Congenital Myopathy-1B due to RYR 1 Gene Mutation in Three Libyan Families

Abstract

Introduction We report a series of patients in three different Libyan families diagnosed with congenital myopathy to study the wide clinical variability between these families, and the genetic heterogeneity.

Description of Cases We describe six patients, one patient presented with severe neonatal-onset RYR1-associated myopathy while the other five patients came mainly due to delay in motor development; genetic testing confirmed the diagnosis of CMY-1B disease due to RYR1 mutation in all patients. Clinical features of congenital widely varied between the families ranging from profound hypotonia during the neonatal period in one family to a motor delay and abnormal gait during childhood in other two families. Whereas the clinical picture is quite similar in the patients of same family, the patient who presented with severe neonatal presentation of RYR1-associated myopathy also had gastrostomy feeding, respiratory involvement, clubfeet, cleft palate, and undescended testes. The five patients who presented due to delay in motor development all were ambulatory without the need of support, except the youngest one aged 4 years still walking with support. The genetic study in the form of whole-exon sequencing as well as next-generation sequencing showed homozygosity of a gene mutation in five patients and a compound heterozygosity in one patient which presented with neonatal severe hypotonia.

Conclusion CMY-1B disease is a rare autosomal dominant and recessive genetic disorder that has variable clinical presentations. The early diagnosis is very important for genetic counseling as well as avoiding malignant hyperthermia. We also report rare and unusual presentations that may further delay the diagnosis.

Keywords

neuromuscular disorder - central hypotonia - genetic tests - malignant hyperthermia - scoliosis

Compliance with Ethical Principles

Prior ethical approval is not required for single cases and small case series. All patients or guardians consented for participation provided idendity is not revealed.

Publication History

Article published online:
06 June 2024

• Reference

• 1 Jungbluth H. Central core disease. Orphanet J Rare Dis 2007; 2: 25
• 2 Quinlivan RM, Muller CR, Davis M. et al. Central core disease: clinical, pathological, and genetic features. Arch Dis Child 2003; 88 (12) 1051-1055
• 3 Talwalkar SS, Parker JR, Heffner RR. et al. Adult central core disease. Clinical, histologic and genetic aspects: case report and review of the literature. Clin Neuropathol 2006; 25 (04) 180-184
• 4 Denborough MA, Forster JF, Lovell RR. et al. Anaesthetic deaths in a family. Br J Anaesth 1962; 34: 395-396
• 5 Rueffert H, Olthoff D, Deutrich C. et al. A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation. Am J Med Genet A 2004; 124A [phone]
• 6 Shuaib A, Paasuke RT, Brownell KW. Central core disease. Clinical features in 13 patients. Medicine (Baltimore) 1987; 66 (05) 389-396
• 7 Robinson RL, Brooks C, Brown SL. et al. RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes. Hum Mutat 2002; 20 (02) 88-97
• 8 Bharucha-Goebel DX, Santi M, Medne L. et al. Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum. Neurology 2013; 80 (17) 1584-1589
• 9 Matthews E, Neuwirth C, Jaffer F. et al. Atypical periodic paralysis and myalgia: a novel RYR1 phenotype. Neurology 2018; 90 (05) e412-e418
• 10 Klein MJ, Kuemin C, Tamulevicius T. et al. Note: a microfluidic chip setup for capillarity-assisted particle assembly. Erratum Rev Sci Instrum 2012; 83 (08) 086109