sons;2016. p. 485–489. .

3. North KN, Wang CH, Clarke N, Jungbluth H, Vainzof M, Dowling JJ, et al. Approach to the diagnosis of congenital myopathies. Neuromuscul Disord. 2014; 24:97–116. PMID: 24456932.

4. Kaplan JC, Hamroun D. The 2016 version of the gene table of monogenic neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2015; 25:991–1020. PMID: 27563712.

5. Maggi L, Scoto M, Cirak S, Robb SA, Klein A, Lillis S, et al. Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul Disord. 2013; 23:195–205. PMID: 23394784.

6. Colombo I, Scoto M, Manzur AY, Robb SA, Maggi L, Gowda V, et al. Congenital myopathies: natural history of a large pediatric cohort. Neurology. 2015; 84:28–35. PMID: 25428687.

7. Amburgey K, McNamara N, Bennett LR, McCormick ME, Acsadi G, Dowling JJ. Prevalence of congenital myopathies in a representative pediatric united states population. Ann Neurol. 2011; 70:662–665. PMID: 22028225.

8. Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. 2009; 132:3175–3186. PMID: 19767415.

9. Amburgey K, Bailey A, Hwang JH, Tarnopolsky MA, Bonnemann CG, Medne L, et al. Genotype-phenotype correlations in recessive RYR1-related myopathies. Orphanet J Rare Dis. 2013; 8:117. PMID: 23919265.

10. Park HJ, Jang H, Kim JH, Lee JH, Shin HY, Kim SM, et al. Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders. Clin Genet. 2017; 91:403–410. PMID: 27363342.

11. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17:405–424. PMID: 25741868.

12. Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006; 129:1470–1480. PMID: 16621918.

13. Broman M, Islander G, Müller CR, Ranklev-Twetman E. Malignant hyperthermia and central core disease causative mutations in Swedish patients. Acta Anaesthesiol Scand. 2007; 51:50–53. PMID: 17081152.

14. Chae JH, Vasta V, Cho A, Lim BC, Zhang Q, Eun SH, et al. Utility of next generation sequencing in genetic diagnosis of early onset neuromuscular disorders. J Med Genet. 2015; 52:208–216. PMID: 25635128.

15. Klein A, Jungbluth H, Clement E, Lillis S, Abbs S, Munot P, et al. Muscle magnetic resonance imaging in congenital myopathies due to ryanodine receptor type 1 gene mutations. Arch Neurol. 2011; 68:1171–1179. PMID: 21911697.

16. Jeong SK, Kim DC, Cho YG, Sunwoo IN, Kim DS. A double mutation of the ryanodine receptor type 1 gene in a malignant hyperthermia family with multiminicore myopathy. J Clin Neurol. 2008; 4:123–130. PMID: 19513315.

17. Lee H, Kim DC, Lee JH, Cho YG, Lee HS, Choi SI, et al. [Molecular genetic analysis of the ryanodine receptor gene (RYR1) in Korean malignant hyperthermia families]. Korean J Lab Med. 2010; 30:702–710. PMID: 21157159.

18. Lee JS, Lim BC, Kim KJ, Hwang YS, Seong MW, Park SS, et al. Rare coincidence of familial central core disease and hemophagocytic lymphohistiocytosis. Pediatr Int. 2014; 56:e88–e91. PMID: 25521991.

19. Jung NY, Park YE, Shin JH, Lee CH, Jung DS, Kim DS. Mild clinical features and histopathologically atypical cores in two Korean families with central core disease harboring RYR1 mutations at the C-terminal region. J Clin Neurol. 2015; 11:97–101. PMID: 25628744.

20. Kim DC, Kim DS. Identification of G7304A mutation in the ryanodine receptor type 1 gene in a patient with malignant hyperthermia and an extended pedigree study in a Korean malignant hyperthermia family. Korean J Anesthesiol. 2003; 44:56–64.

21. Monnier N, Romero NB, Lerale J, Landrieu P, Nivoche Y, Fardeau M, et al. Familial and sporadic forms of central core disease are associated with mutations in the C-terminal domain of the skeletal muscle ryanodine receptor. Hum Mol Genet. 2001; 10:2581–2592. PMID: 11709545.

22. Snoeck M, van Engelen BG, Küsters B, Lammens M, Meijer R, Molenaar JP, et al. RYR1-related myopathies: a wide spectrum of phenotypes throughout life. Eur J Neurol. 2015; 22:1094–1112. PMID: 25960145.

23. Klein A, Lillis S, Munteanu I, Scoto M, Zhou H, Quinlivan R, et al. Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Hum Mutat. 2012; 33:981–988. PMID: 22473935.

24. Dlamini N, Voermans NC, Lillis S, Stewart K, Kamsteeg EJ, Drost G, et al. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscul Disord. 2013; 23:540–548. PMID: 23628358.