Glycogen Storage Diseases Presenting as Hypertrophic Cardiomyopathy

Arad, Michael; Maron, Barry J.; Gorham, Joshua M.; Johnson, Walter H.; Saul, J. Philip; Perez‐Atayde, Antonio R.; Spirito, Paolo; Wright, Gregory B.; Kanter, Ronald J.; Seidman, Christine E.; Seidman, Jonathan G.

doi:10.1056/nejmoa033349

Cited by 578 publications

(485 citation statements)

References 27 publications

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“…Similarly, previous studies have shown glycogen storage diseases mimicking HCM with mutations in PRKAG2-encoding protein kinase gamma 2 and LAMP2-encoding lysosome-associated membrane protein 2 [19]. Compared to myofilament-HCM, both Z-disc-and metabolic-HCM account for a relatively small percentage of HCM leaving a significant proportion of HCM genetically unexplained.…”

Section: Introductionmentioning

confidence: 52%

See 1 more Smart Citation

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Landstrom

Weisleder

Batalden

et al. 2007

Journal of Molecular and Cellular Cardiology

165

163

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Section: Introductionmentioning

confidence: 52%

“…Recent discoveries have implicated several genes encoding components of the Z-disc as well as genes previously associated with dilated cardiomyopathy in the pathogenesis of HCM [19,31,32]. This paper reports the discovery of S101R, Y141H, and S165F mutations in JPH2 as a novel genetic basis for HCM.…”

Section: Discussionmentioning

confidence: 85%

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Landstrom

Weisleder

Batalden

et al. 2007

Journal of Molecular and Cellular Cardiology

165

163

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“…Given the key role of GSK-3 in regulating glycogen storage, we asked whether enhanced glycogen storage, which leads to cardiac hypertrophy in patients with mutations in the γ 2 subunit of AMPK (22), could account for the hypertrophy in the Gsk3a -/-mice. Although we did find that GSK-3α regulated phosphorylation status of the critical Ser641 residue of glycogen synthase ( Figure 1C) and, consequently, glycogen storage in the heart, the absolute amount of glycogen in the heart was small (0.05% of that in the liver), and the increase compared with WT littermates was minimal (12.5 ± 0.36 vs. 15.7 ± 0.95 mg/g of tissue; P = 0.06).…”

Section: Hypertrophy In the Gsk-3α Komentioning

confidence: 99%

GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

Zhou¹,

Lal²,

Chen³

et al. 2010

J. Clin. Invest.

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The glycogen synthase kinase-3 (GSK-3) family of serine/threonine kinases consists of 2 highly related isoforms, α and β. Although GSK-3β has an important role in cardiac development, much remains unknown about the function of either GSK-3 isoform in the postnatal heart. Herein, we present what we believe to be the first studies defining the role of GSK-3α in the mouse heart using gene targeting. Gsk3a -/-mice over 2 months of age developed progressive cardiomyocyte and cardiac hypertrophy and contractile dysfunction. Following thoracic aortic constriction in young mice, we observed enhanced hypertrophy that rapidly transitioned to ventricular dilatation and contractile dysfunction. Surprisingly, markedly impaired β-adrenergic responsiveness was found at both the organ and cellular level. This phenotype was reproduced by acute treatment of WT cardiomyocytes with a small molecule GSK-3 inhibitor, confirming that the response was not due to a chronic adaptation to LV dysfunction. Thus, GSK-3α appears to be the central regulator of a striking range of essential processes, including acute and direct positive regulation of β-adrenergic responsiveness. In the absence of GSK-3α, the heart cannot respond effectively to hemodynamic stress and rapidly fails. Our findings identify what we believe to be a new paradigm of regulation of β-adrenergic signaling and raise concerns given the rapid expansion of drug development targeting GSK-3.

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“…Findings in the proband's mother illustrate that the later stages of illness are sufficiently destructive that characteristic findings may not be readily apparent. In light of the surprisingly high sample prevalence of 6/ 75 (8%) and 3/50 (6%) of LAMP2 mutations in two recent molecular screens of unselected hypertrophic cardiomyopathy patients (Arad et al 2005;Cheng et al 2012), a high index of suspicion for this condition is warranted, and routine screening using a combination of methods appears appropriate.…”

Section: Discussionmentioning

confidence: 99%

Danon Disease Due to a Novel LAMP2 Microduplication

et al. 2013

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Danon disease is a rare X-linked disorder comprising hypertrophic cardiomyopathy, skeletal myopathy, intellectual disability, and retinopathy; mutations of the lysosome-associated membrane protein gene LAMP2 are responsible. Most affected persons exhibit "private" point mutations; small locus rearrangements have recently been reported in four cases. Here, we describe the clinical, pathologic, and molecular features of a male proband and his affected mother with Danon disease and a small LAMP2 microduplication. The proband presented at age 12 years with exercise intolerance, hypertrophic cardiomyopathy, and increased creatine kinase. Endomyocardial biopsy findings were nonspecific, showing myocyte hypertrophy and reactive mitochondrial changes. Quadriceps muscle biopsy demonstrated the characteristic autophagic vacuoles with sarcolemma-like features. LAMP2 tissue immunostaining was absent; however, LAMP2 sequencing was normal.

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Glycogen Storage Diseases Presenting as Hypertrophic Cardiomyopathy

Cited by 578 publications

References 27 publications

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

GSK-3α directly regulates β-adrenergic signaling and the response of the heart to hemodynamic stress in mice

Danon Disease Due to a Novel LAMP2 Microduplication

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