Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings
The ryanodine receptor 1-related congenital myopathies (RYR1-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and resp...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2018-03-01
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Series: | Frontiers in Neurology |
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Online Access: | http://journal.frontiersin.org/article/10.3389/fneur.2018.00118/full |
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doaj-00dd881aa9694ede8ed4875c6ede7607 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Joshua J. Todd Muslima S. Razaqyar Jessica W. Witherspoon Tokunbor A. Lawal Ami Mankodi Irene C. Chrismer Carolyn Allen Mary D. Meyer Anna Kuo Monique S. Shelton Kim Amburgey Dmitriy Niyazov Pierre Fequiere Carsten G. Bönnemann James J. Dowling James J. Dowling Katherine G. Meilleur |
spellingShingle |
Joshua J. Todd Muslima S. Razaqyar Jessica W. Witherspoon Tokunbor A. Lawal Ami Mankodi Irene C. Chrismer Carolyn Allen Mary D. Meyer Anna Kuo Monique S. Shelton Kim Amburgey Dmitriy Niyazov Pierre Fequiere Carsten G. Bönnemann James J. Dowling James J. Dowling Katherine G. Meilleur Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings Frontiers in Neurology genotype phenotype RYR1 neuromuscular magnetic resonance imaging |
author_facet |
Joshua J. Todd Muslima S. Razaqyar Jessica W. Witherspoon Tokunbor A. Lawal Ami Mankodi Irene C. Chrismer Carolyn Allen Mary D. Meyer Anna Kuo Monique S. Shelton Kim Amburgey Dmitriy Niyazov Pierre Fequiere Carsten G. Bönnemann James J. Dowling James J. Dowling Katherine G. Meilleur |
author_sort |
Joshua J. Todd |
title |
Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings |
title_short |
Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings |
title_full |
Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings |
title_fullStr |
Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings |
title_full_unstemmed |
Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings |
title_sort |
novel variants in individuals with ryr1-related congenital myopathies: genetic, laboratory, and clinical findings |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neurology |
issn |
1664-2295 |
publishDate |
2018-03-01 |
description |
The ryanodine receptor 1-related congenital myopathies (RYR1-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RYR1-RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel RYR1 variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant’s medical records. Alamut Visual Software was used to determine if participant’s variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two de novo, three dominant, and one recessive) were identified in individuals with RYR1-RM. Consistent with established RYR1-RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant RYR1 variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive RYR1-RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected RYR1-RM which can be corroborated through histopathology, muscle MRI and clinical examination. |
topic |
genotype phenotype RYR1 neuromuscular magnetic resonance imaging |
url |
http://journal.frontiersin.org/article/10.3389/fneur.2018.00118/full |
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doaj-00dd881aa9694ede8ed4875c6ede76072020-11-24T22:13:51ZengFrontiers Media S.A.Frontiers in Neurology1664-22952018-03-01910.3389/fneur.2018.00118334710Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical FindingsJoshua J. Todd0Muslima S. Razaqyar1Jessica W. Witherspoon2Tokunbor A. Lawal3Ami Mankodi4Irene C. Chrismer5Carolyn Allen6Mary D. Meyer7Anna Kuo8Monique S. Shelton9Kim Amburgey10Dmitriy Niyazov11Pierre Fequiere12Carsten G. Bönnemann13James J. Dowling14James J. Dowling15Katherine G. Meilleur16Neuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeurogenetics Branch, National Institute of Neurological Disorders and Stroke––NINDS (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesDivision of Neurology, Hospital for Sick Children, University of Toronto, Toronto, ON, CanadaDepartment of Pediatrics, Ochsner Medical Center, New Orleans, LA, United StatesDivision of Neurology, Children’s of Alabama, Birmingham, AL, United StatesNeurogenetics Branch, National Institute of Neurological Disorders and Stroke––NINDS (NIH), Bethesda, MD, United StatesDepartment of Paediatrics, Hospital for Sick Children, Toronto, ON, CanadaDepartment of Molecular Genetics, Hospital for Sick Children, Toronto, ON, CanadaNeuromuscular Symptoms Unit, National Institute of Nursing Research (NIH), Bethesda, MD, United StatesThe ryanodine receptor 1-related congenital myopathies (RYR1-RM) comprise a spectrum of slow, rare neuromuscular diseases. Affected individuals present with a mild-to-severe symptomatology ranging from proximal muscle weakness, hypotonia and joint contractures to scoliosis, ophthalmoplegia, and respiratory involvement. Although there is currently no FDA-approved treatment for RYR1-RM, our group recently conducted the first clinical trial in this patient population (NCT02362425). This study aimed to characterize novel RYR1 variants with regard to genetic, laboratory, muscle magnetic resonance imaging (MRI), and clinical findings. Genetic and histopathology reports were obtained from participant’s medical records. Alamut Visual Software was used to determine if participant’s variants had been previously reported and to assess predicted pathogenicity. Physical exams, pulmonary function tests, T1-weighted muscle MRI scans, and blood measures were completed during the abovementioned clinical trial. Six novel variants (two de novo, three dominant, and one recessive) were identified in individuals with RYR1-RM. Consistent with established RYR1-RM histopathology, cores were observed in all biopsies, except Case 6 who exhibited fiber-type disproportion. Muscle atrophy and impaired mobility with Trendelenburg gait were the most common clinical symptoms and were identified in all cases. Muscle MRI revealed substantial inter-individual variation in fatty infiltration corroborating the heterogeneity of the disease. Two individuals with dominant RYR1 variants exhibited respiratory insufficiency: a clinical symptom more commonly associated with recessive RYR1-RM cases. This study demonstrates that a genetics-led approach is suitable for the diagnosis of suspected RYR1-RM which can be corroborated through histopathology, muscle MRI and clinical examination.http://journal.frontiersin.org/article/10.3389/fneur.2018.00118/fullgenotypephenotypeRYR1neuromuscularmagnetic resonance imaging |