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Updated: Apr 27, 2026
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
RYR1-related congenital myopathy with fatigable weakness, responding to pyridostigimine
M A Illingworth1, M Main1, M Pitt2
1Dubowitz Neuromuscular Centre, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
Insights
RYR1 gene mutations can cause a myasthenic-like condition in infants, presenting as fatigable ptosis. This expands the known RYR1-related disease spectrum, even with partial response to pyridostigmine.
Area of Science:
- Neurology
- Genetics
- Muscle Diseases
Background:
- RYR1 mutations are linked to various neuromuscular disorders including congenital myopathies and malignant hyperthermia.
- The clinical spectrum of RYR1-related disorders is broad, but a myasthenic-like presentation is less common.
Observation:
- Two siblings presented with infantile hypotonia and significant fatigable ptosis.
- They showed a notable response to pyridostigmine, but genetic testing for congenital myasthenic syndromes was negative.
- Muscle MRI revealed a pattern suggestive of RYR1-related myopathy.
Findings:
- Genetic analysis identified compound heterozygous mutations in the RYR1 gene (c.6721C>T and c.8888T>C) in both siblings.
- These mutations expand the RYR1-related disease spectrum to include a phenotype mimicking myasthenia gravis.
- The findings highlight a partial response to pyridostigmine in this RYR1-related condition.
Implications:
- RYR1-related myopathy should be considered in infants with fatigable weakness and ptosis, particularly with characteristic muscle MRI findings.
- This broadens diagnostic considerations beyond typical congenital myasthenic syndromes.
- Further research into RYR1 function in neuromuscular transmission is warranted.
Abstract:
The spectrum of RYR1 mutation associated disease encompasses congenital myopathies, exercise induced rhabdomyolysis, malignant hyperthermia susceptibility and King-Denborough syndrome. We report the clinical phenotype of two siblings who presented in infancy with hypotonia and striking fatigable ptosis. Their response to pyridostigimine was striking, but genetic screening for congenital myasthenic syndromes was negative, prompting further evaluation. Muscle MRI was abnormal with a selective pattern of involvement evocative of RYR1-related myopathy. This directed sequencing of the RYR1 gene, which revealed two heterozygous c.6721C>T (p.Arg2241X) nonsense mutations and novel c.8888T>C (p.Leu2963Pro) mutations in both siblings. These cases broaden the RYR1-related disease spectrum to include a myasthenic-like phenotype, including partial response to pyridostigimine. RYR1-related myopathy should be considered in the presence of fatigable weakness especially if muscle imaging demonstrates structural abnormalities. Single fibre electromyography can also be helpful in cases like this.
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