Rhabdomyolysis and fluctuating asymptomatic hyper<scp>CK</scp>emia associated with <i><scp>CACNA</scp>1S</i> variant

Anandan, Charenya; Cipriani, Marina; Laughlin, Ruple S.; Niu, Zhiyv; Milone, Margherita

doi:10.1111/ene.13528

Cited by 18 publications

(10 citation statements)

References 16 publications

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“…Most of these disorders are inherited in an autosomal recessive fashion and a few are X linked. A notable exception is Malignant Hyperthermia (MH), a disease of skeletal muscle calcium (Ca 2+ ) dysregulation due largely to dominant mutations in RYR1 or CACNA1S , that are also associated with exertional rhabdomyolysis, exertional heat illness or a combination of both [ 8 , 9 ]. Although these genetic factors are well recognized in recurrent rhabdomyolysis, underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis

Sambuughin

Mungunsukh

Ren

et al. 2018

Molecular Genetics and Metabolism Reports

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Exertional rhabdomyolysis is a metabolic event characterized by the release of muscle content into the circulation due to exercise-driven breakdown of skeletal muscle. Recurrent exertional rhabdomyolysis has been associated with metabolic myopathies and mitochondrial disorders, a clinically and genetically heterogeneous group of predominantly autosomal recessive, monogenic conditions. Although genetics factors are well recognized in recurrent rhabdomyolysis, the underlying causes and mechanisms of exercise-driven muscle breakdown remain unknown in a substantial number of cases. We present clinical and genetic study results from seven adult male subjects with recurrent exertional rhabdomyolysis. In all subject, whole exome sequencing identified multiple heterozygous variants in genes associated with monogenic metabolic and/or mitochondrial disorders. These variants consisted of known pathogenic and/or new likely pathogenic variants in combination with other rare deleterious alleles. The presence of heterozygous pathogenic and rare deleterious variants in multiple genes suggests an oligogenic inheritance for exertional rhabdomyolysis etiology. Our data imply that exertional rhabdomyolysis can reflect cumulative effects or synergistic interactions of deleterious variants in multiple genes that are likely to compromise muscle metabolism under the stress of exercise.

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Section: Introductionmentioning

confidence: 99%

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis

Sambuughin

Mungunsukh

Ren

et al. 2018

Molecular Genetics and Metabolism Reports

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“…The patient was a heterozygous carrier of missense VUS in collagen type VI alpha 3 chain (COL6A3) gene (c.1214T>C), a reported biomarker of DCM [29], and fukutin (FKTN) gene (c.-7C>G), associated with both DCM and myopathy [29,30]. Further testing for deletion/duplication and sequencing for a comprehensive panel of NMD revealed another missense VUS in calcium voltage-gated channel subunit alpha1 S (CACNA1S) gene (c.3398T>C), which we believe may explain the findings of NM and hyperCKemia in this patient [31]. Additional missense VUSs were reported in the following genes: coiled-coil domain containing 78 (CCDC78) gene (c.416C>T), LDL receptor related protein 4 (LRP4) gene (c.5417_5419delAGA), plectin (PLEC) gene (c.4666C>T), and Sad1 and UNC84 domain containing 1 (SUN1) gene (c.13C>T).…”

Section: Cases With Nmd In Present Studymentioning

confidence: 64%

Genetic Modifiers of Hereditary Neuromuscular Disorders and Cardiomyopathy

Bazrafshan

Kushlaf

Kakroo

et al. 2021

Cells

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Novel genetic variants exist in patients with hereditary neuromuscular disorders (NMD), including muscular dystrophy. These patients also develop cardiac manifestations. However, the association between these gene variants and cardiac abnormalities is understudied. To determine genetic modifiers and features of cardiac disease in NMD patients, we have reviewed electronic medical records of 651 patients referred to the Muscular Dystrophy Association Care Center at the University of Cincinnati and characterized the clinical phenotype of 14 patients correlating with their next-generation sequencing data. The data were retrieved from the electronic medical records of the 14 patients included in the current study and comprised neurologic and cardiac phenotype and genetic reports which included comparative genomic hybridization array and NGS. Novel associations were uncovered in the following eight patients diagnosed with Limb-girdle Muscular Dystrophy, Bethlem Myopathy, Necrotizing Myopathy, Charcot-Marie-Tooth Disease, Peripheral Polyneuropathy, and Valosin-containing Protein-related Myopathy. Mutations in COL6A1, COL6A3, SGCA, SYNE1, FKTN, PLEKHG5, ANO5, and SMCHD1 genes were the most common, and the associated cardiac features included bundle branch blocks, ventricular chamber dilation, septal thickening, and increased outflow track gradients. Our observations suggest that features of cardiac disease and modifying gene mutations in patients with NMD require further investigation to better characterize genotype–phenotype relationships.

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“…Values above 1000IU/L can occur and are consistent with a SMC diagnosis but they are less common 17 and with values this high it is always worth considering the whole presentation and asking if this could reflect an alternative neuromuscular diagnosis (see table 2). Rare cases of CKs above 10 000IU/L and presentation with rhabdomyolysis have been reported in the SMCs 18 .…”

Section: Bloods Tests/ckmentioning

confidence: 99%

Skeletal muscle channelopathies: a guide to diagnosis and management

2021

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Skeletal muscle channelopathies are a group of rare episodic genetic disorders comprising the periodic paralyses and the non-dystrophic myotonias. They may cause significant morbidity, limit vocational opportunities, be socially embarrassing, and sometimes are associated with sudden cardiac death. The diagnosis is often hampered by symptoms that patients may find difficult to describe, a normal examination in the absence of symptoms, and the need to interpret numerous tests that may be normal or abnormal. However, the symptoms respond very well to holistic management and pharmacological treatment, with great benefit to quality of life. Here, we review when to suspect a muscle channelopathy, how to investigate a possible case and the options for therapy once a diagnosis is made.

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Rhabdomyolysis and fluctuating asymptomatic hyperCKemia associated with CACNA1S variant

Abstract: This case underscores the similarity between the phenotypes caused by mutations in two functionally linked proteins, RYR1 and Ca 1.1.

Cited by 18 publications

References 16 publications

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis

Pathogenic and rare deleterious variants in multiple genes suggest oligogenic inheritance in recurrent exertional rhabdomyolysis

Genetic Modifiers of Hereditary Neuromuscular Disorders and Cardiomyopathy

Skeletal muscle channelopathies: a guide to diagnosis and management

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