MYOCARDIAL DISEASE

New approaches to the clinical diagnosisof inherited heart muscle diseaseLuis Rocha Lopes, Perry Mark Elliott

▸ Additional references arepublished online only. To viewthese references please visitthe journal online (http://dx.doi.org/10.1136/heartjnl-2012-301195).

UCL Institute of CardiovascularScience, The Heart Hospital,London, UK

Correspondence toProfessor Perry M Elliott,UCL Institute of CardiovascularScience, The Heart Hospital,16-18 Westmoreland Street,London W1G 8PH, UK;perry.elliott@ucl.ac.uk

Published Online First6 March 2013

To cite: Lopes LR,Elliott PM. Heart2013;99:1451–1461.

Cardiomyopathies are defined as disorders of heartmuscle unexplained by coronary artery disease,hypertension, valvular disease or congenital heartdisease.1 They are classified by morphological andfunctional phenotype into hypertrophic cardiomy-opathy (HCM), dilated cardiomyopathy (DCM),restrictive cardiomyopathy (RCM), and arrhythmo-genic right ventricular cardiomyopathy (ARVC)subtypes.1 Table 1 shows the European Society ofCardiology working group classification ofcardiomyopathies.All forms of cardiomyopathy can be caused by

genetic and non-genetic mechanisms. The firstgenetic locus associated with HCM was discoveredby linkage analysis2 in 1989 and the responsiblegene, β-myosin heavy chain (MYH7), was identifiedin the subsequent year.w1 Since then, extraordinaryprogress has been made in the understanding of themolecular genetic background of all inherited heartmuscle disorders.3 w2 Most genetic forms ofcardiomyopathy are inherited as autosomal domin-ant Mendelian diseases and are characterised bylocus and allelic genetic heterogeneity, highly vari-able intra- and interfamilial expressivity, andincomplete clinical penetrance.1 4 This very highlevel of genotype–phenotype plasticity may resultfrom the influence of modifier genes, epigeneticeffects, post-transcriptional and post-translationalmodifications, and environmental effects.5 6

The genetic and phenotypic heterogeneity thatcharacterises all cardiomyopathies pose major clin-ical challenges. In this article, we focus on the taskof diagnosis, exploring how a systematic clinicalapproach can be used to identify specific disordersand guide the selection of further diagnostic tests,including molecular genetic analysis. The basicpremise is that a cardiomyopathy focused approachto history and examination combined with conven-tional and emerging diagnostic tests can be used toidentify clues or ‘red flags’ that suggest particulargenetic and non-genetic sub-phenotypes (figure 1).

FAMILY HISTORYWhile a brief enquiry about family history is stand-ard clinical practice, evaluation of individualswith cardiomyopathy requires a more thoroughapproach to the assessment of family background.This process is facilitated by the construction of athree to four generation family pedigree thatrecords not only the presence or absence of cardio-myopathy in relatives, but also other features thatsupport the diagnosis of a genetic cardiovasculardisorder, including sudden cardiac death, heartfailure, cardiac transplantation, insertion of

pacemakers or defibrillators, and stroke at a youngage. Non-cardiac manifestations in relatives such asneuromuscular disease and endocrine disordersalso provide diagnostic clues.Autosomal dominant inheritance is the most

common mode of transmission in all forms ofcardiomyopathy.1 Key points that support a diagno-sis of autosomal dominant disease include the pres-ence of affected individuals in every generation andmale-to-male transmission. The majority of auto-somal dominant cardiomyopathies are confined tothe heart, but some uncommon subtypes may beassociated with non-cardiac manifestations—forexample, laminopathies and disorders of theRAS-MAPK pathway such as Noonan syndrome.w3

Autosomal recessive forms of cardiomyopathy aremuch less common, often occurring in consanguin-eous families and as one feature of a multisystemdisease. Examples of autosomal recessive disordersin which the heart is prominently affected includeglycogen storage disease (GSD) type II (caused byacid α-1,4-glycosidase (GAA) deficiency), GSD IIIA(caused by amylo-1,6-glucosidade/debranchingenzyme deficiency), and Friedreich’s ataxia, causedby expansions—GAA triplet repeats—in the fra-taxin gene.7 X-linked cardiomyopathies are uncom-mon but are probably underdiagnosed. Specificclues include the absence of male–male transmis-sion and milder or absent phenotypes in females.Danon’s disease, caused by mutations in theLAMP2 gene (GSD type IIB), and Anderson Fabrydisease,8 a sphingolipidosis caused by mutations inthe α-galactosidase A gene, are inherited asX-linked traits; so are neuromuscular diseases suchas dystrophinopathies (Duchenne’s and Becker’s)and emerin-related Emery–Dreifuss muscular dys-trophy, all of which are associated with a DCMphenotype, sometimes as the predominant clinicalfeature. Finally, the phenomenon of disease trans-ferred only by women to male and female offspringsuggests the presence of mitochondrial diseasescaused by mutations in mitochondrial DNA.w4

Figure 2 illustrates the main inheritance patterns.

MEDICAL HISTORY AND PHYSICALEXAMINATIONAge at presentationAge at presentation is one of the most importantclinical clues to differential diagnosis of a cardio-myopathy. HCM presenting in neonates and infantsshould raise the suspicion of an inborn error ofmetabolism, such as GSD9—for example, Pompe’sdisease (GSD II), Forbes’ disease (GSD IIIA) orDanon’s (GSD IIB) disease—or a mitochondrial

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Table 1 European Society of Cardiology classification of cardiomyopathies

HCM DCM ARVC RCM Unclassified

Familial ▸ Familial, unknown gene▸ Sarcomeric protein mutations▸ GSD (eg, Pompe’s, PRKAG2,

Forbes’, Danon’s)▸ Lysosomal storage diseases

(eg, Anderson–Fabry, Hurler’s)▸ Disorders of fatty acid

metabolism▸ Carnitine deficiency▸ Phosphorylase B kinase

deficiency▸ Mitochondrial cytopathies▸ Syndromic HCM (eg, Noonan’s

syndrome, LEOPARD syndrome)▸ Familial amyloid

▸ Familial, unknown gene▸ Sarcomeric protein▸ Z-band▸ Cytoskeletal protein▸ Nuclear membrane protein▸ Intercalated disc proteins

(desmosomes)▸ Mitochondrial cytopathy

▸ Familial, unknowngene

▸ Intercalated discprotein (desmosomes)

▸ Cardiac ryanodinereceptor

▸ Transforming growthfactor-β3

▸ Titin▸ Lamin A/C

▸ Familial, unknowngene

▸ Sarcomeric proteinmutations

▸ Familial amyloidosis▸ Desminopathy▸ Haemochromatosis▸ Anderson–Fabry

disease▸ GSD

▸ Left ventricularnon-compaction

Non-familial ▸ Obesity▸ Infants of diabetic mothers▸ Athletic training▸ Amyloid

▸ Myocarditis▸ Kawasaki disease▸ Eosinophilic▸ Drugs▸ Pregnancy▸ Endocrine▸ Nutritional▸ Alcohol▸ Tachycardiomyopathy

▸ Myocarditis ▸ Amyloid▸ Scleroderma▸ Endomyocardial

fibrosis▸ Hypereosinophilic

syndrome▸ Drugs▸ Carcinoid heart

disease▸ Metastatic cancers▸ Radiation

▸ Tako-tsubocardiomyopathy

Adapted from Elliott et al1 with permission.ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; GSD, glycogen storage disease; HCM, hypertrophic cardiomyopathy; LEOPARD, lentigines, ECGconduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness; RCM, restrictive cardiomyopathy.

Figure 1 Step-by-step approach for the diagnosis of inherited heart disease. CK, creatine phosphokinase; LVH, leftventricular hypertrophy.

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disorder, such as MELAS (mitochondrialencephalomyopathy, lactic acidosis, and stroke-likeepisodes) or Kearns Sayre syndromes.w4

RASopathies such as Noonan and LEOPARD syn-drome (lentigines, ECG conduction abnormalities,ocular hypertelorism, pulmonary stenosis, abnor-mal genitalia, retardation of growth, and sensori-neural deafness) are also more common at thisage.10 In contrast, presentation with apparently iso-lated HCM in individuals over 60 years of ageshould raise suspicion of amyloidosis.11

Presentation with HCM in adolescence or as ayoung adult is typical of sarcomeric protein disease.

Symptoms and physical examinationFacies and dysmorphic featuresSome cardiomyopathies in children and adolescentsare associated with congenital dysmorphic syn-dromes. Among the most common are Noonansyndrome, characterised by short stature, variabledegrees of developmental delay, cutaneous abnor-malities (‘cafe-au-lait’ spots), hypertelorism, ptosis,

Figure 2 (A) Autosomal dominant inheritance pattern, showing male–male (excluding X-linked) and male–female inheritance with half of thechildren affected. (B) Pedigree from a FHL1 muscular dystrophy family, showing X-linked inheritance pattern. Absence of male–male transmissionand milder and later muscle weakness in females are important clues. Key: black filled circles/squares—affected females/males respectively;empty circles/squares—non-affected females/males respectively; arrow signals the proband; + indicates individuals with the disease-causingmutation; − indicates individuals without the disease-causing mutation.

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low set posteriorly rotated ears, and a webbedneck. Some of these features are shared by the lesscommon LEOPARD syndrome, Costello syndrome(coarse face, redundant skin of hands and feet,curly hair), and cardio-facio-cutaneous syndrome(distinctive craniofacial appearance, hyperkeratosis).These disorders are caused by germline mutationsin components of the RAS-MAPK cascade.

Skin and hairIn Anderson–Fabry disease,8 w5 a large spectrum ofextracardiac manifestations can occur, includingdermatological signs (eg, angiokeratomata, hypohi-drosis). Cutaneous anomalies (eg, lentigines inLEOPARD syndrome or ‘café-au-lait’ spots) canalso be present in RASopathies. Curly and thin hairis another possible manifestation. Syndromic auto-somal recessive forms of ARVC (Naxos andCarvajal syndromes) are characterised by woollyhair and palmoplantar hyperkeratosis.

Central and peripheral neurologic manifestationsand skeletal muscle involvementPsychomotor delay can occur in many diseasesof intermediary metabolism and the RAS-MAPKcascade (sometimes very subtly). Pompe’s disease(GSD II) is characterised by hypotonia. The extra-cardiac features of Forbes’ disease (GSD III) includeperipheral muscular weakness and neurologicalinvolvement.9 Danon’s disease in men typicallypresents with mental retardation and skeletalmyopathy, while women are characterised by a lateronset (in their 20s) and milder phenotype, withsome cases of isolated cardiac involvement.12

PRKAG2 syndrome can include peripheral skeletalmuscle weakness.13 In Anderson–Fabry disease,8 w5

audiological (eg, deafnesss, tinnitus), ophthalmic(eg, cornea verticillata, tortuous vessels), central orperipheral neurological (eg, acroparesthesiae,stroke) manifestations can be part of disease.Mitochondrial disease most frequently affectsorgans with high energy requirements (heart,muscle, brain, eyes); manifestations include enceph-alopathy, lactic acidosis with extreme exerciseintolerance disproportionate to the cardiac involve-ment, stroke-like episodes, diabetes, chronic pro-gressive external ophthalmoplegia, deafness, andpigmentary retinopathy.w4 Neuromuscular diseasesassociated with either DCM (dystrophinopathies,sarcoglycanopathies, laminopathies, myotonic dys-trophy, desminopathy) or HCM (FHL1 associatedEmery–Dreifuss and Friedreich’s ataxia) presentwith muscular weakness as a main feature. Bilateralcarpal tunnel syndrome can be a manifestation oftransthyretin amyloidosis.

ECGWhile an ECG is performed in almost every patientwith a cardiomyopathy, its value in the diagnosis ofspecific subtypes is often overlooked. Some rela-tively simple findings that should be considered arelisted here.

PR intervalVentricular pre-excitation is a common observationin patients with storage diseases (Pompe’s disease,PRKAG2 mutations associated with Wolff-Parkinson-White syndrome, Danon’s disease), andin some individuals with mitochondrial disorders(MELAS, MERFF (myoclonic epilepsy with raggedred fibres)).w4 A short PR interval is also describedin patients with Anderson–Fabry disease and mito-chondrial disease.

Atrioventricular blockAtrioventricular (AV) block is one of the mostimportant ECG clues to diagnosis in all forms ofcardiomyopathy. In individuals presenting acutelywith a mildly dilated left ventricle, AV block canreflect acute/subacute myocardial inflammationcaused by Lyme disease, giant cell myocarditis, andsarcoidosis. In young adults with DCM, AV blockshould always prompt a search for laminopathy(particularly in the context of a history of atrialarrhythmia or a family history of young suddendeaths) or desminopathy when it may occur in thepresence of clinical or subclinical skeletal muscledisease. Causes of AV block in young adults withHCM include mutations in PRKAG2 and mito-chondrial disorders; in older adults progressive AVblock should prompt consideration of Anderson–Fabry disease and amyloidosis.

QRS voltageChanges in QRS voltage are a common and oftennon-specific feature in patients with cardiomyopathy,but extremely large QRS voltage is typical of storagediseases such as Pompe’s and Danon’s disease (figure3A) or may be the consequence of ventricular pre-excitation. Low QRS voltage unexplained by obesity,lung disease or pericardial effusion is common incardiac amyloidosis, but lacks sensitivity and may beseen in patients with progressive myocardial fibrosisand systolic dysfunction. So called ‘pseudoinfarct’patterns are characteristic but not invariable featuresof cardiac amyloidosis (figure 5A), and an inferolat-eral (posterior) infarct pattern in the presence of aDCM phenotype can suggest a dystrophinopathy(prominent R wave V1–V2, figure 3B).

QRS axisQRS axis is often abnormal in patients with variouscardiomyopathies, but extreme superior (north west)QRS axis deviation can be a feature of Noonan’s syn-drome (figure 3C).

T wave inversionRepolarisation abnormalities are very common inall forms of cardiomyopathy, but some patternsshould alert clinicians to specific disorders. Themost important are Twave inversion in the precor-dial leads, which in context (eg, in individuals withunexplained syncope, a family history of prematuredeath or ventricular arrhythmia of right ventricularorigin) suggests ARVC (figure 3D), and deep Twave inversion in the lateral leads in patients with

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Figure 4 Different echocardiographic patterns from two patients with left ventricular hypertrophy. (A) Echocardiogram from a patient withAnderson–Fabry disease, showing mild to moderate symmetrical hypertrophy with biventricular involvement and thickened mitral valve leaflets.(B) Severe asymmetrical septal hypertrophy in a patient with sarcomere hypertrophic cardiomyopathy.

Figure 3 Examples of ECGs from patients with diverse forms of inherited heart muscle disease. (A) Glycogen storage disease type IIIA, with typicalvery high voltages. (B) Duchenne muscular dystrophy, with prominent R waves at the right precordial leads. (C) Noonan’s syndrome. Extremesuperior QRS axis deviation. (D) Arrhythmogenic right ventricular cardiomyopathy, with negative T waves V1–V4.

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distal HCM (sometimes overlooked in patientswith poor apical views on echocardiography).

ECHOCARDIOGRAPHYThe echocardiogram remains the first line imagingtool in patients with suspected cardiomyopathy. Ithas a central role in defining the morphologicaland functional phenotype and in guiding treatmentdecisions. As with all imaging modalities, it is rarefor echocardiography to suggest a specific aetiology,but in context a number of features can be helpfulin directing further investigation, particularly inpatients with HCM. While any pattern of hyper-trophy is consistent with a diagnosis of HCM, thedistribution and severity of left ventricular hyper-trophy (LVH) can be helpful. For example, concen-tric LVH is common in metabolic and infiltrativedisorders whereas asymmetrical septal hypertrophywith reversed septal curvature is the dominantpattern in patients with sarcomeric protein genemutations (figure 4).The diagnosis of myocardial storage or infiltra-

tion should also be suspected when there is coexist-ent hypertrophy of the right ventricular free wall.Systolic function is also important in this context,as various disorders can cause progressive systolic

impairment in patients with LVH—for example,mitochondrial disease and mutations in PRKAG2 inyoung individuals, and amyloidosis and Anderson–Fabry disease in the elderly. Other typical but notuniversal echocardiographic features suggestive ofamyloidosis include ‘granular’ or ‘sparkling’ textureof the myocardium, biatrial dilation, interatrialseptum thickening, pericardial effusion, valve thick-ening, and severe restrictive filling (figure 5B).w6

Localised hypokinesia in the inferolateral/posteriorwall can be a feature of Anderson–Fabry disease.Echocardiography is generally less useful in eluci-dating aetiology in patients with DCM or ARVC,but segmental akinesis or dyskinesis in a non-coronary artery territory (particularly the posteriorbasal segment of the left ventricle) associated withnormal wall thickness, with or without a mild peri-cardial effusion, is seen in myocarditis and dys-trophin related disorders. Left ventriculardysfunction and increased wall thickness with milddilatation of the left ventricle is also seen inpatients with acute myocarditis.Recently, new echocardiographic techniques (eg,

speckle tracking and velocity vector imaging) thatallow angle independent assessment of myocardialdeformation have been examined in patients with

Figure 5 Investigations from a patient with transthyretin cardiac amyloidosis. (A) ECG showing low limb voltages and anterior ‘pseudoinfarct’pattern. (B) Echocardiogram with symmetric hypertrophy, thickened valves and granular appearance of the myocardium. (C) DPD scan showingcardiac tracer uptake (image courtesy of the National Amyloidosis Centre, Royal Free Hospital, London, UK). (D) Histopathology from endomyocardialbiopsy showing features compatible with amyloidosis.

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cardiomyopathy. Strain—a dimensionless measure-ment of myocardial deformation—has beendemonstrated to be more reproducible, less oper-ator dependent, and more sensitive than classicalmethods (eg, ejection fraction) for the assessmentof left ventricular function.w7 Recent studies haveexplored the role of myocardial deformationimaging in the differential diagnosis of unexplainedLVH.w8 w9 When comparing cardiac amyloidosisand HCM,14 these studies showed a reversebasoapical strain gradient in amyloidosis and rela-tive apical sparing (figure 6). In Anderson–Fabry

disease,15 16 a loss of the circumferential strainbasoapical gradient in patients with LVH has beenreported. Also typical of Anderson–Fabry disease isa reduced longitudinal strain at the basal-midinferolateral wall (figure 6).

CARDIAC MAGNETIC RESONANCECardiac magnetic resonance (CMR) provides tomo-graphic imaging in any plane, without window lim-itations and with good spatial resolution. CMR hasan important role in refining morphological charac-terisation in patients with poor echocardiographic

Figure 6 (A) Bull’s eye showing the regional distribution of longitudinal strain; it demonstrates apical sparing in a patient with cardiac amyloidosis(adapted from Phelan et al,16 with permission). (B) Bull’s eye plot in a patient with Anderson–Fabry disease. Characteristically, the basal and midsegments of the inferolateral and anterolateral wall show a notable reduction of myocardial deformation. Colour key: blue corresponds to positivevalues of longitudinal strain (notably reduced longitudinal deformation); darkest red corresponds to normal negative values of longitudinal strain(completely preserved longitudinal deformation); lighter tones of red denote reduced but still negative values of longitudinal strain.

Figure 7 Cardiac magnetic resonance. Late gadolinium enhancement with a typical subendocardial distribution in apatient with senile transthyretin cardiac amyloid.

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Table 2 Summary of the main clinical features for some of the cardiomyopathies discussed in the text

Cardiomyopathy Inheritance Age at presentation Extracardiac manifestations ECG Echocardiogram CMR

Sarcomeric HCM AD Typically adolescent/young adultbut can present at any age

No Variable reflecting degree/distribution of hypertrophy/fibrosis

Typically asymmetrical septalhypertrophy with reverse septalcurvature

▸ Midwall LGE▸ LGE at the insertion

zones of the RV in theseptum

Anderson–Fabry X-linked LVH:>30 years male>40 years female

Acroparesthesias, hypohidrosis,deafness, angiokeratomata, cataracts,proteinuria

▸ Short PR▸ AV block▸ LVH

▸ Increased AV valvethickness

▸ RVH▸ Concentric LVH

Posterolateral LGE

TTR cardiac amyloidosis ▸ AD▸ Sporadic if

senile form

>60 years if senile TTR Bilateral carpal tunnel syndrome,peripheral sensorineuropathy, others

▸ AV block▸ Low QRS voltages

▸ Thickening of theinteratrial septum

▸ Thickening of the AVvalves

▸ RVH▸ Pericardial effusion▸ Ground glass appearance

of the myocardium▸ Concentric LVH▸ Global hypokinesia

▸ Diffuse subendocardialLGE

▸ Abnormal gadoliniumkinetics

GSD II (Pompe’s) AR Neonates/infants Hypotonia ▸ Short PR▸ Pre-excitation▸ Extreme LVH

Extreme concentric LVH

GSD IIIA (Forbes’) AR Adolescence/young adults Muscle weakness, neurologicalinvolvement, hypoglycaemia

▸ Short PR▸ Pre-excitation▸ Severe LVH

Concentric LVH

Danon (GSD IIB) X-linked Neonates/infants Mental retardation, deafness, muscleweakness, elevated CK

▸ Short PR▸ Pre-excitation▸ AV block▸ Severe LVH

▸ Extreme concentric LVH▸ Global hypokinesia

PRKAG2 AD Adolescent/young adult Muscle weakness ▸ Short PR▸ Pre-excitation▸ AV block

LVH with global hypokinesia

RASopathies AD Infants to adolescents Mental retardation, dysmorphicfeatures, lentigines, café-au-lait spots

Northwest QRS axis deviation ▸ LVH▸ Pulmonary stenosis▸ Other congenital heart

diseaseMitochondrialcardiomyopathy

Matrilinear(mitochondrial DNA)AD/AR/X-linked(nuclear DNA)

Neonates/infants Deafness, encephalopathy, diabetes,muscle weakness, others

Short PR ▸ LVH▸ DCM▸ LVNC

DCM related to lamin A/C AD Adolescent/young adult Muscle weaknessRaised CK

AV block Milder DCM compared to othercauses

DCM related to Emery–Dreifuss muscular dystrophy

X-linked (type 1:emerin related)AD (type 2: laminrelated)

Early childhood Muscle weaknessRaised CK

▸ Conduction disease▸ Low P wave amplitude▸ Atrial standstill

Continued

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windows and in assessing localised and often subtleright ventricular wall motion abnormalities inpatients with ARVC. CMR’s greatest contribution isits ability to provide information on myocardialtissue characteristics through the use of late gadolin-ium kinetics or specific imaging sequences. Someimportant CMR diagnostic ‘red flags’ include: lategadolinium enhancement (LGE) localised tothe inferolateral wall in patients with myocardialhypertrophy (Anderson–Fabry disease17) orDCM (dystrophinopathies),18 and circumferentialsubendocardial LGE with difficulty in nulling themyocardial signal in cardiac amyloidosis (figure7).11 T2* imaging is established as a tool to detectand quantify iron deposition within the myocar-dium caused by haemochromatosis.w10 CMR alsohas an emerging role in the diagnosis of myocarditis,in which T2 weighted oedema imaging, earlyenhancement imaging, and LGE arerecommended.w11

LABORATORY INVESTIGATIONSBecause of the myriad of conditions that can causeheart muscle disease, most patients withcardiomyopathy will be subjected to a panel ofblood tests designed to detect disorders that causeor exacerbate myocardial dysfunction (eg, thyroiddisease and anaemia) or assess secondary organ dys-function (renal function). There are few peripheralbiomarkers that are diagnostic for subtypes ofcardiomyopathy, but there are circumstances wherebiochemical testing can be useful. In neonates andinfants standard metabolic panels can aid diagnosisof mitochondrial disease and disorders of inter-mediary metabolism. Similarly, granulocytopenia inan infant with non-compaction suggests a diagnosisof Barth syndrome. In older patients with HCM,renal impairment (including proteinuria) shouldraise the suspicion of Anderson–Fabry disease oramyloidosis. Raised creatine phosphokinase (CK) isparticularly helpful in patients with DCM in whomit suggests a dystrophin related disorder,laminopathy or less commonly myofibrillar myop-athy. In patients with HCM, a raised CK is seen inDanon’s and mitochondrial disease, and in patientswith RCM and a high CK, desminopathy should beconsidered.

NUCLEAR IMAGINGIn general, nuclear imaging has only a limitedrole in determining aetiology in cardiomyopathies.Exceptions include technetium-99m3,3-diphosphono-1,2-propanodicarboxylic acid(99mTc-DPD) scintigraphy, that can identify myocar-dial infiltration with transthyrethin amyloid(figure 5C),w12 w13 and fluorodeoxyglucose posi-tron emission tomography (FDG-PET) in patientswith cardiac sarcoidosis.w14

SUMMARYGiven the genetic background to all forms of heartmuscle disease, it is tempting to assume that thevery clinical approach to diagnosis outlined in thisreview is somewhat redundant in the modern era.

Table2

Continued

Cardiomyopa

thy

Inhe

ritan

ceAge

atpresen

tatio

nExtracardiac

man

ifestations

ECG

Echo

cardiogram

CMR

Dystrophinopathies

X-linked

▸Du

chenne:<

5years

▸Becker:later

▸Dystrophin

associated

DCM:

males

between20–40

years;

females

later

Muscleweakness

Raise

dCK

Posterolateralinfarctpatte

rnPosterolateralhypokinesia

/dyskinesia

PosterolateralLG

E

Desm

inopathies

ADor

ARYoungadult(widerange)

Muscleweakness

Raise

dCK

AVblock

▸LVH

▸Restrictivecardiomyopathy

ARVC

ADor

ARAd

olescent/young

adult

Palmoplantar

keratoderm

aand

woolly

hair(AR)

▸Inverte

dTwaves

right

precordialleads

▸Inverte

dTwaves

inferolateralleads

(left

ventricular

involvem

ent)

▸Epsilon

waves

RVdilation,

globaldysfunction,

wallm

otionabnorm

alities

PosterolateralLG

EinLV

Fatty

replacem

ent

AD,autosom

aldominant;AR

,autosom

alrecessive;AR

VC,arrh

ythm

ogenicright

ventricular

cardiomyopathy;AV,atrioventricular;CK

,creatinephosphokinase;CM

R,cardiacmagnetic

resonance;DC

M,d

ilatedcardiomyopathy;GSD

,glycogenstorage

disease;HC

M,h

ypertro

phiccardiomyopathy;LG

E,late

gadolinium

enhancem

ent;LV,leftventricle;LVH

,leftventricular

hypertrophy;LVN

C,leftventricular

non-compaction;

RV,right

ventricle;R

VH,right

ventricular

hypertrophy;TTR,transthyretin.

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Clinical guidelines19 w15 recommend routinemolecular genetic testing in the most clearlyaffected member of the family in HCM, ARVC,and, with a lower strength, in DCM. Given thehigh level of biological discrimination afforded bygenetic testing, the finding of a potentially causalDNA sequence variant adds weight to the clinicaldiagnosis. Similarly, when metabolic disease is sus-pected from clinical or laboratory findings, screen-ing for mutations in the most likely candidate genes

can be confirmatory. Once a causative mutation isidentified, genetic testing can also be used in acascade screening strategy for families, to providepresymptomatic diagnosis of family members.However, genetic testing does have some import-

ant limitations. For example, it is well recognisedthat genetic testing often identifies genetic variantsof uncertain pathogenicity, and in some disordersmultiple mutations in the same or different genesare remarkably common. There are various molecu-lar approaches to the determination of pathogenicityin this context,w16 but interpretation of genetic find-ings inevitably falls back on clinical phenotyping inpatients and their family members. The key tosuccess in diagnosis is, therefore, a cardiomyopathycentred approach to clinical assessment coupledwith a systematic stepwise use of cardiac and non-cardiac diagnostic tests. Table 2 summarises thetypical findings and diagnostic clues for some of thecardiomyopathies discussed in the text.

Contributors Both authors have contributed to the writing of thisreview article and are responsible for the overall content.

Funding LRL is supported by a grant from the GulbenkianDoctoral Programme for Advanced Medical Education, sponsored byFundação Calouste Gulbenkian, Fundação Champalimaud,Ministério da Saúde and Fundação para a Ciência e Tecnologia,Portugal.

Competing interests In compliance with EBAC/EACCMEguidelines, all authors participating in Education in Heart havedisclosed potential conflicts of interest that might cause a bias inthe article. The authors have no competing interests.

Provenance and peer review Commissioned; internally peerreviewed.

REFERENCES1 Elliott P, Andersson B, Arbustini E, et al. Classification of the

cardiomyopathies: a position statement from the European Societyof Cardiology Working Group on Myocardial and PericardialDiseases. Eur Heart J 2008;29:270–6.

▸ Systematic classification of the cardiomyopathies according to thestructural/functional phenotype, which should constitute thebeginning of the diagnostic approach.

2 Jarcho JA, McKenna W, Pare JA, et al. Mapping a gene forfamilial hypertrophic cardiomyopathy to chromosome 14q1.N Engl J Med 1989;321:1372–8.

3 Kathiresan S, Srivastava D. Genetics of human cardiovasculardisease. Cell 2012;148:1242–57.

▸ Thorough review on the recent advancements regarding theunderstanding of the genetic background of common and rarecardiovascular disease.

4 Jacoby D, McKenna WJ. Genetics of inherited cardiomyopathy.Eur Heart J 2012;33:296–304.

5 Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies.N Engl J Med 2011;364:1643–56.

6 Sen-Chowdhry S, Syrris P, Pantazis A, et al. Mutationalheterogeneity, modifier genes, and environmental influencescontribute to phenotypic diversity of arrhythmogeniccardiomyopathy. Circ Cardiovasc Genet 2010;3:323–30.

7 Richardson DR, Lane DJ, Becker EM, et al. Mitochondrial irontrafficking and the integration of iron metabolism between themitochondrion and cytosol. Proc Natl Acad Sci USA2010;107:10775–82.

8 Gambarin FI, Disabella E, Narula J, et al. When should cardiologistssuspect Anderson-Fabry disease? Am J Cardiol 2010;106:1492–9.

▸ Excellent and comprehensive review addressing the clinicalfeatures that should constitute clues to suspect cardiacinvolvement with Anderson–Fabry disease.

9 Hicks J, Wartchow E, Mierau G. Glycogen storage diseases: a briefreview and update on clinical features, genetic abnormalities,pathologic features, and treatment. Ultrastruct Pathol2011;35:183–96.

Clinical diagnosis of inherited heart muscledisease: key points

▸ Cardiomyopathies are clinically defined byventricular morphology and function.

▸ Some genetic and non-genetic subtypes can beidentified using a step-by-step strategy,including history, physical examination, ECG,echocardiography, laboratory and acardiomyopathy focused approach to theinterpretation of cardiac and non-cardiacinvestigations.

▸ A three generation family pedigree should beobtained for all patients.

▸ Age at presentation is an important clue todifferential diagnosis.

▸ Cardiac imaging should be interpreted in thelight of family history, age and othernon-invasive tests.

▸ Genetic testing is most informative if directedto a specific diagnosis, suspected on the basisof the clinical assessment or, if used forcascade genetic screening, once a clearpathogenic mutation is discovered in theproband.

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10 Kaski JP, Syrris P, Shaw A, et al. Prevalence of sequence variantsin the RAS-MAPK signaling pathway in pre-adolescent childrenwith hypertrophic cardiomyopathy. Circ Cardiovasc Genet2012;5:317–26.

11 Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart:assessment, diagnosis, and referral. Heart 2011;97:75–84.

▸ Review of the different forms of cardiac amyloidosis anddiagnostic algorithms.

12 Maron BJ. A phenocopy of sarcomeric hypertrophiccardiomyopathy: LAMP2 cardiomyopathy (Danon disease) fromChina. Eur Heart J 2012;33:570–2.

13 Gollob MH, Green MS, Tang AS, et al. PRKAG2 cardiac syndrome:familial ventricular preexcitation, conduction system disease, andcardiac hypertrophy. Curr Opin Cardiol 2002;17:229–34.

14 Baccouche H, Maunz M, Beck T, et al. Differentiating cardiacamyloidosis and hypertrophic cardiomyopathy by use ofthree-dimensional speckle tracking echocardiography.Echocardiography 2012;29:668–77.

15 Gruner C, Verocai F, Carasso S, et al. Systolic myocardialmechanics in patients with Anderson-Fabry disease with andwithout left ventricular hypertrophy and in comparison tononobstructive hypertrophic cardiomyopathy. Echocardiography2012;29:810–7.

16 Phelan D, Collier P, Thavendiranathan P, et al. Relative apicalsparing of longitudinal strain using two-dimensional speckletracking echocardiography is both sensitive and specific for thediagnosis of cardiac amyloidosis. Heart 2012;98:1442–8.

17 Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhancedcardiovascular magnetic resonance in Anderson-Fabry disease.Evidence for a disease specific abnormality of the myocardialinterstitium. Eur Heart J 2003;24:2151–5.

▸ One of the first studies on the importance of tissuecharacterisation by cardiac MRI in the differential diagnosisbetween sarcomeric and other causes of LVH.

18 Yilmaz A, Sechtem U. Systemic disorders in heart disease: cardiacinvolvement in muscular dystrophy: advances in diagnosis andtherapy. Heart 2012;98:5420–9.

▸ Recent review describing the cardiac manifestations in musculardystrophy.

19 Charron P, Arad M, Arbustini E, et al. Genetic counselling andtesting in cardiomyopathies: a position statement of the EuropeanSociety of Cardiology Working Group on Myocardial andPericardial Diseases. Eur Heart J 2010;31:2715–26.

▸ Position statement regarding genetic testing and counselling oncardiomyopathies based on available evidence and expertopinion.

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inherited heart muscle diseaseNew approaches to the clinical diagnosis of

Luis Rocha Lopes and Perry Mark Elliott

doi: 10.1136/heartjnl-2012-3019952013 99: 1451-1461 originally published online March 6, 2013Heart 

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