P667V 54 15 2017Cardiac Manifestations in Children with Inborn Errors - PDF document

P667V 54 15, 2017Cardiac Manifestations in Children with Inborn Errors of MetabolismAPADOPOULOU R E V I E WR E V I E WR E V I E WR E V I E WR E V I E WAAAAARRRRRTTTTTIIIIICCC heterogeneous group of disorders with multi-organmanifestations, including the heart. Although theyare individually rare and incidence data is difficultto collect, they may be quite common collectively [1]. Asthe heart is a metabolically active organ,it can beadversely affected by metabolic defects [2]; the reported60% [3-5]. To our knowledge there is no systemic review P668V 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLICstructure disorders. It should be noted; however, thatTable able In many cases, cardiac manifestations dominate theclinical phenotype, as they include one of the prominentsymptoms (e.g., Pompe disease or disorders of fatty acidoxidation). In other metabolic defects; however, heartLastly, there are cases of metabolic errors in which theheart may be the only affected organ ( some some(Table impaired energy production due to enzyme deficiency,disturbed transport of molecules or cellular organelles mitochondrial dysfunction), (intermediary metabolites, which exert a toxic effect onfect on(Fig. 1). It is noteworthy that in many cases more than onemechanisms may be involved, especially in later stages ofthe disease course. Web Table summarizes the main summarizes the mainImpaired Energy ProductionDisturbed energy production is the most prominentcarnitine deficiency, fatty acid oxidation disorders, anddisorders, andIt is estimated that inherited metabolic disordersaccount for approximately 30% of definable causes ofcardiomyopathy in childhood [23]. More specifically,manifestation in children with primary carnitine deficiencycardio-myopathy. The average age of cardiomyopathycarnitine deficiency. While the incidence of dilatedcardiomyopathy, a mild degree of ventricular hypertrophy, a mild degree of ventricular

hypertrophyCardiomyopathy has also been reported in fatty acidmetabolism disorders. Defects involving oxidation of longor very long chain fatty acids are more frequentlyassociated with cardiomyopathy than those involvingoxidation of the short chain fatty acids. In fact, mostthis group of patients. Very-long-chain acyl-CoAery-long-chain acyl-CoAWith regards to other energy production defects,MELAS syndrome (mitochondrial encephalomyopathy,of left ventricular non-compaction. However, very few[26]. Hypertrophy of left ventricle is the dominant patternof myocardial involvement in MERRF (myoclonicdisease, as well as in complex I-V deficiency [2]. Theincidence of these cases in childhood is extremely low.TABLE INVOLVEMENTETABOLICType of inborn error of metabolismCardiomyopathyHeart rhythm disordersValvular diseaseCarnitine deficiency [10-12,22 ]++++++Fatty acid oxidation disorders [8,9]++++++-Organic acidemias17-21 ]++++-Storage disorders [5, 13-16 ]+++++++++Congenital glycosylation disorders [4]+++--+++: Retrospective/prospective studies, ++: Many case reports/series, +: Isolated case reports. P669V 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLICspecial interest. They represent a group of recently gene). Cases ofeffusions) in this group have been reported from thefusions) in this group have been reported from theOn the other hand, dilated cardiomyopathy has beenobserved in few subtypes of glycosylation disorders. Itusually results in lethal outcome and has been associatedwith mutations in dolichol kinase 1 gene. Therefore,patients with congenital disorders of glycosylation type IaTABLE II CARDIAC MANIFESTATIONSETABOLISMDiseaseProminent findingSecondary finding(s)Age at onsetCarnitine deficiencyCardiomyopathyHeart rhythm/ valvularNeonatal to early childhoodFatty acid oxidation disorderCardiomyopathy, heart–Neonatal to earlyAcidemiasCardiomyopathyHeart rhythm disordersNeonatal to childhoodCardiomyopa

thy, valvularHeart rhythm disordersLate infancy to childhoodPompeCardiomyopathy, heart–Infancy to childhoodCardiomyopathy, valvularHeart rhythm disordersLate infancy to childhoodCardiomyopathy, valvularHeart rhythm disordersLate infancy to childhoodCardiomyopathy–Neonatal *Cardiac manifestations ate usually not a presenting feature Enzyme deficiency, Disturbed molecules transport, Cell organelles dysfunctionImpaired energy production (carnitinedeficiency, fatty acid oxidationdisorders) cardiac manifestations are astages and include including heartPathophysiological mechanisms of cardiac involvement in metabolic disorders.    Infiltration of cardiac myocytes withstored substrate (storage disorders) Accumulation of intermediary toxicproducts (acidemias) •cardiomyopathy•heart rhythm disorders •cardiomyopathy•valvular dysfunction Cardiac manifestations are a prominentfinding, usually in early stages and  P670V 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLICABOLICDisturbed energy production is also involved in heartrhythm disorders. Case reports describing prolonged QTcmajor presenting symptom leading to the diagnosis of themajor presenting symptom leading to the diagnosis of the(Table ). Similarly,cases of QTc prolongation and heart rhythm disorders inliterature [10,11,31]. Studies have also shown that specificmutation) are associated with increased risk for Wolff--With regards to other heart-related manifestations,Trivellato, rivellato, urinary carnitine levels in adult patients with idiopathicmitral valve prolapse, but no further information on thistopic is available. Mitral valve regurgitation has beengitation has beenAlthough dysfunction of mitochondria in patients withvalvular disorders has been histopathologically confirmedand associated with aging, no correlation between specificmitochondrial diseases and valvular defects has beenreported [34].Infiltration of Cardiac Myocytes With

Stored Substratestorage disorders. Although hypertrophic cardio-Although hypertrophic cardio-(Table disease and Anderson-Fabry disease, in which cardiacAnderson-Fabry disease, in which cardiac(Table able with late-onset Pompe disease experience slowerprogression of muscle involvement and do not usuallyhave significant cardiac manifestations [13]. In Fabrydisease, left ventricular hypertrophy is the most commonpattern of cardiac involvement in childhood and canappear at an early age in both genders [2,14].Symmetrical hypertrophy of the left ventricle is themost frequent echocardiographic finding in glycogenstorage disease type III [15]. However, according to, according tomyopathy and cardiomyopathy..(Table IIambulatory electrocardiograms [16]. The co-existence ofDanon disease and Wolff-Parkinson-White syndrome,f-Parkinson-White syndrome,Valvular dysfunction is an additional significantfinding with the mitral valve being the most commonlyaffected valve. Cases of valvular defects in childhooddisease and mucopolysaccharidoses [38,39]. According toAccording tosaccharidosis can be associated with upregulation ofenzymes (that degrade collagen or collagen-associatedproteins), as well as with accumulation of glycosamino-glycans (that compete with proteoglycans to bind withcollagen). Macrophage infiltration seems to be the causeof mitral valve pathology in mucopolysaccharidosis VIVIToxic Intermediary Metabolitesof myocardial involvement in acidemias. The most P671V 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLICIt may include hypertrophic or dilated cardiomyopathy,,Isolated cases of prolonged QTc have been reportedpresenting symptom or as an additional finding in childrenalready diagnosed with this defect [19,20]. ArrhythmiasArrhythmiasco-existence of congenital heart structure disorders andorganic acidemias. Ebstein cardiac anomaly andganic acidemias. Ebstein cardiac anomaly andthe above case reports,

a clear pathophysiologicalassociation between structural heart disorders andmetabolic defects has not yet been identified.CLINICAL FEATURESMetabolic disorders have varying and overlappingclinical picture [49,50]. Symptoms and signs from thecardiovascular system are often non-specific and includeshortness of breath, hepatomegaly, edema, pathologicdeath [2]. The aforementioned symptomatology is relatedto a variety of cardiac diseases (cardiomyopathy, heart). It is noteworthy that in some caseschange and intensive exercise [50].for most physicians. A systematic approach is required systematic approach is requiredbiochemical findings are observed, such as metabolicacidosis, hypoglycemia, elevated creatine phospho-kinase, lactate or ammonia. However, the definitebased on advanced laboratory techniques. These includeurine organic acids profile, carnitine analysis, enzymaticassays or even molecular testing [49]. The knowledge ofThe knowledge ofThe diagnosis of cardiac manifestations is usuallybased on electrocardiographic and echocardiographicfindings. Conduction abnormalities and heart rhythmdisorders are easily diagnosed with the electrocardiogram,whilst echocardiography is the most easily applicableimagining tool for the diagnosis of defects of cardiacmorphology. Simple imaging techniques (. Simple imaging techniques (Until now few “genotype-phenotype correlations”have been described with regards to heart disorders due toinborn metabolic errors. The deeper understanding of theThe deeper understanding of theMANAGEMENT OF CARDIAC ABNORMALITIESSignificant progress has been made for the treatment ofmetabolic diseases, especially during the last decade. Alarge number of studies are still being conducted aimingfor better and more targeted therapies. Early diagnosis ischronic treatment. The same strategy is followed forand long-term management. The emergency treatment isTreatment of acute complications

is based on conventionaleatment of acute complications is based on conventionalIt is important; however, to note that cardiaccomplications are resistant to conventional therapies insome metabolic defects. More specifically, cardiacinotropes in patients with primary carnitine deficiency. Onthe contrary, continued therapy with oral L-carnitineefficiently alleviate the signs of cardiomyopathy [22].Positive outcomes have also been reported about the effectthese patients [10,11].underlying pathophysiology. New enzyme replacementtherapies seem to exert a beneficial effect on cardiac P672V 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLICPompe and Anderson-Fabry disease) [13,14] (Web Table Furthermore, liver transplantation represents definiteas organic acidemias. In these cases, cardiomyopathy tooganic acidemias. In these cases, cardiomyopathy tooCONCLUSIONSHeart disorders are increasingly being recognized ascomorbidity in children with inborn errors of metabolism.on this topic, the potential adverse effect of cardiaccannot be overlooked. At a clinical level, children withdefect and promote appropriate diagnostic work-up. Thepatients and their families. On the other hand, associatingdifferential diagnosis and contribute to a more cost-effective investigation.Consultant in Heart Failure and Transplantation, HarefieldHospital, Royal Brompton and Harefield NHS Trust, London,drafting of the manuscript. AE had substantial contributions toCompeting interests1.Applegarth DA, Toone JR, Lowry RB. Incidence of inborn2.Wicks EC, Elliott PM. Genetics and metabolic3.Evangeliou A, Papadopoulou-Legbelou K, Daphnis E,4.Gehrmann J, Sohlbach K, Linnebank M, Böhles HJ,5.Leal GN, de Paula AC, Leone C, Kim CA.6.El-Hattab AW. Inborn Errors of Metabolism. Clin7.Waisbren SE. Expanded newborn screening: information8.Xiong D, He H, James J, Tokunaga C, Powers C, Huang Y,9.Gélinas R, Thompson-Legault J, Bouchard B, Daneault C,

10.Rijlaarsdam RS, van Spronsen FJ, Bink-BoelkensMT, Reijngoud DJ, Wanders RJ, Niezen-Koning KE, 11.De Biase I, Champaigne NL, Schroer R, Pollard LM,atypically with long QT syndrome: A case report. JIMD12.Wang SB, Weng WC, Lee NC, Hwu WL, Fan PC, Lee WT.13.Winkel LP, Hagemans ML, van Doorn PA, Loonen MC,14.Hughes DA, Elliott PM, Shah J, Zuckerman J, CoghlanG, Brookes J, Mehta AB. Effects of enzyme replacementA randomised, double-blind, placebo-controlled clinical15.Mogahed EA, Girgis MY, Sobhy R, Elhabashy H,16.Cook AL, Kishnani PS, Carboni MP, Kanter RJ, Chen YT,17.Rigaud C, Lebre AS, Touraine R, Beaupain B, Ottolenghi18.Spencer CT, Bryant RM, Day J, Gonzalez IL, Colan SD,19.Baumgartner D, Scholl-Bürgi S, Sass JO, Sperl W,20.Jameson E, Walter J. Cardiac arrest secondary to long P673V 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLIC21.Chao PW, Chang WK, Lai IW, Liu C, Chan KH, Tsao CM.22.Fu LJ, Chen SB, Han LS, Guo Y, Zhao PJ, Zhu M, 23.Wang SM, Hou JW, Lin JL. A retrospective24.Fu L, Huang M, Chen S. Primary carnitine deficiency and25.Papadopoulou-Legbelou K, Gogou M, Dokousli V,26.Brisca G, Fiorillo C, Nesti C, Trucco F, Derchi M,27.Rudaks LI, Andersen C, Khong TY, Kelly A, Fietz M,28.Kapusta L, Zucker N, Frenckel G, Medalion B, Ben Gal T,29.Wiles JR, Leslie N, Knilans TK, Akinbi H. Prolonged QTc30.Yusuf K, Jirapradittha J, Amin HJ, Yu W, Hasan SU.31.Roussel J, Labarthe F, Thireau J, Ferro F, Farah C, Roy J, 32.Trivellato M, De Palo E, Gatti R, Parenti A, Piazza M.33.Matsushita T, Sano T, Nakano S, Matsuda H, Okada S.34.Shinde S, Kumar P, Mishra K, Patil N. Defect in35.Kishnani PS, Howell RR. Pompe disease in infants and36.Cheng Z, Fang Q. Wolff-Parkinson-White syndrome and37.Cheng Z, Fang Q. Danon disease: focusing on heart. J Hum38.Celik S, Erdol C, Baykan M, Gokce M, Orem C, Durmus I.39.Cripe LH, Ware SM, Hinton RB. Replacement of the aortic40.Bigg PW, Baldo G, Sleeper MM, O’Donnell PA, Ba

i H,41.Brands M, Roelants J, de Krijger R, Bogers A, Reuser A,42.Romano S, Valayannopoulos V, Touati G, Jais JP, Rabieraciduria are reversible after liver transplantation. J Pediatr.43.Lee TM, Addonizio LJ, Barshop BA, Chung WK. Unusual44.Prada CE, Al Jasmi F, Kirk EP, Hopp M, Jones O, Leslie45.Hanke SP, Gardner AB, Lombardi JP, Manning PB,et al46.Spencer CT, Byrne BJ, Gewitz MH, Wechsler SB, Kao AC,47.Qadi AM, Hamadah HK, Jijeh AM, Hijazi OM, Kabbani48.Palermo RA, Monge MC, Charrow J, Costello JM, Epting49.Burton BK. Inborn errors of metabolism in infancy: a guide50.Ahrens-Nicklas RC, Slap G, Ficicioglu C. Adolescent P 54 15, 2017 & EVANGELIOUANIFESTATIONSETABOLICWEB TABLE I EPORTINGANIFESTATIONSETABOLISMStudy [Ref.]TypePopulation [15 ]Retrospective28 children with glycogen storage9 cases with left ventricular hypertrophy [17 ]Retrospective22 patients with Barth syndromeCardiomyopathy documented in 20 patients. [22 ]Retrospective75 children with unexplained6 diagnosed with carnitine deficiency;cardiomyopathy L-carnitine has a good therapeutic effect on [5]Retrospective28 children with muco-Echocardiographic abnormalities in 26 patients. [14 ]Prospective15 patients with Anderson-FabryRegression of hypertrophic cardiomyopathy(double blinddisease by enzyme replacement therapyBaumgartner, . [19 ]Retrospective10 patients with propionic acidemiaQTc prolongation in 70%, rhythm disorders inleft ventricular contractility in 30% [3]Retrospective287 patients with inborn errors ofCardiac manifestations in 41 patients [16 ]Retrospective12 infants with Pompe diseaseSignificant ectopy in the ECG of 2 patientsSpencer, . [18 ]Retrospective34 patients with Barth syndromeClinical history of cardiomyopathy in 90%Wang, [23 ]Retrospective58 children with unexplained31% diagnosed with inborn errors ofcardiomyopathymetabolismWinkel, [13 ]Retrospective225 patients with Pompe diseaseCardiac symptoms in 25 patie