New approaches to the clinical diagnosis of inherited heart muscle disease
- Correspondence to Professor Perry M Elliott, UCL Institute of Cardiovascular Science, The Heart Hospital, 16-18 Westmoreland Street, London W1G 8PH, UK;
Cardiomyopathies are defined as disorders of heart muscle unexplained by coronary artery disease, hypertension, valvular disease or congenital heart disease.1 They are classified by morphological and functional phenotype into hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) subtypes.1 Table 1 shows the European Society of Cardiology working group classification of cardiomyopathies.
All forms of cardiomyopathy can be caused by genetic and non-genetic mechanisms. The first genetic locus associated with HCM was discovered by linkage analysis2 in 1989 and the responsible gene, β-myosin heavy chain (MYH7), was identified in the subsequent year.w1 Since then, extraordinary progress has been made in the understanding of the molecular genetic background of all inherited heart muscle disorders.3 w2 Most genetic forms of cardiomyopathy are inherited as autosomal dominant Mendelian diseases and are characterised by locus and allelic genetic heterogeneity, highly variable intra- and interfamilial expressivity, and incomplete clinical penetrance.1 ,4 This very high level of genotype–phenotype plasticity may result from the influence of modifier genes, epigenetic effects, post-transcriptional and post-translational modifications, and environmental effects.5 ,6
The genetic and phenotypic heterogeneity that characterises all cardiomyopathies pose major clinical challenges. In this article, we focus on the task of diagnosis, exploring how a systematic clinical approach can be used to identify specific disorders and guide the selection of further diagnostic tests, including molecular genetic analysis. The basic premise is that a cardiomyopathy focused approach to history and examination combined with conventional and emerging diagnostic tests can be used to identify clues or ‘red flags’ that suggest particular genetic and non-genetic sub-phenotypes (figure 1).
While a brief enquiry about family history is standard clinical practice, evaluation of individuals with cardiomyopathy requires a more thorough approach to the assessment of family background. This process is facilitated by the construction of a three to four generation family pedigree that records not only the presence or absence of cardiomyopathy in relatives, but also other features that support the diagnosis of a genetic cardiovascular disorder, including sudden cardiac death, heart failure, cardiac transplantation, insertion of pacemakers or defibrillators, and stroke at a young age. Non-cardiac manifestations in relatives such as neuromuscular disease and endocrine disorders also provide diagnostic clues.
Autosomal dominant inheritance is the most common mode of transmission in all forms of cardiomyopathy.1 Key points that support a diagnosis of autosomal dominant disease include the presence of affected individuals in every generation and male-to-male transmission. The majority of autosomal dominant cardiomyopathies are confined to the heart, but some uncommon subtypes may be associated with non-cardiac manifestations—for example, laminopathies and disorders of the RAS-MAPK pathway such as Noonan syndrome.w3 Autosomal recessive forms of cardiomyopathy are much less common, often occurring in consanguineous families and as one feature of a multisystem disease. Examples of autosomal recessive disorders in which the heart is prominently affected include glycogen storage disease (GSD) type II (caused by acid α-1,4-glycosidase (GAA) deficiency), GSD IIIA (caused by amylo-1,6-glucosidade/debranching enzyme deficiency), and Friedreich's ataxia, caused by expansions—GAA triplet repeats—in the frataxin gene.7 X-linked cardiomyopathies are uncommon but are probably underdiagnosed. Specific clues include the absence of male–male transmission and milder or absent phenotypes in females. Danon's disease, caused by mutations in the LAMP2 gene (GSD type IIB), and Anderson Fabry disease,8 a sphingolipidosis caused by mutations in the α-galactosidase A gene, are inherited as X-linked traits; so are neuromuscular diseases such as dystrophinopathies (Duchenne's and Becker's) and emerin-related Emery–Dreifuss muscular dystrophy, all of which are associated with a DCM phenotype, sometimes as the predominant clinical feature. Finally, the phenomenon of disease transferred only by women to male and female offspring suggests the presence of mitochondrial diseases caused by mutations in mitochondrial DNA.w4
Figure 2 illustrates the main inheritance patterns.
Medical history and physical examination
Age at presentation
Age at presentation is one of the most important clinical clues to differential diagnosis of a cardiomyopathy. HCM presenting in neonates and infants should raise the suspicion of an inborn error of metabolism, such as GSD9—for example, Pompe's disease (GSD II), Forbes’ disease (GSD IIIA) or Danon's (GSD IIB) disease—or a mitochondrial disorder, such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or Kearns Sayre syndromes.w4 RASopathies such as Noonan and LEOPARD syndrome (lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) are also more common at this age.10 In contrast, presentation with apparently isolated HCM in individuals over 60 years of age should raise suspicion of amyloidosis.11 Presentation with HCM in adolescence or as a young adult is typical of sarcomeric protein disease.
Symptoms and physical examination
Facies and dysmorphic features
Some cardiomyopathies in children and adolescents are associated with congenital dysmorphic syndromes. Among the most common are Noonan syndrome, characterised by short stature, variable degrees of developmental delay, cutaneous abnormalities (‘cafe-au-lait’ spots), hypertelorism, ptosis, low set posteriorly rotated ears, and a webbed neck. Some of these features are shared by the less common 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 mutations in components of the RAS-MAPK cascade.
Skin and hair
In Anderson–Fabry disease,8 w5 a large spectrum of extracardiac manifestations can occur, including dermatological signs (eg, angiokeratomata, hypohidrosis). Cutaneous anomalies (eg, lentigines in LEOPARD syndrome or ‘café-au-lait’ spots) can also be present in RASopathies. Curly and thin hair is another possible manifestation. Syndromic autosomal recessive forms of ARVC (Naxos and Carvajal syndromes) are characterised by woolly hair and palmoplantar hyperkeratosis.
Central and peripheral neurologic manifestations and skeletal muscle involvement
Psychomotor delay can occur in many diseases of intermediary metabolism and the RAS-MAPK cascade (sometimes very subtly). Pompe's disease (GSD II) is characterised by hypotonia. The extracardiac features of Forbes’ disease (GSD III) include peripheral muscular weakness and neurological involvement.9 Danon's disease in men typically presents with mental retardation and skeletal myopathy, while women are characterised by a later onset (in their 20s) and milder phenotype, with some cases of isolated cardiac involvement.12 PRKAG2 syndrome can include peripheral skeletal muscle weakness.13 In Anderson–Fabry disease,8 w5 audiological (eg, deafnesss, tinnitus), ophthalmic (eg, cornea verticillata, tortuous vessels), central or peripheral neurological (eg, acroparesthesiae, stroke) manifestations can be part of disease. Mitochondrial disease most frequently affects organs with high energy requirements (heart, muscle, brain, eyes); manifestations include encephalopathy, lactic acidosis with extreme exercise intolerance disproportionate to the cardiac involvement, stroke-like episodes, diabetes, chronic progressive external ophthalmoplegia, deafness, and pigmentary retinopathy.w4 Neuromuscular diseases associated with either DCM (dystrophinopathies, sarcoglycanopathies, laminopathies, myotonic dystrophy, desminopathy) or HCM (FHL1 associated Emery–Dreifuss and Friedreich's ataxia) present with muscular weakness as a main feature. Bilateral carpal tunnel syndrome can be a manifestation of transthyretin amyloidosis.
While an ECG is performed in almost every patient with a cardiomyopathy, its value in the diagnosis of specific subtypes is often overlooked. Some relatively simple findings that should be considered are listed here.
Ventricular pre-excitation is a common observation in patients with storage diseases (Pompe's disease, PRKAG2 mutations associated with Wolff-Parkinson-White syndrome, Danon's disease), and in some individuals with mitochondrial disorders (MELAS, MERFF (myoclonic epilepsy with ragged red fibres)).w4 A short PR interval is also described in patients with Anderson–Fabry disease and mitochondrial disease.
Atrioventricular (AV) block is one of the most important ECG clues to diagnosis in all forms of cardiomyopathy. In individuals presenting acutely with a mildly dilated left ventricle, AV block can reflect acute/subacute myocardial inflammation caused by Lyme disease, giant cell myocarditis, and sarcoidosis. In young adults with DCM, AV block should always prompt a search for laminopathy (particularly in the context of a history of atrial arrhythmia or a family history of young sudden deaths) or desminopathy when it may occur in the presence of clinical or subclinical skeletal muscle disease. Causes of AV block in young adults with HCM include mutations in PRKAG2 and mitochondrial disorders; in older adults progressive AV block should prompt consideration of Anderson–Fabry disease and amyloidosis.
Changes in QRS voltage are a common and often non-specific feature in patients with cardiomyopathy, but extremely large QRS voltage is typical of storage diseases such as Pompe's and Danon's disease (figure 3A) or may be the consequence of ventricular pre-excitation. Low QRS voltage unexplained by obesity, lung disease or pericardial effusion is common in cardiac amyloidosis, but lacks sensitivity and may be seen in patients with progressive myocardial fibrosis and systolic dysfunction. So called ‘pseudoinfarct’ patterns are characteristic but not invariable features of cardiac amyloidosis (figure 5A), and an inferolateral (posterior) infarct pattern in the presence of a DCM phenotype can suggest a dystrophinopathy (prominent R wave V1–V2, figure 3B).
QRS axis is often abnormal in patients with various cardiomyopathies, but extreme superior (north west) QRS axis deviation can be a feature of Noonan's syndrome (figure 3C).
T wave inversion
Repolarisation abnormalities are very common in all forms of cardiomyopathy, but some patterns should alert clinicians to specific disorders. The most important are T wave inversion in the precordial leads, which in context (eg, in individuals with unexplained syncope, a family history of premature death or ventricular arrhythmia of right ventricular origin) suggests ARVC (figure 3D), and deep T wave inversion in the lateral leads in patients with distal HCM (sometimes overlooked in patients with poor apical views on echocardiography).
The echocardiogram remains the first line imaging tool in patients with suspected cardiomyopathy. It has a central role in defining the morphological and functional phenotype and in guiding treatment decisions. As with all imaging modalities, it is rare for echocardiography to suggest a specific aetiology, but in context a number of features can be helpful in directing further investigation, particularly in patients with HCM. While any pattern of hypertrophy is consistent with a diagnosis of HCM, the distribution and severity of left ventricular hypertrophy (LVH) can be helpful. For example, concentric LVH is common in metabolic and infiltrative disorders whereas asymmetrical septal hypertrophy with reversed septal curvature is the dominant pattern in patients with sarcomeric protein gene mutations (figure 4).
The diagnosis of myocardial storage or infiltration should also be suspected when there is coexistent 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 in young individuals, and amyloidosis and Anderson–Fabry disease in the elderly. Other typical but not universal echocardiographic features suggestive of amyloidosis include ‘granular’ or ‘sparkling’ texture of the myocardium, biatrial dilation, interatrial septum thickening, pericardial effusion, valve thickening, and severe restrictive filling (figure 5B).w6 Localised hypokinesia in the inferolateral/posterior wall can be a feature of Anderson–Fabry disease. Echocardiography is generally less useful in elucidating aetiology in patients with DCM or ARVC, but segmental akinesis or dyskinesis in a non-coronary artery territory (particularly the posterior basal segment of the left ventricle) associated with normal wall thickness, with or without a mild pericardial effusion, is seen in myocarditis and dystrophin related disorders. Left ventricular dysfunction and increased wall thickness with mild dilatation of the left ventricle is also seen in patients with acute myocarditis.
Recently, new echocardiographic techniques (eg, speckle tracking and velocity vector imaging) that allow angle independent assessment of myocardial deformation have been examined in patients with cardiomyopathy. Strain—a dimensionless measurement of myocardial deformation—has been demonstrated to be more reproducible, less operator dependent, and more sensitive than classical methods (eg, ejection fraction) for the assessment of left ventricular function.w7 Recent studies have explored the role of myocardial deformation imaging in the differential diagnosis of unexplained LVH.w8 w9 When comparing cardiac amyloidosis and HCM,14 these studies showed a reverse basoapical strain gradient in amyloidosis and relative apical sparing (figure 6). In Anderson–Fabry disease,15 ,16 a loss of the circumferential strain basoapical gradient in patients with LVH has been reported. Also typical of Anderson–Fabry disease is a reduced longitudinal strain at the basal-mid inferolateral wall (figure 6).
Cardiac magnetic resonance
Cardiac magnetic resonance (CMR) provides tomographic imaging in any plane, without window limitations and with good spatial resolution. CMR has an important role in refining morphological characterisation in patients with poor echocardiographic windows and in assessing localised and often subtle right ventricular wall motion abnormalities in patients with ARVC. CMR's greatest contribution is its ability to provide information on myocardial tissue characteristics through the use of late gadolinium kinetics or specific imaging sequences. Some important CMR diagnostic ‘red flags’ include: late gadolinium enhancement (LGE) localised to the inferolateral wall in patients with myocardial hypertrophy (Anderson–Fabry disease17) or DCM (dystrophinopathies),18 and circumferential subendocardial LGE with difficulty in nulling the myocardial signal in cardiac amyloidosis (figure 7).11 T2* imaging is established as a tool to detect and quantify iron deposition within the myocardium caused by haemochromatosis.w10 CMR also has an emerging role in the diagnosis of myocarditis, in which T2 weighted oedema imaging, early enhancement imaging, and LGE are recommended.w11
Because of the myriad of conditions that can cause heart muscle disease, most patients with cardiomyopathy will be subjected to a panel of blood tests designed to detect disorders that cause or exacerbate myocardial dysfunction (eg, thyroid disease and anaemia) or assess secondary organ dysfunction (renal function). There are few peripheral biomarkers that are diagnostic for subtypes of cardiomyopathy, but there are circumstances where biochemical testing can be useful. In neonates and infants standard metabolic panels can aid diagnosis of mitochondrial disease and disorders of intermediary metabolism. Similarly, granulocytopenia in an infant with non-compaction suggests a diagnosis of Barth syndrome. In older patients with HCM, renal impairment (including proteinuria) should raise the suspicion of Anderson–Fabry disease or amyloidosis. Raised creatine phosphokinase (CK) is particularly helpful in patients with DCM in whom it suggests a dystrophin related disorder, laminopathy or less commonly myofibrillar myopathy. In patients with HCM, a raised CK is seen in Danon's and mitochondrial disease, and in patients with RCM and a high CK, desminopathy should be considered.
In general, nuclear imaging has only a limited role in determining aetiology in cardiomyopathies. Exceptions include technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy, that can identify myocardial infiltration with transthyrethin amyloid (figure 5C),w12 w13 and fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with cardiac sarcoidosis.w14
Given the genetic background to all forms of heart muscle disease, it is tempting to assume that the very clinical approach to diagnosis outlined in this review is somewhat redundant in the modern era. Clinical guidelines19 w15 recommend routine molecular genetic testing in the most clearly affected member of the family in HCM, ARVC, and, with a lower strength, in DCM. Given the high level of biological discrimination afforded by genetic testing, the finding of a potentially causal DNA sequence variant adds weight to the clinical diagnosis. Similarly, when metabolic disease is suspected from clinical or laboratory findings, screening for mutations in the most likely candidate genes can be confirmatory. Once a causative mutation is identified, genetic testing can also be used in a cascade screening strategy for families, to provide presymptomatic diagnosis of family members.
However, genetic testing does have some important limitations. For example, it is well recognised that genetic testing often identifies genetic variants of uncertain pathogenicity, and in some disorders multiple mutations in the same or different genes are remarkably common. There are various molecular approaches to the determination of pathogenicity in this context,w16 but interpretation of genetic findings inevitably falls back on clinical phenotyping in patients and their family members. The key to success in diagnosis is, therefore, a cardiomyopathy centred approach to clinical assessment coupled with a systematic stepwise use of cardiac and non-cardiac diagnostic tests. Table 2 summarises the typical findings and diagnostic clues for some of the cardiomyopathies discussed in the text.
Clinical diagnosis of inherited heart muscle disease: key points
Cardiomyopathies are clinically defined by ventricular morphology and function.
Some genetic and non-genetic subtypes can be identified using a step-by-step strategy, including history, physical examination, ECG, echocardiography, laboratory and a cardiomyopathy focused approach to the interpretation of cardiac and non-cardiac investigations.
A three generation family pedigree should be obtained for all patients.
Age at presentation is an important clue to differential diagnosis.
Cardiac imaging should be interpreted in the light of family history, age and other non-invasive tests.
Genetic testing is most informative if directed to a specific diagnosis, suspected on the basis of the clinical assessment or, if used for cascade genetic screening, once a clear pathogenic mutation is discovered in the proband.
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Contributors Both authors have contributed to the writing of this review article and are responsible for the overall content.
Funding LRL is supported by a grant from the Gulbenkian Doctoral Programme for Advanced Medical Education, sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal.
Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. The authors have no competing interests.
Provenance and peer review Commissioned; internally peer reviewed.
- ↵Systematic classification of the cardiomyopathies according to the structural/functional phenotype, which should constitute the beginning of the diagnostic approach.
- ↵Thorough review on the recent advancements regarding the understanding of the genetic background of common and rare cardiovascular disease.
- ↵Excellent and comprehensive review addressing the clinical features that should constitute clues to suspect cardiac involvement with Anderson–Fabry disease.
- ↵Review of the different forms of cardiac amyloidosis and diagnostic algorithms.
- ↵One of the first studies on the importance of tissue characterisation by cardiac MRI in the differential diagnosis between sarcomeric and other causes of LVH.
- ↵Recent review describing the cardiac manifestations in muscular dystrophy.
- ↵Position statement regarding genetic testing and counselling on cardiomyopathies based on available evidence and expert opinion.