Marked Facial Weakness, Ptosis, and Hanging Jaw: A Case with RYR1-Related Congenital Centronuclear Myopathy

Abstract

Congenital myopathies are an expanding spectrum of neuromuscular disorders with early infantile or childhood onset hypotonia and slowly or nonprogressive skeletal muscle weakness. RYR1-related myopathies are the most common and frequently diagnosed class of congenital myopathies. Malignant hyperthermia susceptibility and central core disease are autosomal dominant or de novo RYR1 disorder, whereas multiminicore, congenital fiber type disproportion and centronuclear myopathy are autosomal recessive RYR1 disorders. The presence of ptosis, ophthalmoparesis, facial, and proximal muscles weakness, with the presence of dusty cores and multiple internal nuclei on muscle biopsy are clues to the diagnosis. We describe an 18-year-old male, who presented with early infantile onset ptosis, ophthalmoplegia, myopathic facies, hanging lower jaw, and proximal muscle weakness confirmed as an RYR1-related congenital centronuclear myopathy on genetic analysis and muscle biopsy.

Keywords

myopathy - ophthalmoplegia - centronuclear

Note

The manuscript was approved by the Departmental Review Board.

Authors' Contributions

B.S. and S.K. prepared the initial draft of the manuscript and reviewed the literature. D.A. and D.C. provided histopathological inputs to the manuscript. A.U. provided neuromuscular inputs and intellectual content. R.S. involved in a critical review of the manuscript and reviewed the literature and edited the final version of the manuscript. All the authors approved the final version of the manuscript.

Publication History

Received: 21 November 2020

Accepted: 22 May 2021

Article published online:
03 July 2021

• References

• 1 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 (04) 662-665
• 2 Klein A, Lillis S, Munteanu I. et al. Clinical and genetic findings in a large cohort of patients with ryanodine receptor 1 gene-associated myopathies. Hum Mutat 2012; 33 (06) 981-988
• 3 Biancalana V, Beggs AH, Das S. et al. Clinical utility gene card for: Centronuclear and myotubular myopathies. Eur J Hum Genet 2012; 20 (10) 10
• 4 Wilmshurst JM, Lillis S, Zhou H. et al. RYR1 mutations are a common cause of congenital myopathies with central nuclei. Ann Neurol 2010; 68 (05) 717-726
• 5 Jungbluth H, Zhou H, Hartley L. et al. Minicore myopathy with ophthalmoplegia caused by mutations in the ryanodine receptor type 1 gene. Neurology 2005; 65 (12) 1930-1935
• 6 Jungbluth H, Zhou H, Sewry CA. et al. Centronuclear myopathy due to a de novo dominant mutation in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord 2007; 17 (04) 338-345
• 7 Spiro AJ, Shy GM, Gonatas NK. Myotubular myopathy. Persistence of fetal muscle in an adolescent boy. Arch Neurol 1966; 14 (01) 1-14
• 8 Abath Neto O, Moreno CAM, Malfatti E. et al. Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients. Neuromuscul Disord 2017; 27 (11) 975-985
• 9 Amburgey K, Bailey A, Hwang JH. et al. Genotype-phenotype correlations in recessive RYR1-related myopathies. Orphanet J Rare Dis 2013; 8: 117
• 10 Robinson R, Carpenter D, Shaw MA, Halsall J, Hopkins P. Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 2006; 27 (10) 977-989
• 11 Zhou H, Yamaguchi N, Xu L. et al. Characterization of recessive RYR1 mutations in core myopathies. Hum Mol Genet 2006; 15 (18) 2791-2803
• 12 Fattori F, Maggi L, Bruno C. et al. Centronuclear myopathies: genotype-phenotype correlation and frequency of defined genetic forms in an Italian cohort. J Neurol 2015; 262 (07) 1728-1740
• 13 Bevilacqua JA, Monnier N, Bitoun M. et al. Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization. Neuropathol Appl Neurobiol 2011; 37 (03) 271-284
• 14 Jungbluth H, Davis MR, Müller C. et al. Magnetic resonance imaging of muscle in congenital myopathies associated with RYR1 mutations. Neuromuscul Disord 2004; 14 (12) 785-790
• 15 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. 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 (05) 405-424
• 16 Lawal TA, Todd JJ, Meilleur KG. Ryanodine receptor 1-related myopathies: diagnostic and therapeutic approaches. Neurotherapeutics 2018; 15 (04) 885-899
• 17 Jungbluth H, Ochala J, Treves S, Gautel M. Current and future therapeutic approaches to the congenital myopathies. Semin Cell Dev Biol 2017; 64: 191-200
• 18 Lawal TA, Todd JJ, Witherspoon JW. et al. Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature. Skelet Muscle 2020; 10 (01) 32
• 19 Levano S, Vukcevic M, Singer M. et al. Increasing the number of diagnostic mutations in malignant hyperthermia. Hum Mutat 2009; 30 (04) 590-598
• 20 Garibaldi M, Rendu J, Brocard J. et al. ‘Dusty core disease’ (DuCD): expanding morphological spectrum of RYR1 recessive myopathies. Acta Neuropathol Commun 2019; 7 (01) 3
• 21 Jungbluth H, Wallgren-Pettersson C, Laporte JF. Centronuclear (Myotubular) Myopathy Consortium. 164th ENMC International workshop: 6th workshop on centronuclear (myotubular) myopathies, 16-18th January 2009, Naarden, The Netherlands. Neuromuscul Disord 2009; 19 (10) 721-729
• 22 Samões R, Oliveira J, Taipa R. et al. RYR1-related myopathies: clinical, histopathologic and genetic heterogeneity among 17 patients from a portuguese tertiary centre. J Neuromuscul Dis 2017; 4 (01) 67-76
• 23 Todd JJ, Sagar V, Lawal TA. et al. Correlation of phenotype with genotype and protein structure in RYR1-related disorders. J Neurol 2018; 265 (11) 2506-2524