Danon Disease

D’Souza, Ryan S; Levandowski, Cecilia B.; Slavov, Dobromir; Graw, Sharon; Allen, Larry A.; Adler, Eric; Mestroni, Luisa; Taylor, Matthew R.G.

doi:10.1161/circheartfailure.114.001105

Cited by 176 publications

(131 citation statements)

References 44 publications

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“…67) Danon disease is characterized by defects in autophagosome-lysosome fusion, where a mutation in LAMP2 disrupts intracellular catabolism, contributing to the accumulation of autophagic substrates in cardiomyocytes and skeletal muscle cells. 69,70) Pompe disease is a lysosomal storage disease characterized by defective glycogen metabolism. Enzyme replacement therapy is an effective treatment for Pompe disease, but some resistance to treatment may result from accumulation of autophagic debris.…”

Section: Effect Of Autophagy On the Heartmentioning

confidence: 99%

The Impact of Autophagy on Cardiovascular Senescence and Diseases

et al. 2017

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SummaryThe risk of cardiovascular disease increases with age, causing chronic disability, morbidity, and mortality in the elderly. Cardiovascular aging and disease are characterized by heart failure, cardiac ischemia-reperfusion injury, cardiomyopathy, hypertension, arterial stiffness, and atherosclerosis. As a cell ages, damaged organelles and abnormal proteins accumulate. A system for removing these cytoplasmic substrates is essential for maintaining homeostasis. Autophagy assists tissue homeostasis by forming a pathway by which these substances are degraded. Growing evidence suggests that autophagy plays a role in age-related and disease states of the cardiovascular system, and it may even be effective in preventing or treating cardiovascular disease. On the other hand, overexpression of autophagy in the heart and arteries can produce detrimental effects. We summarize the current understanding of the close relationship between autophagy and cardiovascular senescence.(Int Heart J 2017; 58: 666-673) Key words: Cardiovascular disease, Aging, Heart failure, Atherosclerosis T he human life span has significantly increased over recent decades and is expected to increase even further. Consequently, the prevalence of agerelated cardiovascular disease is also increasing. 1) Many risk factors for cardiovascular disease, such as hypertension, diabetes mellitus, dyslipidemia, and metabolic syndrome, emerge with age, and cardiovascular disease is the leading cause of chronic disability, morbidity, and mortality among the elderly. 2,3)The aging heart is associated with increases in left ventricular wall thickness, stiffness, and chamber size, as well as changes in the diastolic filling pattern, which can lead to cardiac dysfunction. 4,5) Age-related loss of vascular elasticity and stiffness increases cardiac after-load in the elderly. [6][7][8] As the body ages, damaged organelles and abnormal proteins accumulate, disrupting cellular homeostasis.9-11) A system for eliminating damaged organelles, proteins, and intracellular pathogens is critical for maintaining cellular homeostasis as the body ages. In recent years, it has become evident that autophagy plays a pivotal role in this regard. 12,13) In particular, autophagy functions as part of a pathway that delivers cytoplasmic substrates to lysosomes for subsequent degradation and removal. Autophagy modulates homeostasis and the body's response to stress, including energy deprivation in the heart, and altered autophagy is related to cardiovascular aging and disease.14-18) Because autophagy attenuates with age, interventions that increase autophagy may in turn reduce agerelated cardiovascular disease, prolonging the lifespan. 19-21)On the other hand, overexpression of autophagy in the heart can induce atrophy of cardiomyocytes, increasing the risk of ischemia-reperfusion injury. 22,23) This review summarizes our current understanding of the close relationship between autophagy and cardiovascular senescence. Three Types of AutophagyAutophagy is classified into 3 subtypes: macr...

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Section: Effect Of Autophagy On the Heartmentioning

confidence: 99%

The Impact of Autophagy on Cardiovascular Senescence and Diseases

et al. 2017

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“…Specifically, ventricular (Hedberg Oldfors et al, 2015;Miani et al, 2012;Maron et al, 2009;Lobrinus et al, 2005) and atrial (Charron et al, 2004) arrhythmias have both been reported and are often severe, even in women (Miani et al, 2012). Additionally, individuals with Danon disease can also develop (usually relatively mild) skeletal myopathy (80-90% of males), primarily mild cognitive defects and learning disabilities (70-100% of males), and visual problems (69% of males) (Thiadens et al, 2012;Schorderet et al, 2007;Prall et al, 2006;D'souza et al, 2014). For a complete and recent review of clinical descriptions of affected individuals, see D'souza et al (2014).…”

Section: Clinical Manifestations Of Danon Diseasementioning

confidence: 99%

“…The remaining part of exon 9 comprises both a single transmembrane domain (24 amino acids long) and a short cytoplasmic tail (11 amino acids long) at the Cterminal end Konecki et al, 1994Konecki et al, , 1995. The cytoplasmic tail is likely to function as a receptor for the uptake of proteins and, occasionally, other molecules (such as RNA and DNA) into the lysosome for their degradation (D'souza et al, 2014;Nishino et al, 2000). It is worth noting that although LAMP-1, which belongs to the same family as LAMP-2, shares 37% amino acid sequence homology with LAMP-2, these proteins have been found to be distinct and to have largely separate functions (Eskelinen, 2006).…”

Section: Lamp-2 Structure and Isoformsmentioning

confidence: 99%

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Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

Rowland

Sweet

Mestroni

et al. 2016

Journal of Cell Science

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Danon disease is a rare, severe X-linked form of cardiomyopathy caused by deficiency of lysosome-associated membrane protein 2 (LAMP-2). Other clinical manifestations include skeletal myopathy, cognitive defects and visual problems. Although individuals with Danon disease have been clinically described since the early 1980s, the underlying molecular mechanisms involved in pathological progression remain poorly understood. LAMP-2 is known to be involved in autophagy, and a characteristic accumulation of autophagic vacuoles in the affected tissues further supports the idea that autophagy is disrupted in this disease. The LAMP2 gene is alternatively spliced to form three splice isoforms, which are thought to play different autophagy-related cellular roles. This Commentary explores findings from genetic, histological, functional and tissue expression studies that suggest that the specific loss of the LAMP-2B isoform, which is likely to be involved in macroautophagy, plays a crucial role in causing the Danon phenotype. We also compare findings from mouse and cellular models, which have allowed for further molecular characterization but have also shown phenotypic differences that warrant attention. Overall, there is a need to better functionally characterize the LAMP-2B isoform in order to rationally explore more effective therapeutic options for individuals with Danon disease.

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“…18 The matrilineal patter of inheritance is a specific clue of mitochondriopathies caused by mitochondrial DNA mutation. 19 The age is a potential diagnostic clue: the presence of HCM in neonates and children suggests a congenital syndrome or an inherited metabolic disorder; 20 genetic forms due to sarcomeric gene mutations are most common in young adults but can occur in any age of life; 6 Danon disease occurs commonly in the first decades of life, 21 while senile amyloidosis occurs primarily in the elderly. 22 The symptoms in patients with HCM are non-specific and the physical examination is nearly normal in patients without an obstructive.…”

Section: Hypertrophic Phenotypementioning

confidence: 99%

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

2017

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Cardiomyopathies are little known to internists and general practitioners (GPs), and not always able to arouse the interest of cardiologists. Probably, this happens because cardiomyopathies are perceived as rare and complex disorders, a prerogative of a few dedicated centers. This may partly explain why the diagnosis of cardiomyopathy is often missed and, consequently, why cardiomyopathies are largely underdiagnosed. Internists and general practitioners should have an interest in these conditions, because cardiomyopathies are not as rare as generally perceived, and because their complexity can be unravelled with knowledge and methodology. Cardiomyopathies are defined as myocardial disorders in which the heart is structurally and functionally abnormal in the absence of coronary artery disease or abnormal loading conditions. Irrespective of the cardiac imaging technique used, a limited number of phenotypes are defined based on ventricular morphology and function. These basic phenotypes include hypertrophic, dilated, restrictive and right ventricular arrhythmogenic cardiomyopathies. Aim of this review is to describe a simplified approach to the detection of the underlying causes of specific phenotypes. We will focus our attention on the basic phenotypes, presenting a diagnostic work-up and a suggestive clinical case for each phenotype.

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Danon Disease

Cited by 176 publications

References 44 publications

The Impact of Autophagy on Cardiovascular Senescence and Diseases

The Impact of Autophagy on Cardiovascular Senescence and Diseases

Danon disease – dysregulation of autophagy in a multisystem disorder with cardiomyopathy

Diagnosis of Cardiomyopathies: Tips and Tricks for Internists and General Practitioners

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