Scholarly article on topic 'The MOGE(S) Classification for a Phenotype–Genotype Nomenclature of Cardiomyopathy'

The MOGE(S) Classification for a Phenotype–Genotype Nomenclature of Cardiomyopathy Academic research paper on "Basic medicine"

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Academic research paper on topic "The MOGE(S) Classification for a Phenotype–Genotype Nomenclature of Cardiomyopathy"

EXPERT CONSENSUS DOCUMENT gRECS

The MOGE(S) Classification for a Phenotype—Genotype Nomenclature of Cardiomyopathy

Endorsed by the World Heart Federation

Eloisa Arbustini*, Navneet Narulay, G. William Decz, K. Srinath Reddyx, Barry Greenberg", Sudhir Kushwaha{,

Thomas Marwick#, Sean Pinney**, Riccardo Bellazziyy, Valentina Favalli*, Christopher Kramer**

Robert Robertsxx, William A. Zoghbi"", Robert Bonow{{, Luigi Tavazzi##, Valentin Fuster**, Jagat Narula**

Pavia and Cotignola, Italy; New York, New York; Boston, Massachusetts; New Delhi, India; San Diego, California; Rochester, Minnesota; Queensland, Australia; Charlottesville, Virginia; Ottawa, Canada; Houston, Texas; and Chicago, Illinois

In 1956, Blankerhorn and Gall [1] proposed the term myocarditis for inflammatory heart muscle disease, and

myocardiosis for other heart muscle diseases. A year thereafter, Brigden [2] defined cardiomyopathies as uncommon, non-coronary heart muscle diseases. Subsequently, Goodwin and Oakley [3] defined cardiomyopathies as myocardial diseases of unknown origin, and proposed categorization of the disorders as dilated (DCM), hypertrophic (HCM), and restrictive (or obliterative) (RCM) cardiomyopathies. In 1980, the World Health Organization (WHO) and International Society and Federation of Cardiology (ISFC) established the definition of cardiomyopathies as myocardial diseases of unknown etiology, reflecting the general lack of information about the mechanism(s) of disease [4]. Although WHO-ISFC retained the 3 morphological types of cardiomyopathies proposed by Goodwin and Oakley, it also introduced the term specific heart muscle disease, where the cause of myocardial dysfunction was known. The WHO-ISFC classification subsequently expanded the definition of cardiomyopathies by adding the functional component and defined cardiomyopathy as the diseases of myocardium associated with myocardial dysfunction. Two additional classes, arrhythmogenic right ventricular cardiomyopathy (ARVC) and unclassified cardiomyopathy, were introduced during the revision, and the category of the specific heart muscle disease was excluded [5]. The ISFC changed its name to the World Heart Federation (WHF) in 1998 [6], and did not indulge in further revision of the recommendations for either diagnosis or management of cardiomyopathies.

A substantial increase in the knowledge of the genetic basis of cardiomyopathy has occurred, and noninvasive phenotypic characterization has become significantly more sophisticated. Therefore, the American Heart Association (AHA) [7] and the European Society of Cardiology (ESC) [8] in the last decade have proposed revisions to the classification of cardiomyopathic disorders. Whereas both systems have substantial similarities and have made important recommendations, the former has described cardiomyopathies starting from the genetic basis of the etiology followed by the phenotypic description of myocardial involvement. Conversely, the ESC has retained the description in original morphofunctional categories with

further subclassification into genetic (familial) and nonge-netic (nonfamilial) groups. Both classifications continue to exclude specific heart muscle disease (resulting from coronary, hypertensive, valvular, and congenital heart disease) from consideration as a cardiomyopathic disorder.

There is no denying the fact that most cardiomyopathies are genetic diseases, which in the real life are brought to clinical attention (and diagnosed and managed) based on a phenotypic diagnosis. More than 60 disease genes have been identified to date [9]; genes such as MYBPC3 may be associated with different phenotypes (HCM, RCM, DCM), and genes such as DYS may cause a unique phenotype (DCM only). The penetrance of the genetic mutation is variable, and phenotypic manifestations are often age dependent. Most genetic cardiomyopathies are inherited as autosomal dominant traits, with a minority of families demonstrating autosomal recessive, X-linked recessive or dominant (rare), and matrilineal inheritance. Cascade family screening and follow-up have become mandatory [10]. It has become necessary for a more descriptive nosology to be developed that may encompass either all attributes of the individual patient cardiomyopathy or allow a common platform for collaborative research efforts. A number of experts, including clinical cardiologists, heart failure—transplantation physicians, geneticists, and cardiovascular imagers, have proposed a systematic nomenclature endorsed by the WHF Scientific Committee. The proposed classification is a descriptive presentation of the cardiomyopathy process, which is flexibly modifiable and expandable. This nosology is inspired from the TNM staging of tumors and is being simultaneously published by the Journal of the American College of Cardiology and the official journal of the WHF, Global Heart.

The AHA (2006) classification

In 2006, a scientific statement from the AHA redefined cardiomyopathy as a heterogeneous group of diseases of myocardium associated with mechanical and/or electrical dysfunction, which usually (but not invariably) exhibit inappropriate ventricular hypertrophy or dilation, due to a variety of causes that frequently are genetic [7]. The etiology of some cardiomyopathies originally classified as

This study was supported by Grants European Union INHERITANCE project n°241924 and Italian Ministry of Health "Diagnosis and Treatment of Hypertrophic Cardiomyopathies" (n° RF-PSM-2008-1145809) to EA, IRCCS Policlinico San Matteo, Pavia.

Dr. Greenberg is a consultant for Zensun, Celladon, Mesoblast, Novartis, and Teva Pharmaceutical; and is on the Speakers' Bureaus of Otsuka and Boehringer Ingelheim. Dr. Kramer has received research support from Novartis (research funding) and Siemens Healthcare (equipment); and is a consultant for Synarc and St. Jude Medical. Dr. J. Narula has received research grants from GE Healthcare and Phillips. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Supplementary data associated with this article can be found, in the online version, at http://dx.doi. org/10.1016/j.gheart.2 013.11.001.

Manuscript received August 19, 2013; accepted August 28, 2013.

*Center for Inherited Cardiovascular Disease, Pavia, Italy; fDepartment of Pathology, New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York; ZCardiology Division, Massachusetts General Hospital, Boston, Massachusetts; §Public Health Foundation of India, New Delhi, India; ^University of California at San Diego, San Diego, California; {Mayo Clinic College of Medicine, Rochester, Minnesota; #University of Queensland, Princess Alexandra Hospital, Queensland, Australia; **Mount Sinai Medical Center, New York, New York; ffDepartment of Industrial and Information

Engineering, University of Pavia, Pavia, Italy; ZZUniversity of Virginia, Charlottesville, Virginia; §§John & Jennifer Ruddy Canadian Cardiovascular Research Center, University of Ottawa Heart Institute, Ottawa, Canada; ||||Methodist DeBakey Heart & Vascular Center, The Methodist Hospital, Houston, Texas; {{Center for Cardiovascular Innovation, Chicago, Illinois; and the ##Maria Cecilia Hospital, GVM Care & Research, E.S, Health Science Foundation, Cotignola, Italy. Correspondence: Dr. Jagat Narula (narula@ mountsinai.org).

GLOBAL HEART © 2013 by the American College of Cardiology Foundation. Published by Elsevier Ltd. All rights reserved.

VOL. 8, NO. 4, 2013 ISSN 2211-8160/$36.00. http://dx.doi.org/10.1016/ j.gheart.2013.11.001

idiopathic or primary cardiomyopathy, or heart muscle disease of unknown cause had become known, and therefore, such entities could not be described as idiopathic any further. In the AHA 2006 definition, primary cardiomyopathy referred solely or predominantly to the involvement of heart; the primary cardiomyopathy designation in the new definition did not mean diseases of myocardium associated with myocardial dysfunction as intended in the 1996 WHO-ISFC classification. The secondary cardiomyopathy in the AHA classification was applicable when the myocardial dysfunction was part of a systemic process. The proposed classification is reproduced in Figure 1A. Myocardial dysfunction resulting from or associated with coronary, hypertensive, valvular, or congenital heart disease was not classified as cardiomyopathy. The WHF writing group applauds the efforts of the AHA 2006 writing committee for the

first genuine attempt to introduce a genetic basis of classification of cardiomyopathies.

The ESC (2008) classification

Although recognizing the necessity for identifying the causative genetic defect as proposed by AHA (2006) nomenclature, the ESC classification emphasized that because the morphofunctional phenotype was the basis of the management of cardiomyopathy, it must also continue to be the basis of classification. ESC panelists emphasized that some of the so-called primary cardiomyopathies may be associated with extracardiac manifestations and may not justify the primary cardiomyopathy designation. Similarly, so-called secondary cardiomyopathy may occasionally involve the heart predominantly and defy designation as

PRIMARY CARDIOMYOPATHIES (predominantly involving the heart) SECONDARY CARDIOMYOPATHIES (Systemic diseases involving heart)

Genetic

ARVC/D -

PRKAG2 ^ Glycogen Danoni storage~

Conduction Defacts -Mitochondrial myopathies -

Ion Channel Disorders

Mixed*

Acquired

Restrictive {non-hypertrophied and non-dilated)

Inflammatory (myocarditis)

Stress-provoked

("tako-tsubo")

Peripartum

Tachycardia-induced

Infants of insulin-dependent diabetic mothers

LQ.TS Brugada SQTS CVPT Asian SUNDS

FIGURE 1. Current Classifications Of Cardiomyopathies. The 2006 American Heart Association classification proposes genetics-based classification (A). On the other hand, the 2008 European Society of Cardiology classification suggests first the morphofunctional phenotype and then the addition of inheritance information (B). ARVC/D = arrhythmogenic right ventricular cardiomyopathy/dysplasia; CVPT = catecholaminergic polymorphic ventricular tachycardia; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LVNC = left ventricular noncompaction; LQTS = long QT syndrome; RCM = restrictive cardiomyopathy; SQTS = short QT syndrome; SUNDS = sudden unexplained nocturnal death syndrome.

secondary cardiomyopathy [8]. In the ESC classification, cardiomyopathy was defined as a myocardial disorder in which the heart muscle is structurally and functionally

abnormal. Cardiomyopathy was grouped into morpho-functional phenotypes relevant for day-to-day clinical practice. These included dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular cardiomyopathy and unclassified variety. Each of these types was further divided into familial genetic and nonfamilial, nongenetic forms. Ion channelopathies, a genetic subtype included in the AHA classification of primary cardiomyopathy, was not accepted as cardiomyopathy in this classification because genes encoding for ion channels might not result in morphofunctional phe-notypes. However, similar to the AHA classification, myocar-dial dysfunction secondary to coronary, hypertensive, valvular, or congenital heart disease was not considered as cardiomy-opathy. In the ESC 2008 classification, the cardiomyopathy was defined as familial when present in more than 1 member of the family. A genetic cardiomyopathy is sporadic when the causative mutation is de novo, namely occurring for the first time and exclusively in the affected family member. The proposed classification is reproduced in Figure 1B.

The proposed phenotype-genotype-based (2013) classification endorsed by WHF

In the last 10 years, knowledge of the genetics of cardiomyopathies has evolved exponentially, and at least 60 disease genes have been either confirmed or suspected as candidate genes (Table 1). The genetic heterogeneity is established, and the implementation of next-generation sequencing is further expected to increase the existing pool of knowledge. It is conceivable that although the diagnosis based on phenotype is still clinically useful, it is not sufficient to stratify prognosis in cardiomyopathies caused by mutations in different genes and that grouping cardiomyopathies per disease gene provides the basis for implementation of disease-specific research. The major clinical decisions (such as implantable cardioverter-defibrillator [ICD] implantation) are still based on functional (such as left ventricular [LV] ejection fraction [LVEF] in DCM) or morphological (such as maximal LV wall thickness in HCM) criteria regardless of the intrinsic disease risk related to the type of causative gene mutation [11—13]. Troponinopathies may not be associated with severe LV wall thickness but carry a high arrhythmogenic potential [14]. Similarly, lam-inopathies may not necessarily demonstrate severe LV dysfunction when their arrhythmogenic risk first manifests

[15]. On the other hand, dystrophinopathies may display dramatically enlarged and dysfunctioning LV but are less susceptible to the risk of malignant arrhythmias; such patients, however, can deteriorate rather precipitously with as small an insult as a flu episode and deserve timely assistance

[16]. Based on the underlying gene mutations, numerous new terms (such as desmosomalopathies [17], cytoskeletalo-pathies [18], sarcomyopathies [18], channelopathies [19], car-diodystrophinopathies [16], or cardiolaminopathies [20]),

inspired by the general practice of myologists (such as zas-popathies [21], myotilinopathies [22], dystrophinopathies [23], alphaB-crystallinopathies [21], desminopathies [24], or cav-eolinopathies [25]), are being proposed that are likely to cloud the cardiomyopathy description, and it has become important that a uniform nomenclature be developed.

By the classification herein proposed, the cardiomyopathies are described as disorders characterized by morphologically and functionally abnormal myocardium in the absence of any other disease that is sufficient, by itself, to cause the observed phenotype. In this nosology, although the conventional phenotypic subtype of the car-diomyopathy (e.g., dilated, hypertrophic) continues to provide the elements for the basic classification, a genotype-based assessment dictates the diagnostic work-up and treatment decisions in probands and relatives, as well as the follow-up plans. Figure 2 shows an example of the impact of an accurate genetic diagnosis on 2 patients with a similar phenotype at presentation. Once the genetic cause of the cardiomyopathy has been defined, the cascade family screening can help identify healthy mutation carriers that will eventually develop the phenotype over the ensuing years (Fig. 3) [10]. Avoidance of competitive sport activity and tailored monitoring with early medical treatment may favorably influence the natural history of the disease and the development of the manifest phenotype, as well as the risk of life-threatening arrhythmias. Identification of genetic diseases may also help subjects and alert physicians to refrain from the use of injurious agents. For instance, agents triggering malignant hyperthermia (succi-nyl choline) or volatile anesthetics (halothane and iso-flurane) are to be avoided in emerinopathies and laminopathies causing muscular dystrophy [26]. Statins should be administered with caution in patients with genetic cardiomyopathies with possible involvement of the skeletal muscle, even when markers of myopathy are negative [27]. Patients with disorders of the respiratory chain may need surgeries in their long-term care, but anesthetics may interfere with metabolism and may trigger unexpected complications [28]. Patients with mitochon-drial cardiomyopathy and epilepsy should not receive valproate because it could cause pseudoatrophy of brain [29]. Common indications for heart transplantation (HTx) in patients with end-stage cardiomyopathy should take into account the specific diagnosis; conditions such as Danon disease in males, or other comorbidities such as mental retardation, are a matter of debate about indications for HTx [30]. Finally, genotype-based diagnoses can be pooled in large international databases for future clinical trials and validation of novel management strategies.

THE MOGE(S) NOMENCLATURE SYSTEM

While waiting for the complete knowledge that may eventually support a genetic classification of cardiomyopathies (also the ultimate intent of the AHA and ESC classifications), we propose a nosology that addresses 5 simple

TABLE 1. List of Nuclear Genes Associated to Date With Cardiomyopathies

Nuclear Genes Gene Protein or Syndrome HCM RCM DCM ARVC LVNC

ABCC9 601439 ATP-binding cassette, subfamily C, member 9 X

ABLIM1 602330 Limatin (actin-binding LIM domain protein) X

ACTC1 102540 Cardiac actin alpha XXX X

ACTN2 102573 Alpha-actinin 2 X X

ALMS1 606844 ALMS1-C X

608662 Anoctamin 5

ANKRD1 609599 Ankyrin repeat domain- X

containing protein 1 BAG3 603883 BC/.2-associated athanogene X X

CALR3 611414 Calretinin 3 X

CASQ2 114251 Calsequestrin 2 XX

CAV3 601253 Caveolin3 X X

CRYAB 123590 Alpha B crystallin XXX

CSRP3 600824 Cysteine- and glycine-rich X X

protein 3

DES 125660 Desmin XXX

300377 Dystrophin

DMPK 605377 Dystrophia myotonica protein kinase gene X

DOLK 610746 Dolichol kinase X

o r—

o 03 > r— DSC2 125645 Desmocollin 2 X X

PI > DSG2 125671 Desmoglein 2 X X

< DSP 125647 Desmoplakin X X

O r—

Clinical Traits (Red Flags) Phenotypes/Diseases Caused by Mutations of the Same Gene Inheritance

Hypertricosis Cantu syndrome AD

LVNC AD

Nemaline myopathy AD

(70% DCM) Alstrom syndrome AR

Dysphagia Limb girdle muscular dystrophy, Gnathodiaphyseal dysplasia, Miyoshi muscular dystrophy 3 AR

B/AG3-related myofibrillar myopathy, CRVTiß-related myofibrillar myopathy, fatal infantile hypertrophy AD

sCPK elevated; long QT syndrome-9; muscular dystrophy, limb-girdle; myopathy, distal, Tateyama type; rippling muscle disease

Cataract Posterior polar cataract AD

AVB, ÎSCPK Des-related myofibrillar myopathy, neurogenic scapuloperoneal syndrome, Kaeser type AD

>sCPK/myopathy Duchenne muscular dystrophy, Becker muscle dystrophy X-Iinked recessive

AVB (Dystrophia myotonica type 1) or Steinert's disease AD

Myopathy, possible ichthyosiform dermatitis Congenital disorder of glycosylation, type Im AR

With and without mild palmoplantar keratoderma and woolly hair AD

Lethal acantholytic epidermolysis bullosa, keratosis palmoplantaris striata II, skin fragility—woolly hair syndrome AD

DTNA 601239 Dystrobrevin alpha

EMD 300384 Emerin

EYA4 603550 Eyes absent 4

FHL1 300163 Four-and-a-half LIM domains 1

GATAD1 614518 GATA zinc finger domain

containing protein 1

ILK 602366 Integrin-linked kinase

JUP (DP3) 173325 Plakoglobin, desmoplakin III

LMNA 150330 Lamin A/C

LAMA4 600133 Laminin alpha 4

LDB3 605906 LIM domain-binding 3

MYBPC3 600958 Myosin-binding protein C

MYH6 160710 Alpha-myosin heavy chain 6

MYH7 160760 Beta-myosin heavy chain 7

MYL2 160781 Myosin light chain 2

MYL3 160790 Myosin light chain 3

MYOZ1 605603 Myozenin 1

MYOZ2 605602 Myozenin 2

MYPN 608517 Myopalladin

NEBL 605491 Nebulette

NKX2-5 600584 NK2 homeobox 5; cardiac-specific

homeoboxl

PDLIM3 605889 PDZ LIM domain protein 3

PLN 172405 Phospholamban

PKP2 602861 Plakophilin 2

PSEN1 104311 Presenilin 1

600759 Presenilin 2

613171 RNA-binding protein 20

180902 Ryanodine receptor 2

With or without congenital heart AD

defects

AVB, myopathy, EDMD1, X-linked X-linked

TsCPK recessive

Deafness Deafness, autosomal dominant AD

Myopathy EMDM 6, X-linked, myopathy, X-linked

reducing body, childhood-onset recessive,

and severe early-onset, myopathy X-linked

with postural muscle atrophy, dominant

scapuloperoneal myopathy,

X-linked dominant

Naxos traits AD, AR

AVB, possible TsCPK DCM with conduction disease plus 11 additional phenotypes AD

LVNC, ZASP-related myofibrillar myopathy AD

hypertrabeculation;

possible TsCPK

Atrial septal defect, sick sinus syndrome AD

Possible TsCPK Laing distal myopathy; myosin storage myopathy; scapuloperoneal syndrome, myopathic type AD

AD, AR

Possible conduction AD

system disease

Acne inversa, familial, 3, Alzheimer AD

disease, type 3, Frontotemporal

dementia, Pick disease

Alzheimer disease AD

Ventricular tachycardia, AD

catecholaminergic

polymorphic 1

(continued)

OP ZO m

ü» TABLE 1. Continued

MIM* Clinical Traits Phenotypes/Diseases Caused by

Nuclear Genes Gene Protein or Syndrome HCM RCM DCM ARVC LVNC (Red Flags) Mutations of the Same Gene Inheritance

SCN5A 600163 Sodium channel, voltage gated, type V, alpha subunit X Possible LQT or Brugada Syndrome LQT3, Brugada 1, AF, SSS, familial VF AD

SGCD 601411 Delta-sarcoglycan X Limb-girdle muscular dystrophy AD

SYNE1 608441 Nesprin 1, synaptic nuclear envelop protein 1 X EMD4, AD; Spinocerebellar ataxia, autosomal recessive AD

TCAP 604488 Titin-cap; telethonin X X [sCPK Muscular dystrophy, limb-girdle, type 2G AD

TCF21 603306 Transcription factor 21, epicardin X Hearing loss Hearing loss AD

TGFB3 190230 Transforming growth factor beta-3 X X AD

TMEM43 612048 Transmembrane domain 43 X X Emery-Dreifuss muscular dystrophy, AD AD

TMPO 188380 Thymopoietin X AD

TNNC1 191040 Cardiac troponin C1 X X X AD

TNNI3 191044 Cardiac troponin I3 X X X AD

TNNT2 191045 Cardiac troponin T2 X X X X AD

TPM1 191010 Tropomyosin 1 X X X AD

TTN 188840 Titin X X Limb-girdle muscular dystrophy, early-onset myopathy with fatal cardiomyopathy, proximal myopathy with early respiratory muscle involvement, tardive tibial muscular dystrophy AD

VCL 193065 Vinculin X X AD

AD = autosomal dominant; AF = atrial fibrillation; AR = autosomal recessive; ARVC = arrhythmogenic right ventricular cardiomyopathy; AVB = atrioventricular block; DCM = dilated cardiomyopathy; HCM =

hypertrophic cardiomyopathy; LVNC = left ventricular noncompaction; LQT = long QT; MIM = Mendelian Inheritance in Man; RCN = restrictive cardiomyopathy; sCPK = serum creatine phosphokinase; SSS = sick

sinus syndrome; VF = ventricular fibrillation.

*Also reported in Table 3 listing mitochondrial disorders.

■-T-O

LVEDD TAPSE

□hp® ■-T-O

■-T-O

LVEDD TAPSE

■-T-O

Does riot discriminate, highly recurrent In both »so* Does not discriminate, can be present in both

Inheritance mm XLR in emerinopathies, AD in laminopatfiies

12004: HTX In the sbter

FIGURE 2. Importance of Genetic Information in DCM Patients. Two pedigrees with probands (arrows) demonstrate similar DCM phenotypes at the onset of disease. The identification of the causative genes and mutations underscores the importance of the genetic diagnosis on the management of the 2 families (A,B). In family A, the identification of a mutation in the Emerin (EMD) gene provides information about the genetic status of the offspring (C). The son of the proband is obligate negative because a male cannot transmit an X-linked defect to his son. On the other hand, the daughters of affected males in X-linked diseases are obligate carriers of the paternal mutations. (D) In family B, the identification of a mutation in the Lamin A/C (LMNA) gene provides evidence that offspring can inherit the mutation with 50% probability for each pregnancy (D). In this family in the right panel, both children inherited the paternal mutation (+). Pedigree symbols for this and subsequent figures: circles for females, squares for males, diagonal lines represent deceased, solid-dark gray symbols denote cardiomyopathy, dotted circles denotes healthy carriers. AD = autosomal dominant; AVB = atrioventricular block; DCM = dilated cardiomyopathy; ECG = electrocardiogram; EF = ejection fraction; LVEDD = left ventricular end-diastolic dimension; NYHA = New York Heart Association; PM = pacemaker; sCPK = serum creatine phosphokinase; SD = sudden death; TAPSE = tricuspid annular plane systolic excursion; XLR = X-linked recessive.

FIGURE 3. Genotype, DCM, and the Natural History. In

1994, a patient underwent heart transplantation (HTx) (arrow) for end-stage DCM associated with AVB. The patient had received a pacemaker 4 years earlier. His mother had died of heart failure due to DCM, and AVB was treated with pacemaker implantation. In 2001, the LMNA gene was discovered and was found to be the etiology of cardiomyopathy in this family with DCM and conduction disease. The cascade family screening further uncovered 2 sons of the proband and the daughter of his sister as the healthy mutation carriers. In 2004, the sister of the proband underwent HTx for DCM and AVB, and in 2012, the oldest son of the proband was diagnosed with early DCM. This 18-year-long follow-up highlights the importance of genetic characterization in cardiomyopathic disorders. Abbreviations as in Figure 2.

attributes of a cardiomyopathic disorder, including mor-phofunctional characteristic (M), organ involvement (O), genetic or familial inheritance pattern (G), and an explicit etiological annotation (E) with details of genetic defect or underlying disease/cause; information about the functional status (S) using the American College of Cardiology/ American Heart Association (ACC/AHA) (A to D) stage and New York Heart Association (NYHA) (I to IV) functional classes may also be added. The addition of (S) has been left

optional, and should be used at the discretion of the

physician. With the description of 5 attributes, the classification system is designated as MOGE(S).

• The morphofunctional (M) notation provides a descriptive diagnosis of the phenotype (MD = dilated cardiomyopathy; MH = hypertrophic cardiomyopathy; MA = arrhythmogenic right ventricular (RV) cardiomyopathy; MR = restrictive cardiomyopathy; MLVNc = LVnoncompaction). Description of combined/ overlapping phenotypes (MD+R or MH+D) is easy to document, and disease-specific clinical markers can also be added, such as atrioventricular block (AVB), Wolff-Parkinson-White syndrome (WPW), epsilon wave (MD [AVB], Mh[wpw], MA[Ewavei). Although not likely, myocardial dysfunction with a nonspecific phenotype may be mentioned (MNS). Early involvement or no involvement in a mutation carrier with affected family members should be documented as either with early imaging markers (ME[H] or ME[D]) or unaffected (M0) with the expected cardiac phenotype in brackets. When the information about the morphofunctional cardiac phenotype is not available (for example, in deceased relatives), the description is MNA[H].

• The organ involvement (O) is documented as heart only (OH) or involvement of other organs/systems as below. The extracardiac involvement may be described by organ/system notations, such as skeletal muscle (OH+M), auditory system (OH+A), kidney (OH+K), nervous system (OH+N), liver (OH+L), gastrointestinal system (OH+G), cutaneous (OH+C), eye, ocular system (OH+E), or OH+MR for mental retardation. Involvement of other organs may represent the systemic disease. Healthy mutation carriers can be described as (O0), because the heart is not yet involved.

• The genetic or familial inheritance (G) provides information about autosomal dominant (GAD), autosomal recessive (GAR), X-linked (GXL), X-linked recessive (GXLR), X-linked dominant (GXLD), or matrilineal (GM) transmission. GXL could also be used without recessive or dominant specification for conditions when an X-linked inheritance is strongly suspected on the basis of pedigree and family screening but is not yet supported by results of genetic testing and should be clarified in the E notation. Sporadic (GS) indicates only a nonfamilial disease or a disease present in one family member when information or data on other family members are not (and will not be) available. Sporadic (GS) notation is also applied in cases with possible de novo mutation not yet identified. GN indicates negative family history, and Gu indicates unknown family history. G0 indicates that family history has not been investigated so far.

• The etiological annotation (E) adds to the description of the underlying cause. For instance, genetic (EG) etiology can be described by the specific disease gene and mutation(s) such as in the case of HCM (EG-MYH7 p.Arg403Glu]), or familial amyloidosis (EA-TTR[p.Val122Ile]),

and so on. Etiological specification may include: noncarrier (EG-Neg) when the disease gene tested negative; obligate carrier (EG-OC); obligate noncarrier (EG-ONC); presence of more than 1 mutation (or complex genetic defects, EG-C wherein all genetic information should be documented); genetic test not available yet, but the family data clearly indicate a genetic disease or the test is ongoing (EG-NA); genetically orphan patients after completion of the screening of all known disease genes in familial disease (EG-N); or genetic testing is not done or not feasible for any reason (EG-0). All above may facilitate description of mutations that do not segregate with the phenotype or incomplete genotyping. Please see specific examples in the individual cardiomyopathy sections in the following text and in Figures 2 to 10.

On the other hand, the nongenetic etiology can be described as viral (V) adding the virus (e.g., Coxsackie B3 virus [CB3], human cytomegalovirus [HCMV], Epstein-Barr virus [EBV]) as (Ev-hcmv), (Ev-cb3) or (Ev-ebv). Similarly, infectious nonviral disease can be described as (EI) with further specification of the infectious agent when possible. Myocarditis can be described as (EM) when the myocarditis is the proven cause of the myocardial disease; specification about sarcoidosis or nonviral or noninfectious giant cell myocarditis should be added (EM-sarcoidosis). Autoimmune etiology, either suspected or proven, can be added (EAI-S) or (EAI-P), respectively, after having excluded genetic and viral or toxic causes, especially in patients in whom a specific etiology may influence treatment. In the E annotation, nongenetic amyloidosis (EA-K) or (EA-L) or (EA-SAAA) should be described with kappa, lambda, serum amyloid A, or other protein characterization. Toxic cardiomyopathies, either endogenous such as pheochromocytoma-related cardiomyopathy, or drug-induced cardiomyopathy,

are described (ET-Pheochromocytoma or ET-Chloroquine). The

eosinophilic Loeffler endomyocarditis can be described according to the cause as either being idiopathic or a part of myeloproliferative disorder associated with the somatic chromosomal rearrangement of PDGFRa or PDGFRp genes that generate a fusion gene encoding constitutively active PDGFR tyrosine kinases. The E annotation will be modified in the future as various conditions are excluded from the category of cardiomyopathic disorders or as the newer entities are recognized.

• It is proposed that Heart Failure Stage (S) may be provided pertaining to ACC/AHA stage (A to D) and NYHA functional class (I to IV) if deemed necessary. For instance, stage A disease with functional class I can be written as (SA-I) or stage C disease in functional class II symptomatic subjects can be referred to as (SC-II). Addition of the fifth descriptor (S) is optional, but may come in handy for the description of early cardio-myopathy. Early cardiomyopathy is a condition where the clinical criteria for diagnosis of the cardiomyopathy are not present, but genetic mutation has been confirmed and/or subclinical imaging evidence of myocardial

MYH7 R663H HCM onset: 42 years SD: 76 years

MYBPC3 F247C Mild LVH Death: trauma: 84 years

11:1 74 years HCM MYH7 R663H MYBPC3-/-

Onset: 59 years Last control: 68 years MYBPC3 IVS7-30T IVS = 12 mm hypertension

Onset: 36 years Last control: 42 years

ECHO: negative MYBPC3 IVS7-3&T

11:3 11:4 11:5

Onset: 42 years 64 years 62 years

Last control: 71 years Healthy Healthy

EF: 53% - ICD - AF No No

MYH7R6S3H Genetic Genetic

MYBPC3 F247C Test Test

Onset: 32 years Last control: 59 years EF: 53%-ICD MYH7 R663H MYBPC3 -/-

!.. • ■

■ Onset: 20 years m;3 m;4

—" Last control: 37 years MYH7R663H MYH7 R663H

I Onset: 20 years m;3

1 Last control: 37 years MYH7R663H EF: 69% ICD

MYH7 R663H MYBPC3IV57-30T MYBPC3 F247C

^—^ Age: 2 years

MYH7 R663H + MYBPC3 F247C

111:5 MYH7 -/-

111:6 MYH7 -/-

Family member MÖGE

1:1* ^h ^h gad ^G-MYH7[P.R663H]

1:2 ^G-MYBPC31P.F247CI

11:1 mh gad ^G-C-MYH7IP.R663H]*MYBPC3-/-

11:2" mh °h gn ^G-MYBPC3 ¡IVS7-30TJ

11:3 mh ^h gad ^G-t>MYH7 ¡p.fí663H] + MYBPC3 ¡p.F247C]

11:4 mo°ogadeo

11:5 MO°OGADEO

11:7 MH ^H GAD EG-MVH7[P.RGG3HI

111:1 M„ °0 GAD ^G-MYBPC3IIVS7-30V

111:2 MH °H GAD ^G-C-MYHJ¡p.R663H¡ + MYBPC1 [p.F247C¡ * MYBPC3 [IVS7-3C>T]

111:3 mH OH gAD ^G-MYH7 [P.R663HI

111:4 ^H GAD EG-MYH7[P.R663HJ

111:5 M0°0GADEG-Neg

111:6 M0°0GADEG-Nes

IV:1 M0OO GAD EG-C-MYH7 [P.K663H] + MYBPC3 [P.F247C]

Individuals 11:4 and 11:5 are clinically unaffected (M0 O0), members of a family with AD HCM (GAD): they are non-Informative for segregation because they did not have genetic testing (E0). IV:1 is a girl with normal ECG and echocardiography study. *two sibs likely affected, not proven (not shown), "comorbidity = arterial hypertension.

FIGURE 4. The MOGE(S) in a Family With HCM. The MOGE(S) system allows presentation of all essential clinical and genetic information in a family with HCM and complex genetics.The pedigree shows the affected and nonaffected status of family members and the mutations identified in the family. The table (bottom) shows the application of the MOGE(S) system and the comprehensive description of the genetic make-up and phenotype expression in the members of different generations of the family. Although 3 mutations have been identified in this family, the HCM is inherited as autosomal dominant disease, and the mutation that occurs in all affected members is MYH7 p.R663H; other mutations may contribute to worsen the phenotype but do not seem to cause, by themselves, HCM. In families demonstrating autosomal dominant inheritance, the segregation of the mutation from the phenotype is necessary to avoid labeling of the carriers of nondeterministic gene variants as possible future patients, and to provide a correct interpretation of results in case of prenatal diagnosis. Given the high prevalence of HCM in the general population (1:500), families carrying more than 1 mutation are not rare, and are expected to further increase with next-generation sequencing (NGS), that allows sequencing of several common and rare genes in a large number of patients simultaneously. AF = atrial fibrillation; ICD = implantable cardioverter-defibrillator; IVS = Intervening sequence; other abbreviations as in Figure 2. Green filled symbols: mild LVH.

78 years Healthy MtDNA A3243G Dys: negative

49 years Healthy MtDNA :2 A3243G

Dys: negative

75 years Healthy MtDNA A3243G Dys: deletions

22 years MtDNA A3243G .j Dys test positive ' DMD

23 years Healthy MtDNA :1 A3243G

Mild mental retardation, coloboma

16 years: onset with mild neurosensorial hearing loss

20 years: HCM, WPW MtDNA A3243G

21 years: worsening of the LVH, myopathy

22 years: 1st stroke

23 years: multiple strokes, death

Year Pedigree MÖGE

2007 1:1 M0°oGM EG-MtDAM A3243G

1:2 M0°C,Gm EG-MtDAM A3243G; Dys Del +/-

11:1 M0°0GNE0

11:2 M0 °0 GM EG-MtDAM A3243G

11:3 MD °H+M GM,XLR, EG-MtDAM A3243G; Oys Del +

111:1 M0 °0 GM EG-MtDAM A3243G

111:2 MH[WPW] °H+E+A+MR GM EG-MtDAlA A3243G

2009 1:1 M0 °0 GM EG-MtDAM A3243G

1:2 M0°0GM EG-MtDAM A3243G; Oys Del +/-

11:1 mO°OgNeO

11:2 M0°0GM ^G-MtDNA A3243G

111:1 M0°0Gm ^-G-MtDNA A3243G

111:2 Mh[WPW] Oh+E+A+MR GM Ee-MtONA A3243G

2011 1:1 M0O0GM EG-MtDAM A3243G

1:2 M0O0GM EG-MtDAM A3243G; Oys Del +/-

11:1 mO°OgNeO

11:2 M0°oGM EG-MtDAM A3243G

111:1 M0 °0 gm EG-MtDAM A3243G

111:2 MH[WPW] °H+M+E+A+MR+N GM EG-MtDNA A3243G

FIGURE 5. MOGE(S) in a Family With Mitochondrial Cardiomyopathy: Evolution of the Disease in Family and Clarification of the Genetic Basis of Disease During Follow-Up. The pedigree illustrates the case of a young boy who was

affected by mild mental retardation and bilateral coloboma. In 2007 he was first diagnosed with HCM and Wolff-Parkinson-White syndrome (WPW). His family history revealed the death of a maternal cousin at the age of 22 years for Duchenne muscular dystrophy (DMD). Based on family history and pedigree, the first hypothesis was an X-linked recessive disease, which was, however, unlikely because of the HCM phenotype, the WPW, and the mental retardation. The DYS gene tested negative in the proband (both multiplex ligation-dependent probe amplification [MLPA] and sequencing) as well as in the mother and maternal grandmother whose sister was healthy carrier of DYS mutation and mother of the young man with DMD. LAMP2 was analyzed because of the HCM phenotype with WPW and cognitive impairment, and tested negative. Sequencing of the mitochondrial DNA (mtDNA) demonstrated the MT-TL1 MELAS/LS A3243G mutation [tRNA Leu (UUR)], heteroplasmic in all maternal relatives and in the boy. Endomyocardial biopsy was not performed. During the ensuing years, the patient showed worsening of HCM with evolution of left ventricular (LV) dysfunction (LVEF = 35%) and developed stroke-like episodes to result in death. The MOGE(S) system summarizes the clinical and genetic status of the family in 2011 and the key clinical traits of the disease. LVH = left ventricular hypertrophy; other abbreviations as in Figure 2.

Family History

Age: 62 years Stroke at 59 years

42 years Renal Failure

55 years Gastrointestinal Disturban c!es

U27 years Asymptomatic /" 11:2 Incidental diagnosis of

Left Ventricular Hypertrophy A {ECG and ECHO) A

PR interval = 116

Family Screening GLA +/—

ECG PR = 112 msec IVS = 9 mm Dermatologic evaluation: angiokeratomas " Renal function = normal

Dermatologie Evaluation: Angiokeratomas GLA +

Extension of information and tests in ft

Tracing medical reports No cardiac information Dialysis for 9 years Death at 55 years No autopsy No genetic test

GLA +/—

Ophatlmologic evaluation:

Cornea Verticillata ECG PR = 122 IVS = 11 mm Renal function = normal

PR Interval = 120

S 11:2

GLA +/~

87 years

Arterial Hypertension eiA-/-

ECG PR -126 IVS = 11 mm GLA +/-

111:2 J

Intermittent proteinuria

Pedigree MOSE

1:1 mna[h]°kgoceo

1:2 mo°ogoeg-gm-a

11:1 mh[№r] °h+n+c gx-l eg-gw+/-

11:2 mh 0e*ggx-le5-suia

111:1 mh°k«gx-leb-ou.

111:2 mh°kgx-les-gllt

iv:1 mo°ogonceo

FIGURE 6. MOGE(S) in a Family With AFD. On the left side of the figure, the example of Anderson-Fabry disease (AFD) highlights the importance of family study and demonstrates how simple is it to suspect the disease (left). The proband (arrow) was brought to medical attention for the clinical suspicion of HCM.The family history, however, revealed long-lasting maternal gastrointestinal disturbances (common diseases causing such disorders had been excluded), a stroke in the maternal aunt, and renal failure in the maternal male cousin. Further screening of the family uncovered cornea verticillata in the mother and angiokeratomas in the male cousin.The serial examination of urine samples in the proband showed intermittent proteinuria, and the genetic testing confirmed the diagnosis of AFD. The MOGE(S) figure only summarizes the last clinical and genetic status of the family. Individual VI:1 is an obligate noncarrier, whereas individual I:1 (genetic test not performed) is an obligate carrier because the wife tested negative and both daughters carried the mutation. If the genetic test were available in I:1, it would not have been necessary in the daughters because both are naturally obligate carriers. In the right half of the figure, from top to bottom, the pathological features of AFD in endomyocardial biopsy are shown. (A) Hematoxylin and eosin stain shows a large number of vacuolated myocytes (glycosphingolipids are extracted in formalin-fixed, paraffin-embedded tissues); (B) the toluidine blue stain of the semi-thin sections from resin-embedded samples for electron microscopy show characteristic intramyocyte accumulation of osmiophilic bodies of the storage material; and (C) the ultrastructural panel confirms the typical lamellar and dense osmiophilic bodies. Abbreviations as in Figures 2. Grey filled symbols: mild LVH.

Onset with syncope; age: 20 years After 1st pregnancy in 1985

1987-1993:1:2-» 2 further pregnancies 1999: waiting list HTx

1:1 —• 1:2

11:2 11:3

Mental retardation Ocular problems

Year Pedigree MOGE

1986 1:1 M0O0G0

1:2 mh°hgnena

11:1 M0°oGo

1987 -1993 1:1 M0°oGo

1:2 mh°hgn ena

11:1 M0°oGo

11:2 M0°oGo

11:3 mh°h+e+mrgxlena

2003 1:2 mh °„ gn EG-LAMP2lp.Val310lle]+l-

11:1 mo°ogxle6-Nug

11:2 m0[êPR] °h Gxu EG-LAMP2[p.Val310lla}*l-

11:3 mh °h+e+sm+mr gxl ^G-LAMP2[p.Val310lle]+

2004 - 2013 1:2 mh °h gh eg-lamp24>.Val310lle]+I-

11:1 mo°ogxleg-Neg

11:2 mh °„ GXL EG-MMP2/p.Va/3ÏO/fe;+/-

11:3 mh °h+e+sm+mr+lgxl eg-LAMP2lp.Val310lle]*

(Prenatal Genetic test: - 3) n1:1 mo°ogxleg-Neg

(Prenatal Genetic test: + 3) n1:2 ^G-LAMP2[p.Val310lle]+

(Prenatal Genetic test: + $>) n1:3 m0 °0 gxl Ee-LAMP2[p. VaI310lle]*l-

LAUP2 ex7 Val310lle

lll:l 111:2 III =3

Prenatal - Prenatal + Prenatal h

FIGURE 7. MOGE(S) in a Family With Danon Disease. The example of Danon disease caused by a mutation of the LAMP2 gene and the natural history of the disease in the family from 1986 to 2013; the family history of 27 years is summarized in the table (bottom right). Although Danon disease in its typical presentation affects males (LAMP2 gene maps on the X chromosome) who show HCM, myopathy, and mental retardation (see the table), the cardiac phenotype is expressed also in adult female carriers who do not show myopathy and mental retardation.The II:3 male showed the typical phenotype; his sister who had 3 pregnancies and 3 prenatal diagnoses is now affected by cardiomyopathy. Her second pregnancy (a male fetus and a positive genetic test) ended in a voluntary interruption, whereas the third pregnancy (female fetus and positive genetic testing) ended in a Cesarean section due to worsening of ventricular arrhythmias during pregnancy. The girl is now well with normal electrocardiographic and echocardiographic features.The chromatogram shows the mutation identified in the LAMP2 gene in I:2. Abbreviations as in Figure 2.

FIGURE 8. MOGE(S) in RCM With Cardiac Desminopathy and Intramyocyte Storage of Desmin. Typical cardiac des-minopathies with intramyocyte desmin accumulation are clinically characterized by RCM and AVB; the family history is presented in left panel and the typical pathologic features of the myocardium in the right panel. Individual I:1 underwent heart transplantation (HTx), as did her son II:3. The other 2 affected sons died of heart failure after diagnosis of RCM and pacemaker implantation. After transplantation II:3 married the unrelated II:4 (shown in blue letters in the MOGE, 2013 table) who also underwent HTx for DCM. II:4 had undergone HTx without family screening with a presumptive diagnosis of post-myocarditic DCM. However, her heart excised at transplantation did not show features of myocarditis, and the viral genome search was negative. The couple (II:3 and II:4) had a boy (III:1) in which the paternal DES mutation was excluded. However, in case the viral etiology of the DCM was wrong and the mother had a genetic DCM, the genetic status of the boy (although DES mutation is ruled out) remains incomplete, and the risk of developing DCM is unknown. The right panel shows (A) hematoxylin and eosin—stained myocardial samples in desminopathy. The eosinophilic bodies correspond to the accumulation of desmin, and myofibrillar disarray is present. (B) Anti-desmin immunostaining supports the diagnosis but remains nonconclusive in light microscopy study due to the variable orientation of myocytes in small EMB samples with procedure-related contraction bands. (C) Electron microscopy study is the gold standard for the pathological diagnosis. Abbreviations as in Figure 2.

involvement is apparent. The imaging alterations may include increased LV end-diastolic diameter and reduced longitudinal strain with still normal ejection fraction (EF) for DCM, or borderline LV thickening for HCM. The

ACC/AHA guidelines include patients with a family history ofcardiomyopathy in stage A. Therefore, the MOGE(S) can take advantage of the stage to describe individuals that show early markers of disease but do not fulfill the

/ 11:1

DYS II

DYS 997

173 207 175 193 173 230 249 113 197

y 11:1

DYS II

DYS 997

173 207 175 193 173 230 249 113 197

171 1 217 2 163 1 179 1 //1

245 2 127 1 201 1

173 207 175 193 173 230 249 113 197

Pedigree MOSE

1:1 M0O„GnE0

1:2 MoOpGuEj

11:1 MD°H+M1>sCPKGUE0

11:2 M0°0GUE0

11:3 Go Gu Eo

Pedigree MOGE

1:1 MO°OGNEO

1:2 MoOjGyEd

11:1 MD °H+M^SCPK GU ^G-DYS [Del 45-48]+

11:2 M000EuE0

11:3 m„O0CuE0

Pedigree MOGE

1:1 mO°OgNeO

1:2 M0 Go GXLR EG-DKS [Del 45-48}+/—

11:1 MD °H+M1>sCPK GXLR EG-DV5 [Del 4548]+

11:2 M0 °0 GXLR ^G-DYSlDel 45-481-/-

11:3 M0 °0 GXLR EG-0K [Dei 45-48]+/-

11:2 Pregnancy -> cord blood preservation

Vy jy Vv

FIGURE 9. MOGE(S) in Dilated Cardiac Dystrophinopathy. The figure presents 3 diagnostic steps in a family with X-linked recessive DCM caused by deletion mutation of the Dystrophin gene.The proband showed an apparently sporadic DCM with severely dilated left ventricle and decreased EF; the presence of increased sCPK suggested the possibility of a Dystrophin defect. The MLPA demonstrated an in-frame deletion of exons 45 to 48. The noncarrier sister at her first pregnancy asked about private umbilical blood cord preservation for future stem cell (SC) transplantation in the affected brother. This request is increasing in Dystrophin families and, at present, regulatory bodies and scientific societies in different countries do not provide uniform recommendations. We realize that a definite donor cell engraftment is not yet proven, and such a request should only be considered in consultation with SC transplantation experts and specialized centers; private SC preservation with costs covered by the family is feasible.The family study documented the carrier status of the mother and of 1 of the sisters (II:3). Bottom: the myocardial pathology shows that the Dystrophin defect is associated with decreased expression of the protein (B) as compared to abundant expression (A) in a normal heart. A represents an endomyocardial biopsy specimen obtained from a donor heart before transplantation. Abbreviations as in Figure 2.

1:2 Neonatal

UDCM+LVNC Neutropenia ll:l Muscle hypotonia

Pedigree MÖGE

1:1 M0 °0 GXLR EG-G4.5 G441A +/-

1:2 MOOQGNEO

11:1 MCHLVNC°H+M GXLR EG-G4.5G441A +

11:2 prenatal + EG-G4.5G441A +

11:3 prenatal-(J M0°D GXLR EG-G4.5G441A-

Pedlgree MÖGE

1:1 MoOqGnEo

1:2 mo°OgNEO

11:1 md+lvnc°h+m go eo

Pedigree MÖGE

1:1 M0 GN EG-G4.5 G441A +/-

1:2 MOOQGNEO

11:1 ^CHLVNC ®H+M GXLR EG-64.5G441A +

Pedigree MÖGE

1:1 M0 °0 GN EG-G4.5 G441A +/-

1:2 MOOQGNEO

11:1 M[H-LVNC ®H+M GXLR EG-G4.5G441A +

Pedigree MÖGE

1:1 M0 °0 GXLR EG-G4.5 G441A *f-

1:2 MOOQCNEO

11:1 MCHLVNC°H+M GXLR EG-G4.SG441A+

11:2 prenatal + S EG-64.5 G441A +

FIGURE 10. MOGE(S) in Barth Syndrome. The figure shows the case of a boy who demonstrated a severe and rapidly fatal neonatal dilated cardiomyopathy. The family history was negative: both parents were healthy, and there were no relatives affected by cardiac diseases. The presence of LVNC suggested the possibility of Barth syndrome. The genetic testing showed a hemizygous mutation in the G.4.5 gene encoding the nuclear mitochondrial protein tafazzin. The mutation was inherited from the healthy mother whose clinical screening demonstrated a normal heart. At the second pregnancy, the prenatal diagnosis demonstrated a male fetus carrier of the mutation. The pregnancy was interrupted. At the third pregnancy, the prenatal diagnosis showed the male fetus a noncarrier of the mutation. The pregnancy was successful, and the boy is healthy. The mother did not show cardiac problems during or after the 3 pregnancies. Abbreviations as in Figure 2.

diagnostic criteria for the cardiomyopathy. In families with known mutation, the diagnosis of early cardiomyopathies can be further supported by the presence of the mutation(s), whereas in genetically orphan familial cardiomyopathies, only the early imaging markers of the disease can be highlighted. This description could be especially useful for sport worthiness that often requires physicians to provide a definitive recommendation, and (S) notation may allow the description of a gray diagnostic

zone. Although criteria for early diagnosis of cardiomyopathy are not systematically described, the increasing family screening and monitoring have revealed that the cardiomyopathies likely serve a long pre-clinical or subclinical interval before the onset of symptoms or the manifestation of the clinical phenotype [31].

Table 2 shows the MOGE(S) system notations and modeling. The alphabetical components are likely going to

M O G E S Stage; ACC/AHA Stage,

Morphofunctional Phenotype* Organ/System Involvement^ Geneticz Etiological Annotation^ NYHA Functional Class1

(D) Dilated (H) Heart (N) Family history negative (G) Genetic etiology—add gene and mutation; (NC) ACC/AHA stage

(H) Hypertrophic (M) Muscle, skeletal (U) Family history unknown Individual noncarrier plus the gene that tested represented as

(R) Restrictive (N) Nervous (AD) Autosomal dominant negative letter (A, B, C, D)

(A) ARVC (C) Cutaneous (AR) Autosomal recessive (OC) Obligate carrier

(NC) LVNC (E) Eye (XLR) X-linked recessive (ONC) Obligate noncarrier To be followed by

Overlapping (H+R), (A) Auditory (XLD) X-linked dominant (DN) De novo NYHA functional class

(D+A), (NC+H), (K) Kidney (XL) X-linked (C) Complex genetics when >1 mutation (provide represented in Roman

(H+D), (D+NC) or (G) Gastrointestinal (M) Matrilineal additional gene and mutation) numerals (I, II, III, IV)

more complex (S) Skeletal (DN) De novo (Neg) Genetic test negative for the known familial

combinations such as (0) Absence of organ/ (0) Family history not mutation

(H+R+NC) system involvement, e.g., investigated (NA) Genetic test not yet available

(E) Early, with type in family members who (N) Genetic defect not identified

in parentheses are healthy mutation (0) No genetic test, any reason (no blood sample, no

(NS) Nonspecific carriers; the mutation informed consent, etc.)

phenotype is specified in E and Genetic amyloidosis (A-TTR) or hemochromatosis (HFE)

(NA) Information inheritance in G Nongenetic etiologies:

not available (M) Myocarditis

(0) Unaffected (V) Viral infection (add the virus identified in affected heart) (AI) Autoimmune/immune-mediated; suspected (AI-S), proven (AI-P); (A) Amyloidosis (add type of amyloidosis: A-K; A-L, A-SAA) (I) Infectious, nonviral (add the infectious agent) (T) Toxicity (add toxic cause/drug) (Eo) Hypereosinophilic heart disease

Md, Mh, Mr, Ma, Mnc, Oh, Om, Ok, Oc gn, gu, gad, gar, gxlr, EG-MYH7[R403E], EG-HFE[Cys282Tyr+/+], sa-i, sa-ii

Mo, Mh+r, Md+a gxld, gxd, gm, gdn EV-HCMV, EG-A-TTR[V30M], EM-sarcoidosis

ACC/AHA = American College of Cardiology—American Heart Association; NYHA = New York Heart Association; other abbreviations as in Table 1.

*The morphofunctional phenotype description (M) may contain more information using standard abbreviations, such as AVB = atrioventricular block; WPW = Wolff-Parkinson-White syndrome; LQT = prolongation

of the QT interval; AF = atrial fibrillation; YR = low electrocardiogram voltages; YPR = short PR interval.

tOrgan (O) involvement in addition to the H subscript (for heart) should be expanded for the involvement of M = skeletal muscle, E = eye, ocular system, A = auditory system, K = kidney, L = liver, N = nervous

system, C = cutaneous, G = gastrointestinal system, and other comorbidities, including MR = mental retardation.

ZGenetic (G) describes the available information about inheritance of the disease. It also provides complete information if the family history is not proven or unknown, and if genetic testing has not been performed

or was negative for the mutation/mutations identified in the family.

XThe etiologic annotation (E) provides the facility for the synthetic description of the specific disease gene and mutation, as well as description of nongenetic etiology.

IIThe functional annotation or staging (S) allows the addition of ACC/AHA stage and NYHA functional class.

OP ZO m

2 , : o

change in parallel with new scientific discoveries. As anticipated, the proposed nosology is modeled similarly to the universally accepted TNM staging of tumors, which has been consistently expanded and has allowed use of a common language of clinical comprehension and utility [32]. In TNM staging, the T describes the size of carcinoma and extent of local invasiveness, N stands for the status of lymph nodes, and M provides for the presence or absence of metastases. There are additional descriptors; for instance, the prefix y with T indicates that the cancer was resected after neoadjuvant therapy, r indicates recurrence of cancer, and m identifies multifocal cancer. Similarly the nodal status can be i+ (isolated tumor cells), mic (micrometastatic, 0.2 to 2.0 mm), or mac (macro-metastases, >2 mm). The clinical staging is designated as cTNM and the pathological staging of cancer as pTNM.

In the MOGE(S) nomenclature, ion channelopathies are not included, but can be incorporated if so needed in the future. The reason for the exclusion is that due to the high prevalence of genetic variations in ion channel genes and the ever-increasing genetic complexity of cardiomy-opathy, it cannot be excluded that few available reports of ion channel mutations in patients with cardiomyopathy (in the absence of screening of all other disease genes) may in fact represent an incomplete genotyping. In a series of more than 100 DCM patients in whom the SCN5A gene was screened along with other genes, a single mutation was identified in 1 patient who was also carrier of the PLN mutation [33]. The channelopathies are nosologically well-defined arrhythmogenic disorders [34] without LV remodeling and with clinical needs that differ from those of cardiomyopathies. Giving the large spectrum of electrical phenotypes associated with mutations of ion channel genes, this group of diseases likely deserves a specific and independent nomenclature.

The MOGE(S) nomenclature in the diagnostic work-up of cardiomyopathies

It is expected that the clinical and imaging characterization of the phenotype (M) would be routinely defined on morphological (dilated, hypertrophic, LV noncompaction [LVNC]) and morphofunctional (restrictive, arrhythmogenic) traits, and the second descriptor (i.e., the organ involvement, O) would require to specify whether the heart is the only affected organ or other organs/systems are involved (Table 2). The disease may be systemic and the involvement of the heart a part of general disease process. This simple definition of the involvement of the heart only, of the heart as a component of systemic disease process, and the involvement of other organs provides useful clinically discriminatory information. The first combination of (M) and (O) can offer preliminary diagnostic clues. For instance, MH OH+SM+MR suggests the possibility of HCM in either Danon or mitochondrial DNA—related disease; when additional details are available, such as Mh[wpw] Oh, a mutation of PRKAG2 might be suspected. Similar clues

could be available for dilated cardiolaminopathy MD[AVB] OH, dilated cardiodystrophinopathy MD[[sCPK] OH+M, or restrictive desminopathy MR[AVB] OH+M and underscore the importance of identifying clinical indicators ("red flags") in the MOGE(S) nomenclature [35].

Data from family pedigrees, including investigation for the family history and the pattern of inheritance (G), add valuable leads for complete characterization of the cardiomyopathy. For example, a restrictive cardiomyopathy with autosomal dominant inheritance, but without conduction disease and involvement of other organ systems, suggests troponinopathy (MR OH GAD). Information about G may help discriminate similar phenotypes: (MH[WPW] OH GAD) might suggest an HCM associated with PRKAG2 mutation, whereas (MH[WPW] OH+M+MR GXL) suggests Danon disease, or (MH[WPW] OH+M+N GM) mitochondrial DNA—related cardiomyopathy. The etiological annotation (E) provides a descriptive analysis of the genetic defect and/or underlying disease. For nongenetic and nonfamilial cardiomyopathy, the E annotation may include other etiologies.

Although it may seem a bit complex in the beginning, this nomenclature does provide an articulated configuration that is able to transmit all essential information for every cardiomyopathy type, patient, and family; a genetic tree and reference to family members per generation may be appended when needed (Fig. 4). An easy web application (app) for MOGE(S) nomeclature can be accessed from mobile phones and other devices (http://moges.biomeris. com). The app becomes handy for correct notation at least in the initial stages. The abbreviations applied here (such as AVB or WPW) are consistent with terminology systems such as Systematized Nomenclature of Medicine (SNOMED) [36] or SNOMED CT (SNOMED Clinical Terms) [37] and in the International Classification of Diseases (ICD) [38]. The proposed nomenclature reflects the diagnostic work-up of cardiomyopathies for evaluation of the phenotype, implementation of family screening strategies for diagnosis and prevention, and results of genetic testing in the Sanger and post-Sanger era.

MOGE(S) NOMENCLATURE FOR HCM

HCM phenotypically denotes a heterogeneous group of syndromes all sharing a cardiac trait of thickening of the LV wall; the 2 major groups include sarcomeric (up to 90% of all HCM caused by mutations of structural and regulatory genes of the sarcomere) and nonsarcomeric HCM (Table 1).

The diagnosis of sarcomeric HCM implies that a sarcomeric gene defect has been identified, and the mutation is duly noted in the etiological (E) annotation, such as MH Oh Gad EG_MYH7[p.Arg403Glu]. Although earlier studies attempted to correlate distinct gene defects with the severity of the disease, little has been confirmed after 20 years of genotype to phenotype correlation studies [39]. Several disease genes have been identified; defects of MYH7 and MYBPC3 account for up to 70% of sarcomeric HCM, followed by troponin gene defects (TNNI3, TNNT2) and

TABLE 3. Major Mutations in MTDNA* and Nuclear Genes and Cardiac Phenotypes Reported to Date

MTDNA Disease Allele Gene HCM DCM RCM LVNC

MTTL1 MMC/MELAS A3260G tRNALeu(UUR) X X

MTTL1 MMC C3303T tRNALeu(UUR) X X

MTTL1 MELAS A3243G tRNALeu(UUR) X X X X

MTTL1 MELAS G3244A tRNALeu(UUR) X

MTTL1 MM/HCM + RENAL TUBULAR DYSFUNCTION G3242A tRNALeu(UUR) X X

MTTL1 MELAS A3252G tRNALeu(UUR) X

MTTL1 MELAS/myopathy T3258C tRNALeu(UUR) X X

MTTL1 Myopathy A3280G tRNALeu(UUR) X X

MTTL2 DCM/LS/failure to thrive and LA T12297C tRNALeu(CUN) X

MTTI MHCM A4295G tRNAIle X X

MTTI MICM A4300G tRNAIle X X

MTTI FICP A4269G tRNAIle X X

MTT HCM with hearing loss/possible hypertension factor A4316G tRNAIle X

MTTI FICP A4317G tRNAIle X X

MTT Varied familial presentation/spastic paraparesis G4284A tRNAIle X X

MTT Mitochondrial encephalocardiomyopathy C4320T tRNAIle X X

MTTK Cardiomyopathy/SNHL A8348G tRNALys X X

MTTK MERRF A8344G tRNALys X X

MTTK MERRF/MICM+DEAF/autism/LS G8363A tRNALys X X

MTTG MHCM T9997C tRNAGly X

MTTH MICM G12192A tRNAHis X

MTTP DCM T16032TTCTCTGTTCTTTCAT (15 bp dup) tRNAPro X

MTTQ Possibly LVNC-associated T4373C tRNA Gln X

MTTV LS C1624T tRNAVal X X

MTTV Adult LS G1644T tRNAVal X

MTRNR2 MELAS C3093G 16S rRNA X

MTRNR1 Possibly LVNC-associated T921C 12S rRNA X

MTRNR1 Possibly LVNC-associated T850C 12S rRNA X

MTRNR1 DEAF, possibly LVNC-associated T961C 12S rRNA X

MTRNR1 Found in 1 HCM patient T1391C 12S rRNA X

MTRNR1 Found in 1 HCM patient C1556T 12S rRNA X

MTRNR2 Possibly LVNC-associated T2352C 16S rRNA X

MTRNR2 Possibly LVNC-associated G2361A 16S rRNA X

MTRNR2 Possibly LVNC-associated A2755G 16S rRNA X

MTCYB HCM G15243A (G166E) MTCYB X

MTCYB HCM/WPW,DEAF G15498A (G251D) MTCYB X

MTCO1 Idiopathic sideroblastic anemia T6721C (M273T) MTCO1 X

MTCO1 MTND4 Idiopathic sideroblastic anemia Diabetes mellitus T6742C ( I280T) A12026G (I423V) MTCO1 MTND4 X X

(continued)

other less commonly involved genes (ACTC1, CSRP3, CRYAB, CAV3, MYH6, MYL2, MYL, TNNC1, TCAP, MYOZ1, MYOZ2) (Table 1). The extracardiac markers are conspicuously absent in autosomal dominant sarcomeric HCM. A minority of sarcomeric HCM may show associated myopathy, a feature that may be described as MH OH+M

Gad EG-MYH7[p.Arg403Giu]- Autosomal recessive HCM is rare [40]: these families differ from those in which double or triple mutations are identified but inheritance is autosomal dominant. In fact, an increasingly greater proportion of patients with sarcomeric HCM are being recognized with double and compound mutations contributing to worse

TABLE 3. Continued

Nuclear Genes Phenotype Inheritance HCM DCM RCM LVNC

ANT1 (PEOA2) AD-PEO, multiple mtDNA deletions AD X X

AGK Sengers syndrome (HCM, cataract and myopathy) AR X

COXIO Neonatal tubulopathy and encephalopathy, LS AR X

COX15 Early-onset HCM, LS AR X

DNAJC19 DCM and LVNC, early onset, anemia, ataxia, male genital anomalies and methylglutaconic aciduria type V AR X X

FRDA Friedreich ataxia, neuropathy, cardiomyopathy, diabetes AR X X

G4.5 (Tafazzin) Barth syndrome, X-linked dilated cardiomyopathy X-linked X X

MFN2 Charcot-Marie-Tooth disease type 2A2 AD X

POLG (PEOA1) Alpers syndrome, AD-PEO and AR-PEO, male infertility, SANDO syndrome, SCAE AD-AR X X

NDUFS2 Encephalopathy AR X X

NDUFV2 Hypotonia, encephalopathy AR X

SCO2 Neonatal cardio-encephalomyopathy AR X X

DEAF = maternally inherited deafness or aminoglycoside-induced deafness; FICP = fatal infantile cardiomyopathy plus, a MELAS-associated cardiomyopathy; LD = Leigh disease; LS = Leigh syndrome; LA = Lactic Acidosis; LVNC = left ventricular noncompaction; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF = myoclonic epilepsy and ragged red muscle fibers; MHCM = maternally inherited hypertrophic cardiomyopathy; MICM = maternally inherited cardiomyopathy; MMC = maternal myopathy and cardiomyopathy; mtDNA = mitochondrial DNA; PEO = progressive external ophthalmoplegia; SANDO = sensory ataxic neuropathy with dysarthria/dysphagia and ophthalmoplegia; SCAE = spinocerebellar ataxia with epilepsy; other abbreviations as in Table 1.

*http://www.mitomap.org; last accessed November 6, 2013. Short PR electrocardiogram intervals and pre-excitation recur in mitochondrial cardiac phenotypes, especially in the early phases of the disease. Atrioventricular block is more common in late phases of the disease.

phenotype and high arrhythmogenic risk regardless of the ventricular wall thickness; double (or compound) mutations detected by genetic testing may confer a genedose effect in HCM (such as Mh Oh Gad eG-MYH7[p.Arg403au]+ MYBPC3HVS7+10A]) and may predispose patients to adverse disease progression [41,42]. Some examples of MOGE(S) nomenclature for sarcomeric HCM are presented below.

Mh Oh Gad Eg-myh7[p. Arg403Glu] Sb-i represents: mor-phofunctional phenotype (M): hypertrophic (H) cardiomyopathy; organ (O) involvement: heart (H); genetic/ familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G) and caused by the p.Arg403Glu mutation of the MYH7 gene, ACC/AHA stage (S) B, NYHA I.

ME(H) °H GAD EG-MYH7[p. Arg403Glu] SA-I represents

morphofunctional phenotype (M): "early" (E) hypertrophic (H) cardiomyopathy (for example, borderline LV thickness or early diastolic dysfunction or electrocardio-graphic (ECG) abnormalities suggesting hypertrophy with normal LV thickness); organ (O) involvement: heart (H); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G) and caused by the p.Arg403Glu mutation of the MYH7 gene; ACC/AHA stage (S) A, NYHA I.

ME(H) OH Gad Eg-na Sa-i represents: morphofunc-tional phenotype (M): "early" (E) hypertrophic (H) car-diomyopathy organ (O) involvement: heart (H); genetic/ familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic but the mutation is not yet available (NA) (either ongoing or to be done but feasible); ACC/ AHA stage (S) A, NYHA I.

M0 °0 GAD EG-MYH7[p. Arg403Glu] SA-I represents:

morphofunctional phenotype (M): "unaffected" (0) by cardiomyopathy; organ (O) involvement: absence of any cardiac phenotype (zero, 0); in familial/genetic (G) autosomal dominant (AD) cardiomyopathy; etiology (E) genetic (G), healthy carrier of the p.Arg403Glu mutation of the MYH7 gene that causes the disease in the family; ACC/ AHA stage (S) A, NYHA I.

Because the intrafamily variability of the phenotype may include different morphofunctional phenotypes (for example, HCM and DCM, the latter often representing the end-stage evolution of the original hypertrophic pheno-type), a combination of morphofunctional phenotypes is possible (HDD).

Nonsarcomeric HCM may show different types of inheritance, such as AD in PRKAG2-related HCM with WPW [43], AR in Friedrich ataxia [44], X-linked in Danon disease [45] and in Anderson Fabry disease (AFD) [46], AR in Pompe disease [47], or matrilineal (or maternal) in cardiomyopathies caused by mutations in the mitochondrial DNA [48,49] (Table 3, Fig. 5). Mitochondrial diseases constitute a large and heterogeneous group of complex diseases/syndromes (1 per 4,000 to 5,000 live births) caused by mutations of nuclear (inherited according to Mendelian rules) or mitochondrial (matrilineal inheritance with absence of male transmission) genes. Cardiologists encounter mitochondrial diseases in their routine practice either in patients presenting with HCM or DCM, or in patients referred by neurologists or myologists for consultation. The role of the cardiologists is essential for

TABLE 4. Most Common Metabolic Diseases Causing Cardiomyopathy Phenocopies and Synthetic Description of Involvements of Other Organs/Tissues

Disease

MIM # Phenotype

Inheritance Age of Onset

Disease

Gene Cardiac Phenotype

Extracardiac Markers/

Major Involvement (Noncomprehensive) of Other Organs

Glycogen storage disease (GSD) GSDII (Pompe disease, glycogen 232300

storage disease II, acid alpha-glucosidase/acid maltase deficiency)

GSDIII (Forbes or Cori disease, 232400

glycogen debranching enzyme)

GSD IV (Anderson disease, glycogen 232500 branching enzyme)

GSD V (McArdle disease, glycogen 232600

phosphorylase) GSD 0 (muscle) (muscle glycogen 611556

synthase

Other disorders of the glycogen metabolism PRKAG2-related disease 261740

Lethal congenital glycogen storage

disease of heart PRKAG2-related familial hypertrophic 600858

cardiomyopathy Wolff-Parkinson-White syndrome 194200

Danon disease (lysosomal-associated membrane protein 2)

300257

Lysosomal storage diseases: sphingolipidoses Anderson-Fabry disease (alpha- 301500

galactosidase deficiency)

Anderson-Fabry disease—later onset,

cardiac variant GM1 gangliosidosis (beta-galactosidase deficiency)

301500

230500

AR Infant to young adult

Childhood

Perinatal, congenital, infant, childhood, adult Young adult

Childhood

Young adult

Young adult

Young adult

Childhood in males, young adult in females

Childhood to adulthood Adult

PYGM DCM

PRKAG2 HCM

PRKAG2 HCM

PRKAG2 WPW with/without HCM

LAMP2 HCM, HCM evolving through dilation and dysfunction, LVNC

Infancy (infantile form), GLB1 childhood (late-infantile/ juvenile form), adult (chronic form)

Symmetrical HCM

HCM, DCM

Skeletal muscle, liver

Liver, skeletal muscle, hypoglycemia, growth retardation Liver, skeletal muscle, brain

Skeletal muscle;

myoglobinuria Skeletal muscle

Skeletal muscle, cognitive impairment in males, pigmentary retinopathy also in females

Renal, ocular, nervous, cutaneous, gastrointestinal systems

Neurological and skeletal systems,

hepatosplenomegaly

Specific Treatment

m Zn m

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ERT (gene therapy; substrate reduction therapy)

MLD (Metachromatic leucodystrophy) 250100

GM1 gangliosidosis with cardiac 230500

involvement (beta-galactosidase deficiency) [50-53] GM2 gangliosidosis (Tay-Sachs disease) 272800

GM2 gangliosidosis (Sandhoff-Jatzkewitz 268800 disease) [54,55]

Gaucher disease (glucocerebrosidase 230800 deficiency), types I, II and III, perinatal lethal and type IIIC with cardiovascular calcifications (cardiac variant)

Niemann-Pick disease (types C1, D) [56] 257220

Infancy (infantile form), childhood (juvenile form) adult (adult form) Infancy (infantile form), childhood (juvenile form) adult (adult form) Infancy (infantile form), childhood (juvenile form), adult (adult form)

Infancy (infantile form), childhood (juvenile form), adult (adult form)

Childhood to young adult

Infant, childhood, adult

ARSA RCM/DCM

HCM/DCM, mitral valve thickening, CAD Valve disease

Skeletal muscle, nervous, ocular systems

Skeletal muscle, nervous, renal, ocular, and cutaneous systems Nervous, ocular, auditory

HCM, Mitral and aortic Nervous, skeletal muscle, valve disease ocular systems

GBA (HK Cardiovascular gene) calcifications

NPC1 Coronary artery and valvular heart disease

Lysosomal storage diseases: mucopolysaccaridoses (degradation defects of glycosaminoglycans)

MPS I (Hurler and Scheie syndromes) (iduronidase enzyme deficiency)

MPS II (Hunter syndrome)

MPS III A (Sanfilippo syndrome A)

MPS III B (Sanfilippo syndrome B)

MPS III C (Sanfilippo syndrome C)

MPS III D (Sanfilippo syndrome D)

MPS IV A (Morquio syndrome A) MPS IV B (Morquio syndrome B) MPS VI (Maroteux-Lamy syndrome)

607014, 607016, AR 607015

309900

252900

252920

252930

252940

253000 253010 253200

AR AR AR

Childhood to young adult DUA HCM

Late infancy to young adult IDS HCM

Infancy to young adult

SGSH HCM, HF

NAGLU HCM, HF HGSNAT HCM, HF

HCM, HF

Infancy to young adult Infancy to young adult Infancy to adult

GLB1 HCM ARSB DCM

Hemopoietic, nervous, ERT

bone, cutaneous systems,

hepatosplenomegaly

Nervous, bone, cutaneous systems,

hepatosplenomegaly, sea-blue histiocytes

Nervous, skeletal and joints, ERT ocular, cutaneous, respiratory systems Nervous, skeletal, ocular, ERT cutaneous, auditory systems Nervous, skeletal, cutaneous systems; abundant and coarse, often blond hair Nervous; skeletal, ocular,

auditory Nervous, skeletal, ocular,

hypertrichosis Nervous, skeletal, ocular,

auditory, hypertrichosis Nervous, skeletal, ocular Nervous, skeletal, ocular Skeletal, integumental, ERT

ocular, muscular, hepatosplenomegaly

(continued)

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TABLE 4. Continued

Disease MIM # Phenotype Inheritance Age of Onset Disease Gene Cardiac Phenotype Extracardiac Markers/ Major Involvement (Noncomprehensive) of Other Organs Specific Treatment

MPS VII (Sly syndrome) 253220 AR Infancy to adult GUSB HCM Skeletal, nervous, possible

hepatomegaly and

mild ocular

MPS IX 601492 AR Infancy to young adult HYAL1 Heart involvement, Skeletal, nervous, ocular

Lysosomal storage diseases: disorders of glycoprotein and glycosylation metabolism

Galactosialidosis or Goldberg syndrome 256540 AR Infancy (early and late CTSA HCM in late infantile Nervous, skeletal, ocular,

(cathepsin A defect) infantile types), type, DCM cutaneous, auditory

childhood, adult systems; possible

(juvenile/adult type) hepatosplenomegaly

Mucolipidosis or sialidosis, type I and II 256550 AR Infancy to adult NEU1 DCM Nervous, skeletal, ocular,

cutaneous systems

Fucosidosis 230000 AR Infancy to adult FUCA1 DCM, HF Nervous, skeletal, ocular,

cutaneous (angiokeratoma)

systems

Alpha-mannosidosis 248500 AR Infancy to young adult MAN2B1 Possible heart Nervous, skeletal, cutaneous,

involvement, NOS auditory

Beta-mannosidosis 248510 AR Infancy to young adult MANBA Possible heart Nervous, skeletal, auditory,

involvement, NOS cutaneous

Aspartylglucosaminuria 208400 AR Infancy to young adult AGA HCM Nervous, skeletal, cutaneous

Schindler disease juvenile (Kanzaki 609241, 609241 AR Childhood, adult NAGA HCM Nervous, skeletal, muscle,

disease, adult form) cutaneous

Disorders of amino acid and organic

acid metabolism

Methylmalonic aciduria 251000 AR Infancy to young adult MUT DCM Systemic

Beta-ketothiolase deficiency 203750 AR Infancy ACAT1 DCM Liver, kidney, ketoacidotic

attacks, lethargy

Tyrosinemia I 276700 AR Infancy to young adult/adult FAH HCM Liver, kidney, mental

retardation

Hyperoxaluria I (oxalosis I) 259900 AR Infancy to childhood/adult AGXT HCM Kidney

Hyperoxaluria II (oxalosis II) 260000 AR Infancy to childhood/adult GRHPR HCM Kidney

Alkaptonuria (homogentisate 203500 AR Infancy to old age HGD Aortic valve disease Kidney

1,2-dehydrogenase deficiency)

Niemann-Pick ERT = enzyme replacement therapy; HF = heart failure; NOS = not otherwise specified; XLR = X-linked recessive other abbreviations as in Table 1.

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suspecting a mitochondrial disease in patients with cardiomyopathy at onset or as first clinical manifestation. Mitochondrial HCM initially shows symmetrical LV hypertrophy, and subsequently evolves through LV dysfunction and dilation. A number of cardiac (short PR interval, pre-excitation syndrome, AVB) or noncardiac (hearing loss, myopathy, palpebral ptosis, nonvascular neurological involvement, mental retardation) markers, or biochemical (elevated serum creatine phosphokinase [[sCPK], lactacidemia) indicators in probands and relatives provide diagnostic clues [35].

The MOGE(S) system allows a comprehensive summary of the clinical and genetic status of the family once the diagnosis has been made and family screening completed. The availability of the functional status (S) becomes especially important in asymptomatic relatives with manifest causative gene defect. Both cardiac and extracardiac traits contribute to clinical recognition of phenocopies (Table 4) [35,50-56]. A systematic approach leads to better characterization of cardiomyopathy disorder and could identify the need for pathological confirmation of the etiological basis of the disease, such as in AFD (Fig. 6) and in Danon Disease (Fig. 7). An accurate diagnosis is mandatory for genetic counseling and disease management; for example, the availability of enzyme replacement therapy in AFD may change the natural history of the disease and prevent (or delay) the end-stage disease.

MOGE(S) NOMENCLATURE FOR RCM

RCM is clinically characterized by altered relaxation and abnormal LV filling, biatrial dilation, in the absence of significant LV hypertrophy (Table 2). The lack of hypertrophy distinguishes RCM from HCM with restrictive pattern. Troponinopathies and desminopathies are typical examples of pure RCM; the former is not associated with conduction disease, whereas the latter is associated with AVB. Tropo-ninopathies are encountered as de novo or inherited as an AD disease, whereas the desminopathies are inherited as AD (50%), AR (25%), or de novo (25%) [57,58]. The differential diagnosis of desminopathy is based on the presence of AVB and its association with myopathy; a fine-needle biopsy of the skeletal muscle immunostained with anti-desmin antibodies may provide the final diagnosis. Alternatively, endomyocardial biopsy may demonstrate intracellular osmiophilic granulofilamentous inclusions that immunor-eact with anti-desmin antibodies (Fig. 8). Pure RCM due to defects of troponin genes, TNNI3 in particular, may show absence of myocyte hypertrophy on histology but the presence of myocyte disarray otherwise characteristic of sarcomeropathy [59]. The clinical distinction of the tropo-ninopathy [60,61] and desminopathy is important because of the high arrhythmogenic risk in troponinopathy and the negligible risk in desminopathy. In a recent meta-analysis including desmin-related diseases, both myopathies and cardiomyopathies, sudden death was reported in 2 of 195

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MR[AVB] °H + M GAD EG-Des[p.Gly84Ser] SC-III represents

morphofunctional phenotype (M): restrictive cardiomyopathy (R) with AVB; organ (O) involvement: heart (H) and skeletal muscle (M); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G) caused by the p.Gly84Ser mutation in the Desmin gene; ACC/AHA stage (S) C, NYHA III.

ME(R) [AVB] °H + M GAD EG-Des[p.Gly84Ser] SA-I represents morphofunctional phenotype (M): "early" (E) restrictive cardiomyopathy with AVB; organ (O) involvement: heart (H) and skeletal muscle (M); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G) caused by the p.Gly84Ser in the Desmin gene; ACC/AHA stage (S) A, NYHA I.

M0 O0 Gad EG-Des[p.Gly84Ser] Sa-i represents morphofunctional phenotype (M): "unaffected" (0) by cardiomyopathy; organ (O) involvement: none (=absence of any cardiac phenotype); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic and caused by the p.Gly84Ser mutation in the Desmin gene; ACC/AHA stage (S) A, NYHA I.

MOGE(S) CLASSIFICATION FOR AMYLOID HEART DISEASE

Amyloidosis represents a distinct and unique condition of extracellular infiltrative disease. Most cardioamyloidoses are in the context of systemic diseases (genetic or nonge-netic). Its inclusion in MOGE(S) is supported by the cardiac phenotype and clinical presentation as HCM or RCM that must be distinguished from other HCM and RCM. Amyloid shows distinct staining properties (pink-violet color with hematoxylin and eosin, apple-green birefringence with Congo Red under polarized light, and magenta color with crystal violet) and ultrastructural characteristics (fibrils of 7.5- to 10-nm diameter), regardless of the amy-loidogenic protein [64,65]. Amyloidosis may be systemic or localized, the former including primary (AL), secondary (AA), and genetic (multiple and different genes) forms. The heart shows infiltration in the interstitial spaces, vessel walls of epicardial coronary arteries and intramural small vessels, cardiac valves, and epicardial fat [66]. The heart is usually hypertrophied, with thickened cardiac valves, and shows a restrictive functional pattern. The typical patient is an adult or an old individual of either sex with a longstanding history of nonspecific symptoms; family history is positive for heart failure, renal or multiorgan failure in heritable forms. The children with familial Mediterranean fever caused by mutations of the gene Marenostrin (MEFV) may show amyloidosis of kidney, skin, thyroid; the heart is less likely to be involved [67].

In most cases of cardiac amyloidosis, there is an echo-ECG mismatch with increased LV wall thickness and decreased ECG voltages. The amyloidogenic protein can be identified by immunoelectron microscopy study of the endomyocardial biopsy (or the peri-umbilical fat in systemic forms). The genetic testing is mandatory in familial amyloidosis [68,69]; the investigation of the family members not only may provide early or pre-clinical diagnosis, but also contributes to understanding the natural history of the disease. The MOGE(S) system facilitates the description of the amyloid cardiomyopathy. MOGE(S) applies to cardiac amyloidosis as follows.

MH + R(ECG voltages) °H + K GN EA-L SB-II represents

morphofunctional phenotype (M): hypertrophic cardio-myopathy with restrictive pattern (H+R), low ECG

voltages; organ (O) involvement: heart (H) and kidney (K); genetic/familial (G): negative family history (N) (and/ or screening); etiology (E): amyloidosis (A), amyloidogenic light chain lambda (L); ACC/AHA stage (S) B, NYHA II.

MOGE(S) NOMENCLATURE FOR DCM

DCM is characterized by the presence of LV dilation and LV systolic dysfunction in the absence of other disorders sufficient to cause global systolic impairment (Table 2). Right ventricular dilation and dysfunction can be present, but not necessary, for the diagnosis [8]. More than 50% of the DCM cases are familial [10]. Although all DCM phenotypically look alike, most of them are distinct genetic diseases. Mutations in more than 40 genes have been described (Table 1), leading to extreme genetic heterogeneity [70]. Most familial DCMs are AD, and a minority is X-linked recessive, autosomal recessive, or matrilineal [10]. The most common disease gene is Lamin A/C, and the laminopathy constitutes 8% of all DCMs. Dystrophin gene defects account for up to 7% of male patients with DCM; most of these patients show an increase in sCPK without apparent myopathy [16,71,72] (Fig. 9). About one-fourth of the DCM cases have been recently attributed to the mutations in the giant Titin (TTN) gene [73]. The elastic protein titin is expressed in car-diomyocytes in 2 main isoforms, N2B (stiffer spring) and N2BA (more compliant spring). Titin-isoform switching is considered a mechanism for increased myocardial passive stiffness found in patients with heart failure with preserved LVEF [74]. While waiting for confirmatory studies, Titin remains an important disease gene. DCM patients with TTN mutations do not show disease-specific clinical markers [73]. The laminopathies are clinically characterized by conduction tissue disease in up to 80% of patients; the remaining patients demonstrate atrial fibrillation or an ARVC-like phenotype [75]. Dystrophinopathy is associated with severely enlarged and dysfunctional ventricles, and increased sCPK [16,72]. Zaspopathies [76] and tafazzino-pathies show either LVNC or increased trabeculations in the setting of DCM [77]; the tafazzinopathies typically occur in infancy and characteristically show cyclic neutropenia, oral

aphthous ulcers, and hypocholesterolemia [77]. A small number of DCM patients are characterized by autosomal recessive inheritance and are usually brought to the attention of cardiologists when being evaluated for lipid storage disease in a multidisciplinary context. Table 5 summarizes the known disease genes as well as the cardiac phenotypes typically expressed in these disorders [78—83]. Cardiomyopathy, mostly DCM, is one of the common traits recurring in these syndromes, and in some of them it may be the sole manifestation of the disease [79,84,85].

All aforesaid information, including the common cardiac phenotype, the clinical markers, or red flags that may occur in patients/carriers of mutations of the same gene, are systematically organized in the MOGE(S) system, thus generating a common pheno-molecular language that can be easily adopted by clinicians in their daily practice, without the risk of missing out on any necessary information. MOGE(S) applies to DCM as follows.

MD[AVB] OH GAD EG-LMNA[p.Leu197ProfsX2] SC-II represents morphofunctional phenotype (M): dilated cardio-myopathy with atrioventricular block; organ (O) involvement: heart (H); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic and caused by the p.Leu197Pro fs X2 mutation in the LMNA gene; ACC/AHA stage (S) C, NYHA II.

ME(D) OH GAD EG-LMNA[p.Leu197ProfsX2] SA-I represents

morphofunctional phenotype (M): "early" (E) dilated cardiomyopathy (for example, increased LV end-diastolic dimension with normal LV function, or borderline LV function); organ (O) involvement: heart (H); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E) is genetic and caused by the p.Leu197Pro fs X2 mutation in the LMNA gene; ACC/AHA stage (S) A, NYHA I.

ME(D) OH GAD EG-NA SA-I represents morphofunc-tional phenotype (M): "early" (E) dilated cardiomyopathy (see example in the preceding text); organ (O) involvement: heart (H); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic but the mutations is not yet available (NA) (genetic test either ongoing or to be done, but feasible); ACC/AHA stage (S) A, NYHA I.

M0 O0 GAD EG-LMNA[p.Leu197ProfsX2] SA-I represents

morphofunctional phenotype (M): "unaffected" (0) by cardiomyopathy; organ (O) involvement: none (0) (= absence of any cardiac phenotype); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G), healthy carrier of the p.Leu197Pro fs X2 mutation in the LMNA gene that causes the disease in the family; ACC/AHA stage (S) A, NYHA I.

The genetic testing in future is expected to influence clinical decision making for primary prevention of sudden death and ICD implantation. In the current guidelines the severely depressed LVEF constitutes the major indication for ICD implantation in patients with DCM [11—13]. It is now becoming increasingly evident that laminopathies carry high arrhythmogenic risk [15,20] even when they

may not meet guideline recommendations for ICD implantation. On the other hand, some genes and genetic variants may not be at high risk even though they may result in low LVEF [16]. A group of DCM caused by mutations in genes typically related to ARVC have a high risk of life-threatening arrhythmias and may deserve ICD implantation even if they fall short of guideline-based recommendations [11—13]. As we accumulate more knowledge and experience, the indications for ICD implantation will be modified, made more specific, and personalized.

MOGE(S) NOMENCLATURE FOR ARVC

Although predominantly affecting the RV, the spectrum of ARVC now includes possible biventricular involvement as well as the left dominant arrhythmogenic cardiomyopathy [86], referred to as arrhythmogenic cardiomyopathy (ACM)/ARVC in the recent HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Chan-nelopathies and Cardiomyopathies [87]. Although all ACM/ARVC phenotypes are associated with mutations in desmosome genes [88,89], mutations in typically DCM-related genes have also been observed in ARVC-like phenotypes [75]. The practical implication of such genotype-phenotype correlative studies would be to determine whether the arrhythmogenic risk is better associated with the disease gene or the clinical phenotype. MOGE(S) applies to ARVC/ACM as follows.

MA[e] OH GAD EG-DSG2[p.Glu1020AlafsX18] SA-I represents morphofunctional phenotype (M): ARVC with e wave; organ (O) involvement: heart (H); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G) and caused by the p.Glu1020Ala fs X 18 mutation in the DSG2 gene; ACC/AHA stage (S) A, NYHA I.

ME(A) OH GAD EG-DSG2[p.Glu1020AlafsX18] SA-I represents morphofunctional phenotype (M): "early" (E) arrhythmogenic cardiomyopathy (for example, with minor ECG and/or echocardiographic criteria); organ (O) involvement: heart (H); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G) and caused by the p.Glu1020Ala fs X 18 mutation in the DSG2 gene that causes the disease in the family; ACC/ AHA stage (S) A, NYHA I.

M0 O0 GAD EG-DSG2[p.Glu1020AlafsX18] SA-I represents

morphofunctional phenotype (M): "unaffected" (0) by cardiomyopathy; organ (O) involvement: none (0) (=absence of any cardiac phenotype); genetic/familial (G) with autosomal dominant (AD) transmission; etiology (E): genetic (G), healthy carrier of the p.Glu1020Ala fs X 18 mutation in the DSG2 gene that causes the disease in the family; ACC/AHA stage (S) A, NYHA I.

MOGE(S) NOMENCLATURE FOR LVNC

Left ventricular noncompaction (LVNC) is a morphological entity characterized by an excessive trabeculation of the LV

[90,91] (Table 2). Diagnostic criteria are based on echo and cardiac magnetic resonance imaging wherein the non-compacted ventricular muscle layer is substantially thicker than the compact layer [91]. Most LVNC patients are asymptomatic, and the diagnosis is often incidental. The LVNC can occur as isolated morphological phenotype [92] in association with LV systolic dysfunction or with LV hypertrophy. LVNC has been associated with both DCM and HCM, and with mutations in genes typically causing DCM and HCM [93]. LVNC is a typical trait in Barth syndrome [94] (Fig. 10), and it has been reported to occur more frequently in carriers of LDB3 gene mutations. Although true LVNC is rare, hypertrabeculation of the LV is common and may be associated with increased throm-boembolic risk. The MOGE(S) system distinguishes LVNC with LV dilation and dysfunction (MLVNC+D) or with LV hypertrophy (Mlvnc+h) from pure LVNC (Mlvnc).

THE MOGE(S) CLASSIFICATION IN CLINICAL PRACTICE

The MOGE(S) system proposes a nosology that addresses 5 simple attributes of cardiomyopathies, including mor-phofunctional characteristic (M), organ involvement (O), genetic or familial inheritance pattern (G), and an explicit etiological annotation (E) with details of genetic defect or underlying disease/cause, followed by optional information about the functional status (S) using the ACC/AHA stage and NYHA functional class. Although the application of this nosology allows complete description of the diseases, the full notation may appear complex. It is expected that routine nomenclature will continue to be described by the standard, currently practiced morphology, and the proposed nosology is not meant to replace the morphological description. A dilated cardiomyopathy will be called dilated cardiomyopathy, but the complete description of the disease process would be best served by the descriptive terminology such as MOGE(S). In fact, AHA suggests genotyping to supersede the phenotypic description, which is opposed by the ESC; the proposed MOGE(S) system is a compromise. It is prudent to consider an example from the field of oncology. Pathological staging in a patient with lung cancer who has been treated with neoadjuvant therapy and still has multiple residual nodules in the ipsilateral lung and different lobes, has distant metastases, and lymph nodes show isolated tumor cells only, is described using TNM staging as follows: ypT4(m) N0 (i+) M1b G3 LVI + R2. y denotes that the patient has received neoadjuvant therapy prior to resection, p presents pathological stage after resection, T4 offers the extent of tumor which in this case has multiple residual tumor nodules (m) in different lobes of ipsilateral lung, N denotes the nodal status [N0(i+)] isolated tumor cells only in a lymph node that are considered node negative or N0, and M represents metastases where M1b means distant metastases (in contrast to M1a, which is thoracic metastases such as contralateral lung, pleural nodules or malignant pleural, or pericardial

effusion). G in this staging is histological grade (1 = well differentiated; 2 = moderate; 3 = poorly differentiated), LVI + represents lymphovascular invasion (LVI—, absent), and R is residual disease after treatment (R0 = no residual disease; R1 = microscopic residual disease; R2 = grossly identified residual disease). Howsoever complex it may sound, oncologists are expected to use standard TNM staging. TNM nosology is constantly expanding, is very flexible, but ensures completeness. Simply looking at [ypT4(m) N0(i+) M1b G3 LVI+ R2] gives physicians all the information about the patient in question. However, in the common practice, this patient is considered to have lung cancer. Therefore, the

MOGE(S) example MD[AVB] Oh Gad EG-LMNA[p. Argl90Trp] is

complete notation for a patient presenting with a specific DCM. The authors of the MOGE(S) nomenclature have developed an easy web-assisted application that can be conveniently used in daily clinical practice for complete and descriptive classification of cardiomyopaythy (http://moges. biomeris.com).

CONCLUSIONS

We propose a descriptive nosology that combines mor-phofunctional trait and organ/system involvement with familial inheritance pattern, identified genetic defect, or other etiologies. As with the universal TNM staging for tumors, it is expected that this description will be improved, revised, modified, and made more comprehensive and user friendly. It will allow better understanding of the disease, allow easier communication among physicians, and help develop multicenter/multinational registries to promote research in diagnosis and management of cardiomyopathies.

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KEYWORDS: cardiomyopathy ■ diastolic dysfunction ■ heart failure ■ heart muscle disease ■ myocardial hypertrophy ■ systolic dysfunction ■ ventricular arrhythmias