Cardiac disease in children and young adults with various lysosomal storage diseases: Comparison of echocardiographic and ECG changes among clinical groups

Müeller, Peter R.; Jost, Christine H. Attenhofer; Rohrbach, Marianne; Buechel, Emanuela R. Valsangiacomo; Seifert, Burkhardt; Balmer, Christian; Kretschmar, Oliver; Baumgartner, Matthias; Weber, Roland

doi:10.1016/j.ijchv.2013.10.002

Cited by 9 publications

(10 citation statements)

References 45 publications

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“…One such disorder, mucolipidosis II (MLII), is commonly associated with cardiomyopathy, mitral valve prolapse, and aortic regurgitation ( 11 – 13 ). Furthermore, many children with the attenuated disorder, MLIII, have undergone valve replacement surgery ( 14 , 15 ). MLII is caused by loss of mannose-6-phosphate–dependent (M6P-dependent) lysosomal targeting ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Lu¹,

Moreland²,

Christian³

et al. 2020

JCI Insight

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Although congenital heart defects (CHDs) represent the most common birth defect, a comprehensive understanding of disease etiology remains unknown. This is further complicated since CHDs can occur in isolation or as a feature of another disorder. Analyzing disorders with associated CHDs provides a powerful platform to identify primary pathogenic mechanisms driving disease. Aberrant localization and expression of cathepsin proteases can perpetuate later-stage heart diseases, but their contribution toward CHDs is unclear. To investigate the contribution of cathepsins during cardiovascular development and congenital disease, we analyzed the pathogenesis of cardiac defects in zebrafish models of the lysosomal storage disorder mucolipidosis II (MLII). MLII is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (Gnptab) that disrupt carbohydrate-dependent sorting of lysosomal enzymes. Without Gnptab, lysosomal hydrolases, including cathepsin proteases, are inappropriately secreted. Analyses of heart development in gnptab -deficient zebrafish show cathepsin K secretion increases its activity, disrupts TGF-β–related signaling, and alters myocardial and valvular formation. Importantly, cathepsin K inhibition restored normal heart and valve development in MLII embryos. Collectively, these data identify mislocalized cathepsin K as an initiator of cardiac disease in this lysosomal disorder and establish cathepsin inhibition as a viable therapeutic strategy.

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Section: Introductionmentioning

confidence: 99%

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Lu¹,

Moreland²,

Christian³

et al. 2020

JCI Insight

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“…Medical histories of electrocardiogram abnormalities or dysrhythmias previously reported in Pompe disease (e.g., PR interval shortening, 14 Wolff-Parkinson-White syndrome, and/or supraventricular tachycardia 17 ) occurred in a few patients, in the presence or absence of cardiomyopathy.…”

Section: Cardiac Safety Datamentioning

confidence: 98%

Cardiac responses in paediatric Pompe disease in the ADVANCE patient cohort

et al. 2021

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Pompe disease results from lysosomal acid α-glucosidase deficiency, which leads to cardiomyopathy in all infantile-onset and occasional late-onset patients. Cardiac assessment is important for its diagnosis and management. This article presents unpublished cardiac findings, concomitant medications, and cardiac efficacy and safety outcomes from the ADVANCE study; trajectories of patients with abnormal left ventricular mass z score at enrolment; and post hoc analyses of on-treatment left ventricular mass and systolic blood pressure z scores by disease phenotype, GAA genotype, and “fraction of life” (defined as the fraction of life on pre-study 160 L production-scale alglucosidase alfa). ADVANCE evaluated 52 weeks’ treatment with 4000 L production-scale alglucosidase alfa in ≥1-year-old United States of America patients with Pompe disease previously receiving 160 L production-scale alglucosidase alfa. M-mode echocardiography and 12-lead electrocardiography were performed at enrolment and Week 52. Sixty-seven patients had complete left ventricular mass z scores, decreasing at Week 52 (infantile-onset patients, change −0.8 ± 1.83; 95% confidence interval −1.3 to −0.2; all patients, change −0.5 ± 1.71; 95% confidence interval −1.0 to −0.1). Patients with “fraction of life” <0.79 had left ventricular mass z score decreasing (enrolment: +0.1 ± 3.0; Week 52: −1.1 ± 2.0); those with “fraction of life” ≥0.79 remained stable (enrolment: −0.9 ± 1.5; Week 52: −0.9 ± 1.4). Systolic blood pressure z scores were stable from enrolment to Week 52, and no cohort developed systemic hypertension. Eight patients had Wolff–Parkinson–White syndrome. Cardiac hypertrophy and dysrhythmia in ADVANCE patients at or before enrolment were typical of Pompe disease. Four-thousand L alglucosidase alfa therapy maintained fractional shortening, left ventricular posterior and septal end-diastolic thicknesses, and improved left ventricular mass z score. Trial registry: ClinicalTrials.gov Identifier: NCT01526785 https://clinicaltrials.gov/ct2/show/NCT01526785. Social Media Statement: Post hoc analyses of the ADVANCE study cohort of 113 children support ongoing cardiac monitoring and concomitant management of children with Pompe disease on long-term alglucosidase alfa to functionally improve cardiomyopathy and/or dysrhythmia.

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“…Each one of the diseases comprising the group of LSDs is considered a rare genetic disease due to a prevalence ranging between 1:57,000 and 1:4,200,000 individuals; however, a combined prevalence across all LSDs indicates a prevalence as high as 1:5000 [ 2 , 3 ]. Notable symptoms presenting across this disease class include hepatosplenomegaly, ischemic stroke, seizures, cardiovascular involvement, and musculoskeletal and neurodegenerative manifestations [ 4 , 5 , 6 , 7 , 8 ]. The most frequently-occurring LSD, Gaucher disease (GD: OMIM 230800, type 1, non-neuronopathic; OMIM 230900, type 2, acute neuronopathic; OMIM 231000, type 3, sub-acute neuronopathic), has an autosomal recessive mode of inheritance, a neurodegenerative component in the most severe forms, and has been shown to exhibit a marked concurrence with Parkinson’s disease (PD) in patients with GD.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

A Prospective Treatment Option for Lysosomal Storage Diseases: CRISPR/Cas9 Gene Editing Technology for Mutation Correction in Induced Pluripotent Stem Cells

Christensen

Choy

2017

Diseases

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Ease of design, relatively low cost and a multitude of gene-altering capabilities have all led to the adoption of the sophisticated and yet simple gene editing system: clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9). The CRISPR/Cas9 system holds promise for the correction of deleterious mutations by taking advantage of the homology directed repair pathway and by supplying a correction template to the affected patient's cells. Currently, this technique is being applied in vitro in human-induced pluripotent stem cells (iPSCs) to correct a variety of severe genetic diseases, but has not as of yet been used in iPSCs derived from patients affected with a lysosomal storage disease (LSD). If adopted into clinical practice, corrected iPSCs derived from cells that originate from the patient themselves could be used for therapeutic amelioration of LSD symptoms without the risks associated with allogeneic stem cell transplantation. CRISPR/Cas9 editing in a patient's cells would overcome the costly, lifelong process associated with currently available treatment methods, including enzyme replacement and substrate reduction therapies. In this review, the overall utility of the CRISPR/Cas9 gene editing technique for treatment of genetic diseases, the potential for the treatment of LSDs and methods currently employed to increase the efficiency of this re-engineered biological system will be discussed.

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Cardiac disease in children and young adults with various lysosomal storage diseases: Comparison of echocardiographic and ECG changes among clinical groups

Cited by 9 publications

References 45 publications

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Inappropriate cathepsin K secretion promotes its enzymatic activation driving heart and valve malformation

Cardiac responses in paediatric Pompe disease in the ADVANCE patient cohort

A Prospective Treatment Option for Lysosomal Storage Diseases: CRISPR/Cas9 Gene Editing Technology for Mutation Correction in Induced Pluripotent Stem Cells

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