Clinical Spectrum of
            <i>PRKAG2</i>
            Syndrome

Porto, Andrea Giuseppe; Brun, Francesca; Severini, Giovanni Maria; Losurdo, Pasquale; Fabris, Enrico; Taylor, Matthew R.G.; Mestroni, Luisa; Sinagra, Gianfranco

doi:10.1161/circep.115.003121

Cited by 117 publications

(89 citation statements)

References 49 publications

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“…There is variability of cardiac involvement in PRKAG2 as shown in Table 1. He did have a family member die of a sudden cardiac event, and based on current literature, there is a broader clinical spectrum of this disorder beyond cardiac involvement which includes myalgia, myopathy and seizures [6,7]. This patient was diagnosed with a pathogenic mutation in PRKAG2, Gly100Ser.…”

Section: Discussionmentioning

confidence: 98%

“…The disease phenotype is a spectrum that is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation (age range 8 to 42 years of age) of cardiac manifestations such as increased left ventricular wall thickness and ventricular pre-excitation [5]. Also, symptoms of myalgia, myopathy, and seizures have been reported further expanding the phenotype and characterization of it beyond a cardiac syndrome as was previously thought [6,7]. Mutations in the PRKAG2 gene cause chronic activation of AMPK and the underlying mechanism of excess glycogen accumulation in PRKAG2 syndrome is illustrated in Fig.…”

Section: Introductionmentioning

confidence: 96%

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Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation

Austin

Chiou

Sun

et al. 2017

Molecular Genetics and Metabolism

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a b s t r a c t a r t i c l e i n f oObjective: PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with alglucosidase-alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene. Case report: At 2.5 months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11 months. However, 1 month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted. Conclusion: This report outlines the benefits of ERT with alglucosidase alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 96%

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation

Austin

Chiou

Sun

et al. 2017

Molecular Genetics and Metabolism

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“…have been linked to hypertrophic cardiomyopathy and arrhythmias. 36 PRKAG2 is highly expressed in the heart, and it was reported that the g2b-3b isoform was most highly expressed in the heart. 46 In healthy left ventricles, we found that ~55% of transcripts originated from the g2b promoter and ~35% originate from the g2-3b promoter.…”

Section: Discussionmentioning

confidence: 99%

“…We annotated a significant promoter switch in PRKAG2, a gene linked to hypertrophic cardiomyopathy and critical to heart metabolism. [36][37][38] Three major PRKAG2 promoters were identified, encoding three different isoforms-g2a, g2-3b, and g2b ( Figure 5D).…”

Section: Correlation Of Cage-sequencing and Rna-sequencingmentioning

confidence: 99%

Enhancer and promoter usage in the normal and failed human heart

Am¹,

Dellefave‐Castillo²,

Pgt³

et al. 2020

Preprint

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Word count: 5331 (excluding references and legends)Short title: Promoter and enhancer shifts in heart failure ABSTRACTThe failed heart is characterized by re-expression of a fetal gene program, which contributes to adaptation and maladaptation in heart failure. To define genomewide enhancer and promoter use in heart failure, Cap Analysis of Gene Expression (CAGE-seq) was applied to healthy and failed human left ventricles to define short RNAs associated with both promoters and enhancers. Integration of CAGE-seq data with RNA sequencing identified a combined ~17,000 promoters and ~1,500 enhancers active in healthy and failed human left ventricles. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered amino-terminal protein sequences. Comparing enhancer usage between healthy and failed hearts revealed a majority of differentially utilized heart failure enhancers were intronic and primarily localized within the first intron, identifying this position as a common feature associated with tissue-specific gene expression changes in the heart. This dataset defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Wang from the Northwestern University sequencing core and Yujiro Takegami from DNAFORM for their excellent technical support. AG conducted the analysis and drafted the mansuscript. LDC secured patient consent and genotype information. PP assisted with genotyping. JAW provided access to control samples. DYB and MJP provided helpful advice and commentary and assisted with interpretation. MAN and EMM assisted with analysis, writing and editing the manuscript.

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“…We describe a 6‐year‐old child with a 12‐Mb deletion of the region 7q35q36.3. Among the deleted genes, two genes have cardiac implications: KCNH2 , coding for a cardiac potassium channel involved in long QT syndrome (LQTS) (Perrin, Subbiah, Vandenberg, & Hill, ); and PRKAG2 , associated with hypertrophic cardiomyopathy, cardiac conduction disease, and sudden death (Porto et al, ). Our report underlines the relationship among potential cardiac complications and rare multiorgan and proteiform disease, with pharmacological implications in the daily management.…”

Section: Introductionmentioning

confidence: 99%

Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription

Stolfo

Accadia²,

Mastroianno

et al. 2019

Molec Gen & Gen Med

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Background The deletion of the distal 7q region is a rare chromosomal syndrome characterized by wide phenotypic manifestations including growth and psychomotor delay, facial dysmorphisms, and genitourinary malformations. Methods We describe a 6‐year‐old child with a 12‐Mb deletion of the region 7q35q36.3. Results Among the deleted genes, two genes have cardiac implications: PRKAG2 (OMIM #602743), associated with hypertrophic cardiomyopathy, cardiac conduction disease, and sudden death, and KCNH2 (OMIM #152427), coding for a cardiac potassium channel involved in long QT syndrome, unmasked by the chlorpheniramine treatment. At same time, the SHH gene (OMIM #600725), encoding sonic hedgehog, a secreted protein that is involved in the embryonic development, is deleted. Conclusion Our report underlines potential cardiac complications linked to the common pharmacological treatment in this rare multiorgan and proteiform disease.

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Clinical Spectrum of PRKAG2 Syndrome

Cited by 117 publications

References 49 publications

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation

Enhancer and promoter usage in the normal and failed human heart

Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription

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