Abstract Details

Title The Potential Role of Estrogen in Moderating Symptom Severity in Women with RYR1-Related Myopathy

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-012

Objective To describe a family with a mild RYR1-related myopathy with progressive weakness noted after menopause.

Background Mutations in the ryanodine receptor (RYR1) gene have been associated with a range of clinical presentations, including exercise-induced rhabdomyolyisis, malignant hyperthermia, and congenital myopathy. Malignant hyperthermia susceptibility (MHS) associated with some RYR1 mutations displays a male predominance, raising the possibility that higher estrogen levels may be protective in females.

Design/Methods We evaluated a 49 year-old, previously healthy, marathon-running woman who presented with muscles aches and weakness beginning at menopause. The patient, along with her unaffected brother and son, and symptomatic daughter were evaluated with whole exome sequencing. We also evaluated the effects of Tamoxifen (an estrogen receptor antagonist) on muscle function and response to volatile anesthetics of mice with RYR1 mutations, which have been associated with MHS and myopathy.

Results

Examination of our patient revealed ptosis and mild proximal weakness. Her mother developed proximal weakness after discontinuation of hormone replacement therapy at age 62. Her daughter was found to have ptosis, but does not have proximal muscle weakness.

Whole exome sequencing of the patient and family revealed a variant of unknown significance (p.S2776F) in the RYR1 gene in symptomatic individuals only. This mutation has been reported in a 16 year-old girl with King-Denborough syndrome.

Additionally, both male and female RYR1 mice treated with Tamoxifen showed decreased muscle performance and increased probability of death upon exposure to volatile anesthetics, suggesting a protective effect of estrogens.

Conclusions

This is, to our knowledge, the first case reported of a possible hormonal contribution to the severity of symptoms in RYR1-related myopathy, and could potentially contribute to the phenotypic variability observed with certain RYR1 mutations. This case also raises the question of hormonal replacement therapy as a possible intervention for muscle weakness in women with RYR1 related mutations.

Authors/Disclosures
Lydia Sharp, MD PRESENTER	The institution of Dr. Sharp has received research support from McNair Foundation. The institution of Dr. Sharp has received research support from ALS Association.
Milvia Y. Pleitez, MD (Baylor College of Medicine Neurology)	An immediate family member of Dr. Pleitez has received stock or an ownership interest from Medtronic. Dr. Pleitez has received stock or an ownership interest from Abbvie. An immediate family member of Dr. Pleitez has received stock or an ownership interest from Merck. Dr. Pleitez has received stock or an ownership interest from QualCom.
	No disclosure on file
	No disclosure on file

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