Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Abstract

Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

Keywords: arrhythmogenic disorders; cardiomyopathies; congenital disorders of glycosylation; congenital heart disease; disorders of pentose phosphate pathway; disorders of sugar transporters; glycogen storage disorders; heart failure; inborn errors of metabolism; lysosomal storage disorders.

Figure 1

PRISMA flow diagram of the systematic search strategy. (a) Definition of the terms used for the systematic search performed for each IMD [7,14]. (b) Pooled results of the systematic searches, including the total number of studies found, screened and included. The terms used to build the search queries are reported in Supplementary Table S1. The details of the separate systematic searches performed for each disorder (e.g., excluded and included articles) are reported in Supplementary Tables S2 and S3. For four disorders, G6PDH-, GAA-. GLA- and GALNS-deficiency, respectively, we selected the articles manually and not systematically due to the high volume of records identified (>300 articles/each).

Figure 2

Summary of the inherited disorders of carbohydrate metabolism associated to cardiac manifestations, contextualized with the main carbohydrate metabolic pathways in cardiac cells. Abbreviations: CDG, congenital disorder of glycosylation; ECM, extracellular matrix (yellow); ER, endoplasmic reticulum (orange); GA, Golgi apparatus (red); GSD, glycogen storage disorder; MT, mitochondrion (green). Other symbols: fucose molecules, red triangles; galactose molecules, yellow circles; glucose molecules, blue circles; GlcNAc molecules, blue squares; mannose molecules, green circles; sialic acid molecules, purple diamonds; transporters, grey ovals; cell nucleus colored in purple; cytoplasm colored in pink.