Kaski, Juan Pablo

Limongelli, Giuseppe

Monda, Emanuele

English

UCL Discovery

TYPE EditorialPUBLISHED 10 February 2023| DOI 10.3389/fped.2023.1147527EDITED AND REVIEWER BYRuth Heying,University Hospital Leuven, Belgium*CORRESPONDENCEGiuseppe Limongellilimongelligiuseppe@libero.itSPECIALTY SECTIONThis article was submitted to PediatricCardiology, a section of the journal Frontiers inPediatricsRECEIVED 18 January 2023ACCEPTED 25 January 2023PUBLISHED 10 February 2023CITATIONMonda E, Kaski JP and Limongelli G (2023)Editorial: Cardiovascular genetics—focus onpaediatric cardiomyopathy.Front. Pediatr. 11:1147527.doi: 10.3389/fped.2023.1147527COPYRIGHT© 2023 Monda, Kaski and Limongelli. This is anopen-access article distributed under the termsof the Creative Commons Attribution License(CC BY). The use, distribution or reproduction inother forums is permitted, provided the originalauthor(s) and the copyright owner(s) arecredited and that the original publication in thisjournal is cited, in accordance with acceptedacademic practice. No use, distribution orreproduction is permitted which does notcomply with these terms.Frontiers in PediatricsEditorial: Cardiovasculargenetics—focus on paediatriccardiomyopathyEmanuele Monda1, Juan Pablo Kaski2 and Giuseppe Limongelli1,2*1Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University ofCampania “Luigi Vanvitelli”, Monaldi Hospital, Naples, Italy, 2Centre for Paediatric Inherited and RareCardiovascular Disease, Institute of Cardiovascular Science, University College London, London,United KingdomKEYWORDScardiomyopathy, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrthythmogenic rightventricular cardiomyopathy, restrictive cardiomyopathyEditorial on the Research TopicCardiovascular genetics—focus on paediatric cardiomyopathyCardiomyopathies (CMPs) are a large group of disorders characterized by structural, functional,and electrical abnormalities of the heart muscle (1). These conditions are rare in childhood butassociated with increased mortality and morbidity (1). Over the last few years, data on thegenetic basis, natural history, risk stratification, and treatment of childhood CMPs have emerged.In this Research Topic, experts in the field explored this poorly characterised area withcomprehensive and state of the art reviews, original articles, and challenging case reports,dealing with molecular basis, role of genetic testing, clinical manifestations, outcome, andmanagement of childhood CMPs.This Research Topic collected 14 articles, and we are pleased to introduce them to readers ofFrontiers in Pediatrics.CardiomyopathiesChildhood CMPs include a large spectrum of diseases, with outcome mainly depending onphenotype, aetiology, and clinical characteristics (2). CMPs are generally categorized into 5 mainphenotypes, namely hypertrophic (HCM), dilated (DCM), restrictive (RCM), arrhythmogenic(ACM), and left ventricular non-compaction (LVNC) cardiomyopathy (3). In this regard,Rath et al. provided an overview of childhood CMPs, with a focus on epidemiology, naturalhistory, and outcomes according to clinical phenotype and aetiology.Recently, it has been observed that morphological, functional, and electrical abnormalities ofthe heart muscle may be part of the spectrum of Marfan syndrome and heritable thoracic aorticdisease (4), contributing to morbidity and mortality of these patients. In their review, LauraMuiño-Mosquera et al. reported data on preclinical studies (i.e., mouse models of Marfansyndrome) and described the clinical presentation of cardiovascular involvement of childrenand adults with genetic aortic diseases.Hypertrophic cardiomyopathyHCM is a myocardial disease characterized by increased left ventricular wall thickness notsolely explained by abnormal loading conditions (5). It represents the second most common01 frontiersin.orgMonda et al. 10.3389/fped.2023.1147527cause of CMP presenting in childhood. The aetiology of childhoodHCM is more heterogenous than seen in the adult population (6),and includes genetic syndromes (e.g., RASopathies) (7), inbornerrors of metabolism (8), and neuromuscular disorders (9).Among the different causes of HCM in childhood, mutations insarcomeric genes account for the large majority of cases. Norrishet al. provided a comprehensive review of sarcomeric HCM inchildren, highlighting the variability in disease expression andunanswered questions. In contrast, Monda et al. presented adetailed review of the non-sarcomeric causes of HCM in children,focusing on their pathophysiology, clinical features, diagnosis, andetiological therapy.In the large spectrum of HCM aetiologies, inborn errors ofmetabolism represent an extremely rare cause. For example,methylmalonic acidaemia is an inherited disease caused bymutations in different genes, which result in impairment ofmethylmalonyl-CoA mutase or impaired intracellular cobalamintransport and processing (10). Large studies describing the cardiacinvolvement of patients with methylmalonic acidaemia are lacking.Thus, Liu et al. screened 99 patients with methylmalonic acidaemiausing electrocardiography and echocardiography. In their originalarticle, the authors described the prevalence of congenital heartdisease, cardiomyopathy, and pulmonary hypertension, anddetailed electrocardiographic ed echocardiographic characteristicsof patients with this rare life-threatening disease.Exome sequencing demonstrated a high diagnostic yield inachieving a genetic diagnosis of rare disorders (11), and its role inthe diagnosis of rare CMPs is expanding (12). In this ResearchTopic, two well-characterized case reports of patients with raremitochondrial disorders associated with HCM diagnosed usingexome sequencing are described. Wang et al. described two cases ofSengers syndrome, a rare autosomal recessive disorder due tomutations in acylglycerol kinase (AGK) gene. Both cases exhibitedthe classic clinical presentation of Sengers syndrome, includingHCM, bilateral cataract, myopathy, and lactic acidosis. Furthermore,they provided a comprehensive literature systematic review ofpreviously published cases and discussed the importance of exomesequencing for the diagnosis of rare genetic diseases. Moreover,Wang et al. described the cases of a 14-year-old boy with HCM,exercise intolerance, ptosis, and lactic acidosis, and his 9-year-oldbrother with similar clinical feature. Using exome sequencing, thesetwo patients were diagnosed with early onset combined oxidativephosphorylation deficiency 33 (COXPD33), a rare mitochondrialdisease caused by a homozygous mutation in the C1QBP gene.Finally, Wang et al. in their mini-review, summarized thephysiological function of complement C1q binding protein (C1QBP)and its mutation-associated mitochondrial CMP.Dilated cardiomyopathyDilated cardiomyopathy is a myocardial disease characterized byleft ventricular dilation and dysfunction not solely explained bycongenital heart disease, valve disease, or coronary artery disease(13). DCM is the most common cause of childhood CMP and isassociated with a high risk for mortality (14). Several varieties ofcausation have been described for DCM and are generally classifiedFrontiers in Pediatrics 02as genetic and non-genetic causes (1). Among genetic causes ofchildhood DCM, a rare cause is represented by neuromusculardisorders (NMDs). NMDs may be inherited in autosomaldominant or recessive, or X-linked recessive patterns. Emery-Dreifuss muscular dystrophy is dominated by skeletal muscleweakness and cardiac involvement. However, cardiac abnormalitiesrarely appear in paediatric age. Kovalchuk et al. described fivepatients with different forms of Emery-Dreifuss musculardystrophy caused by mutations in EMD or LMNA genes,presented with early-onset of cardiac abnormalities and noprominent skeletal muscle phenotype.The pathophysiology of DCM is complex and not fullyelucidated. Recently, it has been reported that long non-codingRNAs (lncRNAs) play a crucial role in regulating diseasepresentation and severity of several cardiovascular diseases (15).Cai et al. evaluated the expression profile of lncRNAs in childrenwith DCM and explored their possible function, providing newrelevant perspective for future research.Arrhythmogenic cardiomyopathyArrhythmogenic right ventricular cardiomyopathy (ARVC) is amyocardial disease characterized by ventricular arrhythmias andventricular abnormalities, mainly manifesting as right ventriculardilation and/or dysfunction, caused by progressive fibrofattyreplacement of the myocardium (16). ARVC very rarely manifestsin childhood, and when it occurs is generally associated withworse outcome (17). Due to its rarity, several gaps in knowledgestill exist. In their clinically focused review, Te Riele et al.describes the spectrum of childhood ARVC, the geneticarchitecture of the disease, and current diagnostic and therapeuticstrategies.Restrictive cardiomyopathyRCM is a myocardial disease characterized by abnormal diastolicfunction with restrictive physiology and normal ventricular diameter,wall thickness and systolic function (1). While two thirds of childrenhave pure RCM phenotype, the remaining part has a mixed RCM-HCM phenotype (18). Children with RCM present the worstoutcomes among any paediatric CMP group. In their review,Ditaranto et al. summarized the causes of childhood RCM, theirpathophysiology, clinical presentation, and management.Left ventricular non-compactioncardiomyopathyLVNC is a myocardial disease characterized by prominent leftventricular trabeculae and deep intertrabecular recesses (1). LVNCis a very heterogeneous condition ranging from asymptomaticcases to severely affected individuals with need for transplantationor at risk for sudden cardiac death. Schultze-Berndt et al. describedthe genotype-phenotype correlation and clinical outcome of acohort of 149 patients (both paediatric and adult) with LVNC.frontiersin.orgMonda et al. 10.3389/fped.2023.1147527They found that reduced left ventricular systolic function was themain independent predictor for adverse events.Finally, next to articles purely focused on CMPs, Sarquella-Brugada et al. provide a comprehensive description of genotype-phenotype correlation of all rare variants in TRDN leading tomalignant arrhythmias in paediatric patients.The editors hope that readers of this Research Topic will find it ofinterest.Author contributionsEM, JPK and GL contributed equally to the conception anddrafting of the editorial. All authors contributed to the article andapproved the submitted version.Frontiers in Pediatrics 03Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Lipshultz SE, Law YM, Asante-Korang A, Austin ED, Dipchand AI, Everitt MD,et al. Cardiomyopathy in children: classification and diagnosis: a scientific statementfrom the American heart association. Circulation. (2019) 140(1):e9–e68. doi: 10.1161/CIR.00000000000006822. Norrish G, Field E, Mcleod K, Ilina M, Stuart G, Bhole V, et al. Clinical presentationand survival of childhood hypertrophic cardiomyopathy: a retrospective study in UnitedKingdom. Eur Heart J. (2019) 40(12):986–93. doi: 10.1093/eurheartj/ehy7983. Limongelli G, Adorisio R, Baggio C, Bauce B, Biagini E, Castelletti S, et al.Diagnosis and management of rare cardiomyopathies in adult and paediatric patients.A position paper of the Italian society of cardiology (SIC) and Italian society ofpaediatric cardiology (SICP). Int J Cardiol. (2022) 357:55–71. doi: 10.1016/j.ijcard.2022.03.0504. Hetzer R, Siegel G, Delmo Walter EM. Cardiomyopathy in Marfan syndrome. EurJ Cardiothorac Surg. (2016) 49(2):561–7;discussion 567–8. doi: 10.1093/ejcts/ezv0735. Ommen SR, Mital S, Burke MA, Day SM, Deswal A, Elliott P, et al. 2020 AHA/ACCguideline for the diagnosis and treatment of patients with hypertrophic cardiomyopathy:a report of the American college of cardiology/American heart association jointcommittee on clinical practice guidelines. Circulation. (2020) 142(25):e558–e631.doi: 10.1161/CIR.0000000000000937 Erratum in: Circulation. 2020 Dec 22;142(25):e633.6. Limongelli G, Monda E, Tramonte S, Gragnano F, Masarone D, Frisso G, et al.Prevalence and clinical significance of red flags in patients with hypertrophiccardiomyopathy. Int J Cardiol. (2020) 299:186–91. doi: 10.1016/j.ijcard.2019.06.0737. Lioncino M, Monda E, Verrillo F, Moscarella E, Calcagni G, Drago F, et al.Hypertrophic cardiomyopathy in RASopathies: diagnosis, clinical characteristics,prognostic implications, and management. Heart Fail Clin. (2022) 18(1):19–29.doi: 10.1016/j.hfc.2021.07.0048. Lioncino M, Monda E, Caiazza M, Fusco A, Cirillo A, Dongiglio F, et al.Cardiovascular involvement in mtDNA disease: diagnosis, management, andtherapeutic options. Heart Fail Clin. (2022) 18(1):51–60. doi: 10.1016/j.hfc.2021.07.0039. Monda E, Lioncino M, Rubino M, Passantino S, Verrillo F, Caiazza M, et al.Diagnosis and management of cardiovascular involvement in friedreich ataxia. HeartFail Clin. (2022) 18(1):31–7. doi: 10.1016/j.hfc.2021.07.00110. Huemer M, Diodato D, Schwahn B, Schiff M, Bandeira A, Benoist JF, et al.Guidelines for diagnosis and management of the cobalamin-related remethylationdisorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit MetabDis. (2017) 40(1):21–48. doi: 10.1007/s10545-016-9991-411. Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinicalwhole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. (2013)369(16):1502–11. doi: 10.1056/NEJMoa130655512. Girolami F, Iascone M, Pezzoli L, Passantino S, Limongelli G, Monda E, et al.Indicazioni all’esecuzione del test genetico nella diagnosi delle cardiomiopatie adesordio pediatrico: percorso clinico della Società Italiana di Cardiologia Pediatrica[Clinical pathway on pediatric cardiomyopathies: a genetic testing strategy proposedby the Italian Society of Pediatric Cardiology]. G Ital Cardiol (Rome). (2022) 23(7):505–15. Italian. doi: 10.1714/3831.3816813. Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al.Classification of the cardiomyopathies: a position statement from the EuropeanSociety Of Cardiology Working Group on Myocardial and Pericardial Diseases. EurHeart J. (2008) 29(2):270–6. doi: 10.1093/eurheartj/ehm34214. Monda E, Lioncino M, Pacileo R, Rubino M, Cirillo A, Fusco A, et al. Advancedheart failure in special population-pediatric age. Heart Fail Clin. (2021) 17(4):673–83.doi: 10.1016/j.hfc.2021.05.01115. Das S, Shah R, Dimmeler S, Freedman JE, Holley C, Lee JM, et al. NoncodingRNAs in cardiovascular disease: current knowledge, tools and technologies forinvestigation, and future directions: a scientific statement from the American heartassociation. Circ Genom Precis Med. (2020) 13(4):e000062. doi: 10.1161/HCG.000000000000006216. Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, et al.Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposedmodification of the Task Force Criteria. Eur Heart J. (2010) 31(7):806–14. doi: 10.1093/eurheartj/ehq02517. Smedsrud MK, Chivulescu M, Forså MI, Castrini I, Aabel EW, Rootwelt-NorbergC, et al. Highly malignant disease in childhood-onset arrhythmogenic right ventricularcardiomyopathy. Eur Heart J. (2022) 43(45):4694–703. doi: 10.1093/eurheartj/ehac48518. Webber SA, Lipshultz SE, Sleeper LA, Lu M, Wilkinson JD, Addonizio LJ,et al. Outcomes of restrictive cardiomyopathy in childhood and theinfluence of phenotype: a report from the Pediatric CardiomyopathyRegistry. Circulation. (2012) 126(10):1237–44. doi: 10.1161/CIRCULATIONAHA.112.104638frontiersin.org

Editorial: Cardiovascular genetics-focus on paediatric cardiomyopathy

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Editorial: Cardiovascular genetics-focus on paediatric cardiomyopathy

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