Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort

Ahamed, Hisham; Balegadde, Aniketh Vijay; Menon, Shilpa; Menon, Ramesh; Ramachandran, Anand; Mathew, Navin; Natarajan, K; Nair, Indu R.; Kannan, R.; Shankar, Meghna; Mathew, Oommen K.; Nguyen, Thong Tien; Gupta, Ravi; Stawiski, Eric; Ramprasad, Vedam; Seshagiri, Somasekar; Phalke, Sameer

doi:10.1038/s41598-020-77124-9

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…It is generally accepted that HCM associated with sarcomere gene mutations has a worse prognosis than non-sarcomeric forms of the disease ( Ho et al, 2018 ; Marstrand et al, 2020 ). However, several exceptions exist, such as HCM, associated with PRKAG2 gene mutations ( Ahamed et al, 2020 ). Thus, such rare clinical variants are waiting for more cases reported along with broader clinical and prospective descriptions.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant

et al. 2022

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Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary diseases, and it is associated with fatal complications. The clinical heterogeneity of HCM requires risk prediction models to identify patients at a high risk of adverse events. Most HCM cases are caused by mutations in genes encoding sarcomere proteins. However, HCM is associated with rare genetic variants with limited data about its clinical course and prognosis, and existing risk prediction models are not validated for such patients’ cohorts. TRIM63 is one of the rare genes recently described as a cause of HCM with autosomal-recessive inheritance. Herein, we present two cases of HCM associated with TRIM63-compound heterozygous variants in young male sportsmen. They demonstrated progressively marked hypertrophy, advanced diastolic dysfunction, a significant degree of fibrosis detected by magnetic resonance imaging, and clear indications for implantable cardioverter-defibrillator. One of the cases includes the first description of TRIM63-HCM with extreme hypertrophy. The presented cases are discussed in light of molecular consequences that might underlie cardiac and muscle phenotype in patients with mutations of TRIM63, the master regulator of striated muscle mass.

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Section: Discussionmentioning

confidence: 99%

Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant

et al. 2022

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“…Clinically, PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration ( 15 , 16 ). Typical clinical symptoms can develop at approximately 40 years.…”

Section: Discussionmentioning

confidence: 99%

Atrial Lesions in a Pedigree With PRKAG2 Cardiomyopathy: Involvement of Disrupted AMP-Activated Protein Kinase Signaling

Chen

Lin

Zhu

et al. 2022

Front. Cardiovasc. Med.

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PRKAG2 cardiomyopathy is a rare progressive disease characterized by increased ventricular wall thickness and preexcitation. Dysfunction of the protein 5′-AMP-activated protein kinase (AMPK) plays a decisive role in the progression of ventricular lesions. Although patients with the PRKAG2-R302Q mutation have a high incidence of atrial fibrillation (AF), the molecular mechanism contributing to the disease remains unclear. We carried out whole-genome sequencing with linkage analysis in three affected members of a family. Atrial samples were obtained from the proband via surgical intervention. Control atrium biopsies were obtained from patients with persistent AF. Pathological changes were analyzed using the hematoxylin and eosin (H&E), Masson, and periodic acid–Schiff (PAS) staining. The AMPK signaling pathway was investigated by western blot. A murine atrial cardiomyocyte cell line (HL-1) and human induced pluripotent stem derived atrial cardiomyocytes (hiPSC-ACMs) were transfected with an adenovirus carrying the same mutation. We used enzyme linked immunosorbent assay (ELISA) to determine the AMPK activity in HL-1 cells and hiPSC-ACMs overexpressing PRKAG2-R302Q. Pathological results showed a large quantity of glycogen accumulation and vacuolization in cardiomyocytes from the proband atrial tissue. Western blot analysis revealed that the AMPK activity was significantly downregulated compared with that of the controls. Furthermore, remarkable glycogen deposition and impairment of AMPK activity were reproduced in HL-1 cells overexpressing PRKAG2-R302Q. Taken together, PRKAG2-R302Q mutation directly impair atrial cardiomyocytes. PRKAG2-R302Q mutation lead to glycogen deposition and promote the growth of atrial lesions by disrupting the AMPK pathway.

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“…In previous studies, a group of heterogeneous diseases with specific genetic mutations was found to have similar HCM phenotypes, such as Anderson–Fabry disease (GLA), PRKAG2 syndrome, Danon disease (LAMP2), Pompe’s disease (GAA), LEOPARD, Noonan’s syndromes (RAF1 and PTPN11), TTR (amyloidosis), and Friederich’s ataxia (FXN) [ 4 , 5 ]. However, the prevalence of these rare diseases is diverse in different regions [ 6 ]. At present, it remains a challenge to accurately identify these rare diseases among patients with phenotypic HCM.…”

Section: Introductionmentioning

confidence: 99%

The Value of Cardiac Magnetic Resonance Imaging in Identification of Rare Diseases Mimicking Hypertrophic Cardiomyopathy

Fang

Wang

Kang

et al. 2021

JCM

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Background: The cardiac Magnetic Resonance Imaging (MRI) characteristics of rare diseases with the hypertrophic cardiomyopathy (HCM) phenotype are not well defined. Methods: Seventy-three sequential patients and 34 of their relatives, who have the HCM phenotype, were included. All subjects underwent cardiac MRI and genetic testing. Results: Of these 107 patients with phenotypic HCM, seven rare diseases were identified: four cases with LAMP2, one case with PRKAG2, one case with TTR mutation, and one case with senile systemic amyloidosis. Subjects with rare diseases had diffuse LGE, and the percentage of those with LGE was significantly higher than that of other HCM (median: 18.9%, interquartile range (IQR): 14.05 to 28.2% versus 7.8%, IQR: 4.41 to 14.56%; p = 0.003). Additionally, global T1 and ECV were significantly higher in subjects with rare diseases (global T1: 1423.1 ± 93.3 ms versus 1296.2 ± 66.6 ms; global ECV: 44.3 ± 11.5% versus 29.9 ± 4.5%; all p < 0.001). Conclusions: Cardiac MRI suggests the existence of distinct imaging characteristics, including via LGE and T1 mapping, among rare diseases that mimic HCM and HCM itself.

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Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort

Cited by 14 publications

References 36 publications

Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant

Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant

Atrial Lesions in a Pedigree With PRKAG2 Cardiomyopathy: Involvement of Disrupted AMP-Activated Protein Kinase Signaling

The Value of Cardiac Magnetic Resonance Imaging in Identification of Rare Diseases Mimicking Hypertrophic Cardiomyopathy

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