Cardiomyopathic Lentiginosis/LEOPARD Syndrome Presenting as Sudden Cardiac Arrest

Woywodt, Alexander; Welzel, Julia; Haase, Henning; Duerholz, Anke; Wiegand, Uwe K.H.; Potratz, Juergen; Sheikhzadeh, Abdolhamid

doi:10.1378/chest.113.5.1415

Cited by 32 publications

(24 citation statements)

References 8 publications

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“…In fact, it has been reported that LS patients with hypertrophic cardiomyopathy appear to be at increased risk of adverse events during follow-up. 32 Among the cardiac disorders, although conduction defects are frequent, the Wolf-Parkinson-White syndrome described in one of our patients is not a common manifestation.…”

Section: Discussionmentioning

confidence: 62%

See 1 more Smart Citation

LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

Carcavilla

Santomé

Pinto

et al. 2013

Revista Española de Cardiología (English Edition)

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Section: Discussionmentioning

confidence: 62%

“…In our setting, congenital heart disease has led to the definitive diagnosis in a large proportion of cases, and remains the most dangerous comorbidity in these patients. 32 Pulmonary valve stenosis was identified in 6 of our 19 patients, making it the second most common cardiac diagnosis. Three patients had both conditions simultaneously.…”

Section: Discussionmentioning

confidence: 91%

LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

Carcavilla

Santomé

Pinto

et al. 2013

Revista Española de Cardiología (English Edition)

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“…Interestingly, despite the recent demonstration of dilated cardiomyopathy in Shp2 null mice, 38 Shp2 loss-of-function in Leopard syndrome is accompanied by hypertrophic cardiomyopathy. 39 Conversely, only mild changes in myocardial mass have been reported in patients and mice with Shp2 gain-of-function in Noonan syndrome. 40,41 These observations imply that a reduced or increased activity of Shp2 may determine hypertrophic or hypotrophic phenotypes, respectively.…”

Section: Shp2 and Cardiomyocyte Hypertrophymentioning

confidence: 99%

Shp2 Negatively Regulates Growth in Cardiomyocytes by Controlling Focal Adhesion Kinase/Src and mTOR Pathways

Marin

Clemente

Santos

et al. 2008

Circulation Research

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Abstract-The aim of this study was to investigate whether Shp2 (Src homology region 2, phosphatase 2) controls focal adhesion kinase (FAK) activity and its trophic actions in cardiomyocytes. We show that low phosphorylation levels of FAK in nonstretched neonatal rat ventricular myocytes (NRVMs) coincided with a relatively high basal association of FAK with Shp2 and Shp2 phosphatase activity. Cyclic stretch (15% above initial length) enhanced FAK phosphorylation at Tyr397 and reduced FAK/Shp2 association and phosphatase activity in anti-Shp2 precipitates. Recombinant Shp2 C-terminal protein tyrosine phosphatase domain (Shp2-PTP) interacted with nonphosphorylated recombinant FAK and dephosphorylated FAK immunoprecipitated from NRVMs. Depletion of Shp2 by specific small interfering RNA increased the phosphorylation of FAK Tyr397, Src Tyr418, AKT Ser473, TSC2 Thr1462, and S6 kinase Thr389 and induced hypertrophy of nonstretched NRVMs. Inhibition of FAK/Src activity by PP2 {4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine} abolished the phosphorylation of AKT, TSC2, and S6 kinase, as well as the hypertrophy of NRVMs induced by Shp2 depletion. Inhibition of mTOR (mammalian target of rapamycin) with rapamycin blunted the hypertrophy in NRVMs depleted of Shp2. NRVMs treated with PP2 or depleted of FAK by specific small interfering RNA were defective in FAK, Src, extracellular signal-regulated kinase, AKT, TSC2, and S6 kinase phosphorylation, as well as in the hypertrophic response to prolonged stretch. The stretch-induced hypertrophy of NRVMs was also prevented by rapamycin. These findings demonstrate that basal Shp2 tyrosine phosphatase activity controls the size of cardiomyocytes by downregulating a pathway that involves FAK/Src and mTOR signaling pathways. Key Words: hypertrophy Ⅲ cell signaling Ⅲ cardiomyocytes Ⅲ focal adhesion kinase C ardiomyocytes respond to increases in functional demand by hypertrophic growth. This reactive hypertrophy involves concerted gene expression and the accumulation of myocyte proteins and organelles that are coordinated by signaling cascades activated by mechanical stress and a variety of soluble endocrine, paracrine, and autocrine factors. 1 Focal adhesion kinase (FAK) is involved in the hypertrophic response of cardiomyocytes to biomechanical stress and agonists such as phenylephrine and endothelin. [2][3][4][5][6] In cardiomyocytes, FAK is highly expressed, has a relatively low basal level of activity, and is promptly activated by hypertrophic stimuli. [2][3][4]7 FAK overexpression upregulates marker genes associated with hypertrophy in cardiomyocytes, 8 whereas a loss of FAK function impairs the upregulation of these genes in response to hypertrophic stimuli. 4 -6 The involvement of FAK in reactive hypertrophy has been confirmed in mice with cardiomyocyte-restricted FAK deletion or myocardial FAK silencing, 9 -11 but the mechanistic pathways that link FAK to hypertrophy in cardiomyocytes remain uncertain.Intracellularly, FAK is kept quiescent by intramolecular in...

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“…The 53-year-old Japanese man in this report is In the literature, other features associated with LEOPARD syndrome have been reported (5), including slowed peripheral nerve conduction (6), Gerstmann tetrad (7), Chiari I malformation (8), aneurysm (9,10) and intrahepatic portosystemic venous shunt (11). Moreover, Tojyo et al (12) reported a patient who had associated familial idiopathic brain calcification with dyschromatosis symmetrica hereditaria.…”

Section: Case Reportmentioning

confidence: 76%

Severe Cerebral Calcification in a Case of LEOPARD Syndrome

2008

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Cardiomyopathic Lentiginosis/LEOPARD Syndrome Presenting as Sudden Cardiac Arrest

Cited by 32 publications

References 8 publications

LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

Shp2 Negatively Regulates Growth in Cardiomyocytes by Controlling Focal Adhesion Kinase/Src and mTOR Pathways

Severe Cerebral Calcification in a Case of LEOPARD Syndrome

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