Cardiogenetics 2011; volume 1:e9

Genetics of cardiomyopathies basis and the pathophysiological mechanisms responsible for the disorders. Correspondence: Matteo Vatta, Department of in children Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Matteo Vatta,1 Jeffrey A. Towbin2 E-mail: [email protected] DCM is characterized by an enlarged left 1Department of Molecular and Human ventricular chamber, left ventricular wall thin- Key words: sudden cardiac death, dilated car- Genetics, Baylor College of Medicine, ning and systolic dysfunction.1-4 Individuals diomyopathy, hypertrophic cardiomyopathy, left Houston, TX; 2The Heart Institute, with DCM commonly present with sympto- ventricular noncompaction, restrictive cardiomy- Cincinnati Children’s Hospital Medical matic heart failure, arrhythmias or conduction opathy, arrhythmogenic right ventricular car- Center, Cincinnati, OH, USA disturbance.1-4 DCM in children has an esti- diomyopathy, Nav1.5, LQTS, ion channels. mated incidence of approximately 0.57/100,000 cases compared to the report of 1/2,500 inci- Received for publication: 16 May 2011. Accepted for publication: 20 July 2011. dence in adult subjects.2 However, the actual Abstract incidence could be far higher due to reduced This work is licensed under a Creative Commons detection rate caused by incomplete pene- Attribution NonCommercial 3.0 License (CC BY- Cardiomyopathies are diseases of the heart trance and variable expressivity observed in NC 3.0). DCM, which can lead to a prolonged asympto- muscle leading to heart failure and/or an ©Copyright M. Vatta and J.A. Towbin, 2011 increased risk of arrhythmogenic sudden car- matic period preceding the development of overt heart failure. Licensee PAGEPress, Italy diac death. These disorders represent a major Cardiogenetics 2011; 1:e9 Although a significant proportion of child- cause of morbidity and mortality in children. In doi:10.4081/cardiogenetics.2011.e9 childhood forms of cardiomyopathy, genetic hood DCM could be attributed to infections 5,6 etiologies are frequent, but non-genetic or causing myocarditis (16%), a large fraction of pediatric DCM can be genetic in origin, acquired causes, such viral infection, also play either sporadic, if the child has no previous perinuclear membrane, can lead to a transient a significant role. In the last twenty years, the family history and screening of first degree rel- hypertrophic phase, followed by decompensat- genetic causes of cardiomyopathies have been only atives is negative, or familial if it occurs in two ed systolic performance, left ventricular wall increasingly identified and clinical correla- or more close relatives.1-7 Currently, familial thinning and left ventricular chamber dila- tions are beginning to be defined. Here we DCM is estimated to occur in up to 67% of tion.7 present an overview of the recent advances in cases after accurate screening of the relatives Currently, approximately 33 have our understanding of the genetics of cardiomy- of idiopathic DCM subjects.8 use been identified to cause DCM in isolation, opathies in children and what is known about A significant percentage of DCM cases may demonstrating a high level of genetic hetero- the pathophysiological mechanisms underly- be explained by mutations in single genes that geneity (Table 1), and many private mutations ing these -related forms of disease. affect critical pathways of contractile function, have been observed in unrelated subjects sug- ion distribution, or cellular function. This was gesting a high level of allelic heterogeneity.7 In initially demonstrated by the breakthrough addition, several genes have also been identi- Introduction identification of , the gene respon- fied that are associated with syndromic forms sible for Duchenne (DMD) and Becker muscu- of DCM, such as genes involved in metabolism lar dystrophy (BMD) and the associated skele- and mitochondrial function, besides loci allelic Primary cardiomyopathies remain a major tal myopathy and DCM, as the gene responsi- to other cardiomyopathic phenotypes.7,11 In cause of morbidity and mortality in children ble for the X-linked form of DCM (XLCM) by particular, primary diseases of the skeletal with an estimated incidence of 1.13/100,000 Towbin and colleagues in 1993.9 However, muscle, such as various forms of muscular dys- cases in the U.S., and they represent the lead- defects in the DMD gene could explain only a trophy and other skeletal myopathies frequent- ing cause of transplantation in children over fraction of all DCM cases; later, other genes ly present with a DCM phenotype.12,13 one year of age.1,2 Several classified forms of responsible for DCM were identified, defining Despite the large number of genes associat- cardiomyopathy exist which have diverse clin- DCM as a genetically heterogeneous entity. ed with DCM, they account for only approxi- ical, structural, morphological, and functional Based on these findings, we formulated the mately 40% of all cases, with LMNA (5%), presentations. These forms includeNon-commercial dilated final common pathway hypothesis (1998) in MYH7 (4%), and TNNT2 (3%) being the most cardiomyopathy (DCM), hypertrophic car- which it was suggested that abnormalities in frequently involved in familial DCM, while diomyopathy (HCM), left ventricular non-com- other genes encoding for dystrophin-associat- mutations in all associated sarcomeric genes paction (LVNC), arrhythmogenic right ventric- ed and proteins involved in the struc- cover only up to 10% of all DCM cases.7 ular cardiomyopathy (ARVC) and restrictive tural formation and maintenance of cardiomy- In addition, genes encoding for ion channels cardiomyopathy (RCM).1-4 Among the various ocyte structure and contractile function could such as the cardiac sodium channel (SCN5A), types of cardiomyopathies, DCM represents also potentially lead to the development of which causes long-QT syndrome (LQTS) and approximately 40% of all cases in children, fol- DCM.10 It is now known that perturbation of Brugada syndrome, as well as ABBC9, coding lowed by HCM, LVNC and more rarely by ARVC cardiomyocyte proteins involved in contractile for the Kir6.2 regulatory subunit, an inwardly and RCM.1-4After over two decades of genetic force generation and transmission, such as rectifying cardiac KATP channel, are implicat- and molecular research, many causative genes cytoskeletal, sarcomeric, ion channel and tran- ed in the pathogenesis of DCM.7 This suggests have been identified and overlap in the genet- scription factor proteins, are involved in the that ion channels not only influence the elec- ic causes of the various forms of cardiomy- pathogenesis of DCM.7 In vitro models and trocardiographic (ECG) findings and potenti- opathies have also been identified, in which animal models recapitulating the human dis- ate arrhythmias in DCM,14 but may also weak- defects in the same gene could lead to allelic ease suggest that alteration of the con- en the cardiomyocytes structure leading to disorders.1-4 Here, we will briefly describe the tinuum connecting the cardiomyocyte plasma DCM and vice versa, as recently reported in a most important forms of cardiomyopathy and membrane (sarcolemma) to the , mouse model harboring the a LDB3-encoded what is currently known about their genetic and through the intermediate filaments, to the ZASP mutation causing DCM in humans.15

[Cardiogenetics 2011; 1:e9] [page 37] Review

Another potential mechanism, particularly in Table 1. Genes associated with cardiomyopathies and their allelic disorders. the case of the SCN5A-ecnoded Nav1.5, is its Gene OMIM* Gene name° Associated relationship with dystrophin. Nav1.5 binds to phenotypes° dystrophin and could potentially disrupt the ABCC9 601439 12p12.1 ATP-binding cassette, sub-family C, member 9 DCM function of dystrophin and lead to a dys- trophin-related cardiomyopathy, as would be ACTC1 102540 15q14 , alpha, cardiac muscle 1 DCM predicted by the final common pathway HCM hypothesis. Clinically, the presentation of idio- RCM pathic, acquired and genetic forms of DCM is ACTN2 102573 1q42-q43 , alpha 2 DCM indistinguishable. This suggests that clinical HCM evaluation of relatives of children with DCM BAG3 603883 10q25.2-q26.2 BCL2-associated athanogene 3 MFM should always be considered when a diagnosis DCM of DCM is reached. Unfortunately, a significant CSRP3 600824 11p15.1 Cysteine and glycine-rich protein 3-cardiac LIM protein DCM proportion of DCM remains idiopathic, where HCM a firm etiologic diagnosis cannot be reached. DES 125660 2q35 MFM This suggests that many more genes are yet to DCM be discovered, and that genetic testing in the DMD 300377 Xp21.2 Dystrophin DMD clinical setting using the standard Sanger BMD sequencing technique appears to have limita- DCM tions due to the large number of genes DSC2 125645 18q12.1 Desmocollin 2 ARVC involved. It is likely that the molecular diagno- sis of DCM will benefit from the clinical appli- DSG2 125671 18q12.1 Desmoglein 2 ARVC cation of high throughput technologies such as DCM whole genome or exome sequencing, multi- DSP 125647 6p24 ARVC plex ligation-dependent probe amplification DCM (MLPA), array comparative genomic hybridiza- DTNA 601239 18q12.1 Dystrobrevin, alpha only LVNC tion (aCGH) and high density arrays combin- EMD 300384 Xq28 Emerin EDMD ing single nucleotide polymorpshism (SNP) DCM and copy number variation (CNV) probes EYA4 603550 6q23-q24 Eyes absent homolog 4 DFNA using the currently available platforms.16,17 use DCM FKTN 607440 9q31 Fukutin FCMD Hypertrophic cardiomyopathy DCM Hypertrophic cardiomyopathy is one of the HSPB7 610692 1p36.13 Heat shock 27kDa protein family, member 7 DCM most common genetic disorders with a preva- JUP 173325 17q21 Junctional ARVC lence of 1/500, representing also the most fre- ND quent cause of sudden cardiac death in young LAMP2 309060 Xq24 Lysosomal-associated 2 DD athletes in the United States.3-4 HCM is charac- HCM terized by excessive thickening generally lim- DCM ited to the left ventricular myocardium and LDB3 605906 10q22-q23 LIM domain binding 3 DCM±LVNC interventricular septum, in the absence of MFM insults that increase after load such as aortic LMNA 150330 1q21.2 A/C DCM±CD stenosis or hypertension, and morphologically CMT2B1 is typically characterized by myocyte disarray.3- EDMD 4 The interventricular septal thickening most HGPS commonly demonstrates asymmetric hypertro- LGMD MADA phy but focal areas of septal hypertrophyNon-commercial or FPLD2 concentric hypertrophy may occur.3-4 Left ven- MYBPC3 600958 11p11.2 binding protein C, cardiac DCM tricular outflow tract obstruction may also HCM occur. Individuals with HCM may be asympto- MYH6 160710 14q12 Myosin, heavy chain 6, cardiac muscle, alpha DCM matic or present signs of sudden death or HCM heart failure. Clinical presentations therefore include syncope or non-resuscitated sudden MYH7 160760 14q12 Myosin, heavy chain 7, cardiac muscle, beta DCM HCM death, dyspnea, diaphoresis, chest pain, palpi- RCM tations, or arrhythmias. The age of onset of HCM-related symptoms varies from infancy to MYL2 160781 12q23-q24 Myosin, light chain 2, regulatory, cardiac, slow HCM adulthood. However, most appear in adoles- MYL3 160790 3p21.3-21.2 Myosin, light chain 3, alkali; ventricular, skeletal, slow HCM cence. As previously described for DCM, pri- MYPN 608517 10q21.1 Myopalladin DCM mary HCM has a genetic basis in most cases. NEBL 605491 10p13-p12 Nebulette DCM Approximately 21 genes, mostly encoding for NEXN 613121 1p31.1 Nexilin DCM sarcomeric proteins and mainly involved in HCM force generation, have been identified to cause PKP2 602861 12p11 2 ARVC HCM, and many of them are allelic to DCM (Table 1).18 PKP4 604276 2q23-q31 Plakophilin 4 ARVC Similar to DCM, HCM is characterized by Continued in the next page

[page 38] [Cardiogenetics 2011; 1:e9] Review significant genetic and allelic heterogeneity Table 1. Continued from previous page. and variable expressivity.19 However, contrary to DCM, genetic testing in HCM using the cur- Gene OMIM* Locus Gene name° Associated rent technology has a high detection rate phenotypes° because mutations in four sarcomeric genes, β-myosin heavy chain (MYH7), myosin bind- PLN 172405 6q22.1 DCM ing protein-C (MYBPC3), cardiac T PRKAG2 602743 7q36.1 Protein kinase, AMP-activated, gamma 2 non-catalytic subunit HCM ± WPW (TNNT2), and cardiac (TNNI3), FCNCG cause approximately 80% of all familial HCM PSEN1 104311 14q24.3 Presenilin 1 AD cases. Mutations can also be identified in DCM about 40% of sporadic and idiopathic cases of FAI HCM.11 Although genotype-phenotype correla- PSEN2 600759 1q31-q42 Presenilin 2 AD-4 tion is imperfect, it has been reported that DCM mutations in MYH7 are associated with early RBM20 613171 10q25.2 RNA binding motif protein 20 DCM onset disease, and in some cases, a more RYR2 180902 1q43 2 ARVC severe phenotype, while MYBPC3 mutations CPVT have been identified in subjects with later SCN5A 600163 3p21 Sodium channel, voltage-gated, type V, alpha subunit BRS onset presentation, and TNNT2 mutations are LQTS associated with a high incidence of sudden DCM ± CD cardiac death.20-21 SGCB HCM is a monogenic disorder in most cases, SGCD 601411 5q33-q34 Sarcoglycan, delta LGMD although double heterozygote mutations have DCM been described and appear to be associated TAZ 300394 Xq28 Tafazzin BTS with earlier-onset and a more dramatic pheno- LVNC type.11 DCM TCAP 604488 17q12 -cap-telethoninonly LGMD Despite the high detection rate of clinical HCM genetic testing in HCM, the lack of good geno- DCM type-phenotype correlation has lessened the TGFB3 190230 14q24 Transforming growth factor, beta 3 ARVC clinical utility of genetic screening in affected patients. However, clinical genetic testing is TMEM43 612048 3p25.1 useTransmembrane protein 43 ARVC quite useful for the screening of clinically TMPO 188380 12q22 Thymopoietin DCM affected and unaffected family members due to TNNC1 191040 3p21.1 type 1 DCM the lack of symptoms in most people with HCM HCM and the relatively high risk of sudden death. TNNI3 191044 19q13.4 Troponin I type 3 DCM Genetic counseling by trained professionals is HCM highly recommended for accurate familial risk RCM assessment and to reduce the potential psy- TNNT2 191045 1q32 type 2 DCM chological impact of the genetic testing. HCM RCM Arrhythmogenic right ventricular TPM1 191010 15q22.1 1 DCM HCM cardiomyopathy TTN 188840 2q31 Titin TMD ARVC is a myocardial disease morphologi- LGMD cally characterized by fibrosis with or without EOMFC fatty infiltration and dilation of the right ven- DCM tricle, along with thinning of the right ventric- HCM ular wall, arrhythmias and suddenNon-commercial cardiac HMERF death.22 However, left ventricular involvement VCL 193065 10q22.1-q23 DCM is being more commonly identified as well typ- HCM ically of the posterior lateral wall, in an age- AD, Alzheimer disease; ARVC, arrhythmogenic right ventricular cardiomyopathy; BMD, Becker muscular dystrophy; BRS, Brugada syndrome; CD, dependent fashion.22 conduction defects; CMT2B1, Charcot-Marie-tooth disease type 2B1; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilat- ed cardiomyopathy; DD, Danon disease; DFNA, autosomal dominant late-onset progressive nonsyndromic deafness; DMD, Duchenne muscular ARVC is often diagnosed secondary to dystrophy; EDMD, Emery-Dreifuss muscular dystrophy; EOMFC, early-onset myopathy with fatal cardiomyopathy; FAI, familial acne inverse; arrhythmias, palpitations, syncope, and abort- FCMD, Fukuyama congenital muscular dystrophy; FCNCG, fatal congenital nonlysosomal cardiac glycogenosis; FPLD2, familial partial lipodys- ed sudden death. ARVC can manifest in the trophy of the Dunnigan type; HCM, hypertrophic cardiomyopathy; HGPS, Hutchinson-Gilford progeria syndrome; HMERF, myopathy with early respiratory muscle involvement; LGMD, Limb-Girdle muscular dystrophy; LQTS, long QT syndrome; LVNC, left ventricular non-compaction; ND, early teenage years with the majority of naxos disease; MADA, mandibuloacral dysplasia type A with partial lipodystrophy; MFM, myofibrillar myopathy; RCM, restrictive cardiomyopa- patients being in their late teenage years or thy; TMD, tibial muscular dystrophy, tardive; WPW, Wolff-Parkinson-White syndrome. The symbol ± indicates that a phenotype can be associat- young adulthood, especially in athletes.23 ARVC ed or not with other clinical presentations. *OMIM, Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/omim Accessed: May 2011; °Genetic Home References. http://ghr.nlm.nih.gov/ Accessed: May 2011. is predominantly genetically determined and often inherited within families, mostly as an autosomal dominant trait with reduced pene- trance and variable expression.24 However, autosomal recessive inheritance has been observed in individuals affected by Naxos dis- ease presenting with ARVC, diffuse non-epi-

[Cardiogenetics 2011; 1:e9] [page 39] Review dermolytic palmoplantar keratoderma, and leagues suggested that the cytoplasmic portion However, because of the reduced penetrance woolly hair, as well as in Carvajal syndrome, of a highly phosphorylated Cx43 protein binds and variable expressivity, which characterizes characterized by striate palmoplantar kerato- the DSC2a isoform, connecting the gap junc- ARVC, single mutations in individual genes derma, woolly hair, and LV cardiomyopathy.25 tion to the desmosome.28 They identified a may not be sufficient to cause the development ARVC has an estimated prevalence of 1/2000- novel variant in DSC2 as well as a DSG2 vari- of the disease.22,25 Compound heterozygous 5000, although regional differences may sig- ant in an individual with a family history of mutations or double heterozygous, digenic nificantly vary this estimate worldwide.25-26 sudden death, mild ECG abnormalities in her- mutations in desmosomal genes may be Diagnostic assessment for ARVC includes self and her daughter, and immunohistochem- required for disease development and clinical cardiac MRI (CMR), echocardiography, and istry demonstrated severe depression of the PG manifestation.24,27 In fact, although frameshift electrocardiography. The CMR classically signal at the intercalated disk, whereas mutations are regarded as deleterious changes demonstrates a dilated RV with RV wall thin- Western blot showed minimal reduction of according to the current recommendations,30 ning and fatty replacement of the myocardium, DSG2 and DSC2 expression levels and mild many PKP2 mutations demonstrate low pene- systolic dysfunction and the RV outflow tract reduction of Cx43. Electrophoretic mobility of trance and an additional mutation in another may be aneurysmal. Gadolinium late enhance- Cx43 was abnormal and consistent with differ- ARVC gene is necessary to develop the disease. ment typically identifies areas of fibrosis. The ential phosphorylation, suggesting a lower pro- Therefore, despite much literature suggesting LV may also be affected with a DCM appear- portion of the highly phosphorylated protein. that PKP2 mutations cause approximately 25% ance. The echocardiogram may demonstrate a All other desmosomal proteins were normal. of ARVC cases, this is not the primary cause of dilated RV or LV with systolic dysfunction and Therefore, the authors suggested that the the disease in a high percentage of subjects. the electrocardiogram demonstrates T wave DSC2a isoform provides a critical link between This complex genetic behavior makes clinical inversion in leads V1 through V3, QRS duration the desmosome and gap junction and that dis- genetic testing challenging to interpret.

110 msec in V1 through V3, an epsilon wave ruption leads to the clinical features of disease Therefore, despite the apparent autosomal (electric potentials after the end of the QRS upon physiologic trigger. They also suggested dominant mode of inheritance, clinical genetic complex), an ST-elevation pattern similar to that the combination of PG loss and Cx43 dis- testing should be comprehensive and multi- that seen in Brugada syndrome may be noted, turbance is an early indicator of developing modal for all the known ARVC genes and and a prolonged S-wave upstroke in V1 through clinical disease, with the risk of arrhythmias genetic-based diagnosis should be conserva- (and therefore sudden death) lurking for tivelyonly and thoughtfully considered. V3 measuring 55 msec. Right ventricular biop- sy may be definitive when typical fibrofatty future clinical presentation. An extension of replacement of the myocardium and inflamma- this suggestion leads to the possibility that Left ventricular noncompaction tion is visible; this is more obvious, in mutations in desmosomal proteins could pos- Left ventricular non compaction (LVNC) is advanced disease. Commonly, only fibrosis and sibly alter Cx43 phosphorylation and weakenusecharacterized by a trabeculated left ventricular inflammatory infiltrates are seen, particularly the linkage between the gap junction and myocardium associated with deep inter-trabec- in earlier disease presentations. Since the pri- desmosome, causing loss of electrical coupling ular recesses in the left ventricular wall, typi- mary area of fibrofatty replacement is in the between cardiac myocytes, and leading to cally most evident in the apical region of the LV triangle of dysplasia in the apical and myocyte cell death, fibrofatty replacement and but also notable in the LV free wall and, occa- infundibular regions of the RV, making biopsy arrhythmias. We suggested that, if correct, sionally the septum in some patients. The RV, diagnosis more challenging. Autopsy or these findings could potentially be used for which normally is trabeculated, may be hyper- explant after transplantation will commonly early genotype-phenotype biomarker disease trabeculated as well in some cases, resulting in demonstrate classic histopathologic diagnostic diagnosis, risk stratification and outcome pre- biventricular noncompaction. The diagnosis is criteria.26-27 diction, and possibly preventive therapy, but typically made by echocardiography where api- Currently, 13 loci and mutations in 9 genes that significant caution should be used before cal trabeculations are noted with or without have been identified in ARVC individuals assuming this to be correct.22 trabeculations in the free wall, septum or RV. (Table 1). Most of the genes causing ARVC In addition to abnormalities in desmosomal Some published criteria use a ratio of compact encode proteins of the cardiac desmosome genes, mutations in the TGFβ3, RYR2, and to noncompact layer of the LV myocardium >2 such as plakoglobin (PG), desmoplakin (DSP), TMEM43 genes have been also associated with but this measurement is dependent on the plakophilin-2 (PKP2), plakophillin-4 (PKP4), ARVC and are thought to cause ARVC via sec- area sampled and measured. In addition, car- desmocollin-2 (DSC2) and desmoglein-2 ondary disruption of the desmosome.27 The diac MRI may demonstrate the trabeculations (DSG2), resulting in defective cell-to-cellNon-commercialTGFβ3-encoded transforming growth factor β3 and inter-trabecular recesses well. Due to the adhesion and altered nuclear signaling, lead- is a cytokine, which stimulates fibrosis and trabeculations and inter-trabecular recesses ing to diminished desmosomal protein local- modulates cell adhesion, while the RYR2- there is a theoretical increase in the suscepti- ization and dramatic reduction in immunore- encoded human ryanodine receptor 2 induces bility to form clots in the LV with high risk of active signal for the GJA1-encoded gap junc- the release of calcium from the myocardial sar- thromboembolism and death, but this usually tion protein connexin-43 (Cx43) at the inter- coplasmic reticulum. TMEM43, which encodes occurs only in subjects with a dilated and poor- calated disks.25-28, 29 transmembrane protein 43, is a response ele- ly functioning LV.31 LVNC can be observed with Connexin-43 is a highly phosphorylated pro- ment for the peroxisome proliferator-activated or without congenital heart diseases (CHD) tein, whose phosphorylation pattern plays receptor gamma (PPARγ) gamma, an adi- such as ventricular (VSD) and atrial septum important roles in the regulation of protein pogenic transcription factor, which may defects (ASD), pulmonic stenosis (PS), turnover, trafficking, intercalated disk assem- explain the fibrofatty replacement of the Ebstein’s anomaly, and hypoplastic left heart bly, internalization, degradation, and channel myocardium.27 syndrome (HLHS), amongst others. When not gating properties. In the failing RV, altered Although most ARVC cases follow an autoso- associated with CHD, the associated pheno- phosphorylation of Cx43 leads to a non-phos- mal dominant pattern, autosomal recessive type may include a DCM-like, HCM-like, com- phorylated protein, causing a weaker pattern was recognized with homozygous bined HCM/DCM-like picture, a restrictive car- immunoreactive signal to be observed in the mutations in the plakoglobin-encoding gene diomyopathy (RCM)-like picture, or simply LV RV myocardium of patients and animal models causing Naxos disease, and homozygous trabeculations with normal LV size, thickness with ARVC.28,29 Recently, Gehmlich and col- mutations in DSP in Carvajal syndrome.26,27 and function.32,33 The latter phenotype appears

[page 40] [Cardiogenetics 2011; 1:e9] Review to be benign unless associated with arrhyth- and characterized by one PDZ domain at its N- other criteria for RCM. Cardiac catheterization mias while the other forms tend to follow a terminus and up to three LIM domains at its C- may demonstrate elevated LV or RV end dias- similar course to the associated phenotype. terminus.40 Mutations in these genes cause tolic pressures, pulmonary hypertension with The only exception is the undulating pheno- LVNC with or without CHD.39 elevation in pulmonary artery pressure is fre- type, a change from one appearance to anoth- quently present at the time of initial catheteri- er, which most commonly occurs in those with Restrictive cardiomyopathy zation and markedly elevated pulmonary vas- the combined HCM/DCM-like picture. LVNC Restrictive cardiomyopathy (RCM) is cular resistance can occur within 1 to 4 years can also present associated with syndromes uncommon, accounting for up to 5% of car- of diagnosis.49 Endomyocardial biopsy reveals such as Barth,31 Marfan,34 Sotos,35 trisomy 13, diomyopathies in children41 Restrictive car- myofiber hypertrophy and mild to moderate 36 and monosomy of band 1p3637,38 diomyopathies are characterized by dilated interstitial fibrosis. as well as Duchenne and Becker muscular dys- atria with normal ventricular size, thickness In children in the U.S. and Australia, RCM trophy. LVNC is believed to occur due to an and systolic function in the face of diastolic accounts for 2.5-5% of the diagnosed cardiomy- arrest in the ventricular development during ventricular dysfunction with elevated left (and opathies, with the majority having no specific embryogenesis, in which the initially trabecu- at times right) ventricular end-diastolic pres- cause identified. 41,52 In Australia, RCM lated myocardium provides enough surface for sures.42-43 In the 2006 classification consensus accounted for 2.5% of the cardiomyopathies the blood to infiltrate and bring oxygen and statement by the AHA, primary restrictive car- diagnosed in children <10 years of age,53 while nutrients to myocardial cells.31 Subsequently, diomyopathy was defined as a rare form of the U.S report from the Pediatric with a higher blood demand, the coronary heart disease characterized by normal or Cardiomyopathy Registry (PCMR) investiga- artery system develops and the myocardium decreased volume of both ventricles associated tors reported that RCM accounted for 3% of the undergoes remodeling associated with com- with biatrial enlargement, normal left ventric- cardiomyopathies in children <18 years of paction of the hypertrabeculated myocardium. ular wall thickness and atrioventricular valves, age.52 The estimated annual incidence in the The disruption of this process is believed to impaired ventricular filling with restrictive U.S. and Australia is 0.04/100,000 and cause the ventricular noncompaction.31 physiology, and normal (or near normal) sys- 0.03/100,000 children, respectively.52,53 Multiple LVNC was considered a rare disease in the tolic function.3 causes of RCM have been described in adults past due to limited awareness and knowledge The most common presenting signs and andonly children. of the disease and limitations of echocardiog- symptoms in children with RCM include dysp- Some cases are inherited and most com- raphy.32 However, the American Heart nea that is frequently exacerbated by an inter- monly have autosomal dominant transmission. Association recently classified LVNC as a sepa- current respiratory illness or asthma, fatigue, Causative mutations have been reported in rate clinical entity.3 The actual incidence and exercise intolerance, syncope, and sudden sarcomere-encoding genes such as troponin I, prevalence of LVNC remains unclear, but the death.44-45 The electrocardiogram is use abnormal troponin T, β-myosin heavy chain, and actin.54 reported incidence of 0.05% in isolated LVNC in approximately 98% of patients.46-48 The most Another complex subgroup of patients have in adult subjects appears to be underestimat- common abnormalities are right and/or left been identified with RCM associated with atri- ed, and is probably far lower than the true inci- atrial enlargement; however ST segment oventricular block and skeletal myopathy, and dence and prevalence in children.3,31 In fact, depression and ST-T wave abnormalities are these are usually caused by mutations in LVNC is now assumed to account for approxi- frequently present. Right and/or left ventricu- desmin or lamin A/C.54 mately 10% of all cardiomyopathies. Currently, lar hypertrophy can also be seen as well as con- The prognosis in children with RCM is mutations in many genes have been identified duction abnormalities. Holter and event moni- poor.41,55 Half of the children die or undergo in LVNC (Table 1), but the genes more com- tors are useful to evaluate for rhythm distur- transplant within 3 years of diagnosis.41,55 monly associated with LVNC in children are bances, conduction abnormalities and evi- Sudden cardiac death has been reported to be sarcomere-encoding genes, TAZ, DTNA and dence of ischemia based on ST segment analy- a common mode of death in children with LDB331,32,39 The TAZ gene, located on chromo- sis.46-48 Arrhythmias have been reported in RCM.46 Patients who appear to be at greater some Xq28, encodes the tafazzin protein approximately 15% of pediatric patients and risk for sudden death include those who pres- believed to function as phospholipids- include atrial flutter, high grade second and ent with signs and symptoms of ischemia, lysophospholipid transacylase involved in car- third degree atrioventricular block, atrial fibril- such as syncope and chest pain. However, diolipin metabolism and part of the inner mito- lation, atrial tachycardias, Wolff-Parkinson- heart failure related deaths are the most com- chondrial membrane.31 The TAZ geneNon-commercial was ini- White syndrome with supraventricular tachy- mon. tially identified in patients with Barth syn- cardia and ventricular tachycardia and tor- drome, an X-linked disease characterized by sades. Symptomatic sinus bradycardia requir- Metabolic cardiomyopathies cardiomyopathy, skeletal myopathy, cyclic neu- ing pacing has also been reported.47-48 The Although the major focus of this review is tropenia, abnormal cholesterol metabolism, most striking finding on echocardiography is the description of primary cardiomyopathies, lactic acidosis, 3-methylglutaconic aciduria, massive atrial dilatation in the absence of atri- which present usually in isolation affecting and cardiolipin abnormalities.33 More recently, oventricular valve regurgitation.49 In children, only the cardiac muscle, defects in the metab- TAZ mutations have been identified in subjects findings consistent with restrictive filling and olism usually appear early in life and may lead presenting with isolated LVNC, and endocar- increased left ventricular end diastolic pres- to complex clinical phenotype in which the dial fibroelastosis and isolated LVNC.32 sure are noted.50 Systolic function is typically function of multiple tissues including the α-Dystrobrevin is a cytoskeletal protein preserved although some degree of systolic myocardium results severely hampered. encoded by the DTNA gene and is a component dysfunction has been seen in some patients at Metabolic cardiomyopathies can be recognized of the dystrophin associated glycoprotein com- presentation and deterioration of systolic dys- as early as the perinatal period or infancy, and plex, which provides structural stability during function over time has also been reported in among the best known there are approximate- muscle contraction and relaxation. The LIM- children.51 Ventricular hypertrophy is not ly 50 different forms of lysosomal accumula- domain binding protein 3 (LDB3), also known prominent, but some degree of concentric tion of substrates, which results to be toxic for as ZASP (Z-band alternatively spliced PDZ- increase in septal and left ventricular posteri- the cell, namely the lysosomal storage diseases motif protein), is a component of the sarcom- or wall thickness is seen in a significant pro- (LSDs).56 Among the various LSD here we will eric Z-line and is encoded by the LDB3 gene portion of cases otherwise fulfilling all the mention Pompe disease, Fabry disease and

[Cardiogenetics 2011; 1:e9] [page 41] Review

Gaucher disease. According to their age of HCM as its predominant feature is represent- reticulum (SR) through the intermediate fila- onset, variable clinical presentation and sever- ed by Danon disease and it is caused by muta- ment (IF) protein desmin, which provides the ity, they are also divided in various sub-types. tions in the LAMP2 gene, which encodes the necessary ratio of mitochondria to IF for the Pompe disease is an autosomal recessive dis- lyosome-associated protein-2 and maps to optimal exchange of ions, lipids, and other order caused by mutations in the GAA gene Xq24.57-58 Affected hemizygote males usually metabolites.61 mapping to chromosome 17q25.2-q25.3 and present with severe cardiac hypertrophy in Thus, it should not be surprising that encoding the enzyme acid alpha-glucosidase, early childhood and adolescence, while most altered integrity of the mitochondria could lead which is essential for the degradation of glyco- female carriers develop dilated cardiomyopa- to functional and structural impairment of car- gen to glucose in the lysosomes. Defects in thy (DCM) rather than HCM during adulthood diac cells. In fact, the absence of desmin in this process lead to glycogen storage disease (as late as their 40s).57-58 However, DCM has mouse hearts leads to an abnormal accumula- type II with the toxic accumulation in various also been observed in males with Danon dis- tion of subsarcolemmal clusters of mitochon- organs such as striated muscles, impairing ease.58 Danon disease individuals suffer of var- dria, degeneration of the mitochondrial their normal function.56 Pompe disease has an ious degree of intellectual disability and skele- matrix, and proliferation associated with the estimated prevalence of 1: 40,000 and may tal muscle impairment. Skeletal muscle biopsy development of dilated cardiomyopathy and present as early as in infancy with progressive usually reveals glycogen containing (PAS posi- heart failure.61 left ventricular hypertrophy, but late-onset tive) cytoplasmic vacuoles.57-58 The mtDNA is approximately 16kb in length forms such as in late adolescents and young Because LSDs are caused by the deficiency and encodes 13 of the 69 proteins required for adults may not present with heart failure. in enzyme activity, this prompted the oxidative metabolism performed by Complex I- However, subjects with Pompe disease present researchers to develop an enzyme replacement V, 22 transfer RNA (tRNAs) and two ribosomal a significant risk of sudden cardiac death due therapy (ERT) using recombinant enzyme, RNA (rRNA). Mitochondria are inherited from to the association of hypertrophic cardiomy- which appears to be effective when adminis- the mother and they can vary in number with- opathy along with Wolff-Parkinson-White syn- tered early in the natural history of the dis- in the cells from various tissues (heteroplas- drome, a form of atrioventricular reentrant ease. Unfortunately, the enzymes do not pass my), accounting for the pleiotropic effect. tachycardia or ventricular pre-excitation.56 the brain-blood barrier and they are not effec- Recently, mutations leading to mitochondrial Fabry disease is an X-linked form of LSD tive in ameliorating the neurological symp- defects (mtDNA, nDNA), have been identified only 62 caused by impaired activity of the enzyme α- toms.51,56 in subjects with isolated LVNC, as well as galactosidase (α-Gal A) due to mutations in DCM and HCM,63 thus supporting the impor- the GLA gene, mapping to chromosome Xq22.56 Mitochondrial genome and nuclear tance of mitochondrial genome screening in primary cardiomyopathies. In addition, com- Subejcts with Fabry disease accumulate gly- genes with mitochondrial function cosphingolipid ceramide trihexoside (GL-3), useplex mitochondrial diseases such as Kearns- which is deposited into lysosomes in most cell and cardiomyopathies Sayre syndrome, myoclonic epilepsy with types in the body. Mitochondria provide the major energy ragged red muscle fibers (MERRF)33 syndrome The prevalence of Fabry disease is approxi- source for the myocardium, and abnormalities and mitochondrial encephalopathy, lactic aci- mately 1: 40,000, although the prevalence may of the mitochondrial genome (mtDNA) and dosis, and stroke-like episodes (MELAS)64 have be much higher in subsets of patients.56 Fabry nuclear genes encoding proteins involved in also been associated with cardiomyopathies, disease classically occurs in hemizygote males mitochondrial respiratory chain function are suggesting that a multimodal approach includ- in early childhood or adolescence with period- seen in cardiomyopathies. The mitochondrial ing novel technologies for the screening of the ic crises of severe pain in the extremities respiratory chain consists in five enzyme com- nuclear DNA (nDNA) and the mtDNA should (acroparesthesias), vascular cutaneous plexes (I-V) in the inner membrane of the be employed in both research and clinical test- lesions (angiokeratomas), kidney failure, mitochondria and the energy that is generated ing in individuals with cardiomyopathies, par- corneal and lenticular opacities, proteinuria is used to produce ATP via oxidative phospho- ticularly babies. The currently available tech- and heart failure or death.56 rylation.59,60 Defects in oxidative phosphoryla- nologies such as whole genome or exome However, Fabry disease may also present tion could originate from alterations in any of sequencing, MLPA, aCGH for nDNA and with HCM as the prominent symptom although the five complexes of the respiratory chain, mtDNA and high density array combining sin- restrictive cardiomyopathy has also been although the most frequently affected include- gle nucleotide polymorpshism (SNP) and copy observed. complexes I (NADH-CoQ reductase) and IV number variation (CNV) probes using the cur- Gaucher disease (GD) is an autosomalNon-commercial(cytochrome-c oxidase).60 Mitochondrial dis- rently available platforms could allow for rapid recessive LSD caused by mutations in the GBA eases usually manifest in early childhood, results with increasingly lower cost, improve- gene (1q21) leading to deficient activity of the although different levels of heteroplasmy in ments in turn-around times, and facilitating encoded acid-β-glucosidase. Gaucer disease various tissues may be associated with comprehensive investigation of the underlying has a prevalence of approximately in 1: 50,000 pleiotropic effects clinically and age-dependent genetic etiologies involved in cardiomy- to 100,000 people in the general population expressivity. Children affected by mitochondri- opathies. and can present as a perinatal lethal disorder, al diseases commonly present with cardiomy- although the variable clinical presentation opathy (17%) and cardiac involvement is gen- Final remarks include some mild or sub-clinical forms.56 erally associated with worse prognosis and In this review article we discussed the cur- However, GD Type 1 is the most common increased mortality.59-61 rent knowledge about the genetics of car- form of the disorder, occurring more frequent- Mitochondria occupy a significant portion diomyopathies in children. Despite over three ly in individuals with Ashkenazi Jewish (20-30%) of cardiac cell volume, and their decades of research and the discovery of a descent compared to the other genetic back- dynamic nature allow them to respond to the large number of causative genes, modest grounds, affecting 1: 500 to 1000 Ashkenazi level of energy requirement by altering their advances have been made about the manage- Jews.56 unit number.59 In cardiomyocytes, mitochon- ment and therapies of cardiomyopathies in Another form of LSDs recently classified in dria are not only functionally related to cardiac children as well as in adults. However, the the subgroup of autophagic vacuolar contraction and energy homeostasis, but they advances in the genetics of heart diseases pro- myopathies (AVMs) and that can present with are also physically linked to the sarcoplasmic vided a formidable tool for counseling car-

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