Why are some patients with Duchenne muscular dystrophy dying young: An analysis of causes of death in North East England

Ruiten, H.J.A. van; Bettolo, C. Marini; Cheetham, Tim; Eagle, Michelle; Lochmüller, Hanns; Straub, Volker; Bushby, Kate; Guglieri, Michela

doi:10.1016/j.ejpn.2016.07.020

Cited by 70 publications

(52 citation statements)

References 19 publications

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“…Thbs proteins are induced in cardiac and skeletal muscle during injury or disease (8,10,11,29,44,45), which is likely a compensatory protective mechanism that increases membrane trafficking of integrins and DGC components to prevent mechanical loadinduced sarcolemmal damage, as well as increase secretion of ECM proteins involved in healing and overall structural integrity. Importantly, heart failure is a leading cause of mortality in Duchenne muscular dystrophy and other muscular dystrophies (46)(47)(48)(49), so therapeutic strategies that could bolster DGC complex stability at the plasma membrane with selectively enhanced ECM content in cardiomyocytes could potentially extend the life span of muscular dystrophy patients.…”

Section: Discussionmentioning

confidence: 99%

Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

Brody

Vanhoutte

Schips

et al. 2018

Molecular and Cellular Biology

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Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle where it activates an adaptive endoplasmic reticulum (ER) stress-response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. Here we generated transgenic mice with cardiac-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions. Like wild-type Thbs4, the secretion-defective mutant upregulates the adaptive ER stress response and expands the ER and intracellular vesicles in cardiomyocytes. However, only the secretion-defective Thbs4 mutant produces cardiomyopathy with sarcolemmal weakness and rupture that is associated with reduced adhesion-forming glycoproteins in the membrane. Similarly, deletion of in the mouse model of Duchenne muscular dystrophy enhances cardiomyocyte membrane instability and cardiomyopathy. Finally, overexpression of the secretion-defective Thbs4 mutant in , but not wild-type Thbs4, impaired muscle function and sarcomere alignment. These results suggest that transit through the secretory pathway is required for Thbs4 to augment sarcolemmal stability, while ER stress induction and vesicular expansion mediated by Thbs4 is an exclusively intracellular process.

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Section: Discussionmentioning

confidence: 99%

Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

Brody

Vanhoutte

Schips

et al. 2018

Molecular and Cellular Biology

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“…The focal myocardial fibrosis, diffused fatty infiltration and disarray of partial cardiomyocytes were observed morphologically, demonstrating that the decedent suffered from an early DCM [13,14]. Although the heart failure is the leading cause of death in DMD patients, deaths resulting from pneumonia, multi-organ failure, malnutrition, fat embolism and adrenal insufficiency cannot be ignored [4]. It is difficult to make sure the immediate cause of death without any clinical information.…”

Section: Discussionmentioning

confidence: 99%

“…According to the gross and histopathological examination, we excluded the other possible causes of death, such as pneumonia, fat embolism, malnutrition and multiple organ failure. Adrenal insufficiency could also be ruled out because it often occurs in the patients who rely on regular corticosteroids [4]. As mentioned above, it is concluded that the sudden death of the decedent was linked to an early DCM/LV dysfunction secondary to DMD, leading to acute cardiac failure.…”

Section: Discussionmentioning

confidence: 99%

“…The patients, particularly in prolonged course of this disease, are vulnerable to the highest risk of cardiac complications. The leading cause of death is cardio-respiratory failure, followed by pneumonia, multi-organ failure, malnutrition, fat embolism and adrenal insufficiency [4]. Given the diagnosis of DMD relies on clinical history and manifestations, it is a challenge to determine the cause of death in patients with DMD if no clinical information is provided in forensic practice.…”

Section: Introductionmentioning

confidence: 99%

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Sudden cardiac death of Duchenne muscular dystrophy with NT-proBNP in pericardial fluid as a useful biomarker for diagnosis of the cause of death: a case report

Zhang

Zhao

et al. 2017

Forensic Sciences Research

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Duchenne muscular dystrophy (DMD) is one of the most common and severest muscular dystrophies. Although it can be a cause of death when associated with cardiac muscle and/or respiratory muscles, no cases of sudden deaths in the setting of undiagnosed DMD with cardiac involvement have been reported in the literatures. Previous studies showed that N-terminal-proBNP (NT-proBNP) was a robust laboratory biomarker to diagnose and monitor cardiac failure in clinical situations, suggesting that it may be used as an auxiliary indicator for diagnosis on left ventricular dysfunction in sudden cardiac deaths in forensic settings. Here, we reported a case of 29-year-old man who died suddenly. Autopsy revealed that muscles of the body were almost replaced by fatty and fibrotic tissues. The heart was enlarged with disarray and degeneration of cardiomyocytes in cardiac muscle. Total absence of dystrophin was detected by immunohistochemical staining, which confirmed DMD. Postmortem biochemical test of pericardial fluid revealed a high level of NT-proBNP, indicating dysfunction of the left ventricle before death. The cause of death was certified as an early dilated cardiomyopathy (DCM)/dysfunction of the left ventricle secondary to DMD, suggesting that sudden cardiac death with cardiac dysfunction could be identified by immunohistochemical method in combination with pericardial fluid NT-proBNP determination after systemic autopsy.

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“…Patients with MD may have subclinical involvement for years prior to symptom onset and even otherwise asymptomatic genetic carriers of muscular dystrophies may develop cardiac manifestations [2]. Many patients with cardiac involvement are at higher risk for advanced heart failure and/or sudden cardiac death [3,4]. It is important to identify early on markers of cardiac involvement to initiate cardio-protective therapies, to limit progression and to attenuate symptoms of heart failure [5,6].…”

Section: Introductionmentioning

confidence: 99%

The Added Value of Cardiac Magnetic Resonance in Muscular Dystrophies

Lamacie

Warman‐Chardon

Crean

et al. 2019

JND

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Muscular dystrophies (MD) represent a heterogeneous group of rare genetic diseases that often lead to significant weakness due to progressive muscle degeneration. In many forms of MD, cardiac manifestations including heart failure, atrial and ventricular arrhythmias and conduction abnormalities can occur and may be a predominant feature of the disease. Cardiac magnetic resonance (CMR) can assess cardiac anatomy, global and regional ventricular function, volumes and mass as well as presence of myocardial inflammation, infiltration or fibrosis. The role for cardiac MRI has been well-established in a wide range of muscular dystrophies related cardiomyopathies. CMR is a more sensitive technique than echocardiography for early diagnosis of cardiac involvement. It has also great potential to improve the prediction of long-term outcome, particularly the development of heart failure and arrhythmic events; however it still has to be validated by longitudinal studies including large populations. This review will outline the utility of CMR in patients with muscular dystrophies for assessment of myocardial involvement, risk stratification, and in guiding therapeutic management.

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Why are some patients with Duchenne muscular dystrophy dying young: An analysis of causes of death in North East England

Cited by 70 publications

References 19 publications

Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy

Sudden cardiac death of Duchenne muscular dystrophy with NT-proBNP in pericardial fluid as a useful biomarker for diagnosis of the cause of death: a case report

The Added Value of Cardiac Magnetic Resonance in Muscular Dystrophies

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