RYR1-related myopathic disease: confirmation of clinical and genetic heterogeneity with reported novel phenotypic and genetic features


Ultra-Rare myopathies and dystrophies (<1:100,000 worldwide)

Poster Number: 206


Constantine Farmakidis, MD, Michaela Walker, MPH, Jeffrey Statland, MD


1. University of Kansas Medical Center, 2. University of Kansas Medical Center, 3. University of Kansas Medical Center

BACKGROUND: Skeletal muscle ryanodine receptor (RYR1) gene sequence alterations are associated with inherited myopathies and malignant hyperthermia susceptibility. The clinical spectrum of RYR1 gene disorders is broad and information continues to emerge about its manifestations across age groups.

OBJECTIVE: Continue to define aspects of RYR1-related neuromuscular disorders with the goal of better identifying and managing malignant hyperthermia susceptibility.

APPROACH: This is a single-center, retrospective study. Medical records were reviewed from patients with myopathic disease/evidence of malignant hyperthermia susceptibility and concurrent RYR1 gene variants suspected to be pathogenic. Clinical, histopathologic, genetic and laboratory data were obtained.

RESULTS: This is a cohort of 4 non-related patients. Three patients had previously described clinical presentations: a male with adult-onset limb-girdle pattern centronuclear myopathy, a female with congenital myopathy but without specific myopathology findings, and a female with adult-onset limb-girdle weakness, myalgias and episodic severe weakness. A fourth, otherwise neurologically intact patient, presented with severe paroxysmal myalgias, hyperCKemia and a suspected autosomal dominant inheritance. Additional clinical review revealed a history of recurrent postoperative fever (>4 operations), that has always been followed by a negative infectious workup and no further malignant features. A son who has not been genetically tested, has had similar episodes of unexplained postoperative fever. Two of 4 patients in this cohort had previously unreported sequence alterations in the RYR1 gene. Two of 4 patients had severe myalgias that caused significant impairment.
CONCLUSION: This report expands the clinical spectrum of known RYR1-associated disease with what appears to be a milder postoperative fever variant of an apparent “non-malignant” hyperthermia—although the risk of future malignant hyperthermia remains unknown. This report underscores that myalgias in patients with RYR1-associated disease can be severe and disabling even in patients without weakness. Finally, the presented data expand the spectrum of known genetic variants associated with RYR1 gene disorders. The addition of patients to this cohort is ongoing.