Genetics: Genotype/Phenotype Correlations in Cardiomyopathies

Phenotypic finding

Cardiac features

Diseases to consider

Sensorineural deafness

HCM

Mitochondrial diseases

Anderson–Fabry disease

LEOPARD syndrome

DCM

Epicardin mutation

Mitochondrial diseases

Muscle weakness

HCM

Mitochondrial diseases

Glycogenosis

DCM

Dystrophinopathies

Sarcoglycanopathies

Laminopathies

Myotonic dystrophy

Desminopathies

RCM

Desminopathies

Learning difficulties, mental retardation

HCM

Mitochondrial diseases

Noonan Syndrome

Danon disease

DCM

Dystrophinopathies

Mitochondrial diseases

Myotonic dystrophy

FKTN mutations

RCM

Noonan syndrome

Myotonia (involuntary muscle contraction with delayed relaxation)

Myotonic dystrophy (type 1 and type 2)

Paraesthesia/sensory abnormalities/neuropathic pain

HCM

Amyloidosis

Anderson–Fabry disease

RCM

Amyloidosis

HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, RCM restrictive cardiomyopathy, LEOPARD syndrome lentigines, echocardiograph conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness, FKTN fukutin

Table 2.2

Examples of skin/eyes signs that should raise suspicion of specific cardiac features

Phenotypic finding	Cardiac features	Disease to be considered
Visual impairment	HCM	TTR-related amyloidosis (vitreous opacities, cotton wool type)
		Danon disease (retinitis pigmentosa)
		Anderson–Fabry disease (cataracts, corneal opacities)
	DCM	CRYAB (polar cataract) type 2 myotonic dystrophy (subcapsular cataract)
Carpal tunnel syndrome (bilateral)	HCM	TTR-related amyloidosis
Carpal tunnel syndrome (bilateral)	RCM	Amyloidosis
Lentigines/café au lait spots	HCM	LEOPARD syndrome
Angiokeratoma hypohidrosis	HCM	Anderson–Fabry disease
Palmoplantar keratoderma, woolly hair	ARVC	Naxos and Carvajal syndromes

HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, RCM restrictive cardiomyopathy, ARVC arrhythmogenic right ventricular cardiomyopathy, TTR transthyretin protein, LEOPARD syndrome lentigines, echocardiograph conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness

CMP may also be a feature of rare congenital dysmorphic syndromes that are diagnosed during infancy and childhood [31]. A detailed description of these disorders is outside of the aim of this chapter. It is evident that CMP are a common feature of multisystem diseases. The mechanisms of multiorgan involvement are heterogeneous, and a complete evaluation includes researching red flags, such as the following [32, 33]:

Physical examination (Tables 2.1 and 2.2)

Electrocardiogram abnormalities (Table 2.3)

Table 2.3

Laboratory findings that should raise the suspicion of specific cardiac features

High serum creatine kinase (CK)	HCM	Mitochondrial diseases
		Glycogenosis
		Danon disease
	DCM	Dystrophinopathies
		Sarcoglycanopathies
		Zaspopathies (LDB3 gene)
		Laminopathies
		Myotonic dystrophy
		FKTN mutations
	RCM	Desminopathies
		Myofibrillar myopathies
Proteinuria with/without low glomerular filtration rate	HCM	Anderson–Fabry disease
	RCM	Amyloidosis
High transaminase	HCM	Mitochondrial diseases
		Glycogenosis
		Danon disease
High transferrin saturation/hyperferritinemia	DCM	Hemochromatosis
	RCM
Lactic acidosis	HCM	Mitochondrial diseases
	DCM
Myoglobinuria	HCM	Mitochondrial diseases
	DCM
Leukocytopenia	HCM	Mitochondrial diseases (TAZ gene/Barth syndrome)
	DCM

Laboratory tests (Table 2.4)

Table 2.4

Examples of electrocardiographic (ECG) abnormalities that should raise the suspicion of specific diagnoses grouped according to the main cardiac features

Phenotypic finding	Cardiac features	Diseases to be considered
Short PR/pre-excitation (WPW like)	HCM	Glycogenosis
		Danon
		PRKAG2
		Anderson–Fabry
		Mitochondrial disease
AV block	HCM	Amyloidosis
	HCM	Danon disease
	DCM	Laminopathy
		Emery Dreifuss
		Sarcoidosis
		Desminopathy
	RCM	Desmin-related cardiomyopathy
	RCM	Amyloidosis
Extreme LV hypertrophy (Sokolow criteria)	HCM	Danon disease
Extreme LV hypertrophy (Sokolow criteria)	HCM	Pompe disease
Low QRS voltage	HCM	Amyloidosis
Low P wave amplitude atrial standstill	DCM	Emery Dreifuss
Q waves in posterolateral leads	DCM	Dystrophin-related cardiomyopathy
		Limb-girdle muscular dystrophy
		Sarcoidosis
Inverted T waves in inferolateral leads	ARVC	ARVC with biventricular involvement
Epsilon waves in inferolateral leads	ARVC	ARVC with biventricular involvement

WPW Wolff-Parkinson-White syndrome, AV arteriovenous, LV left ventricular, HCM hypertrophic cardiomyopathy, DCM dilated cardiomyopathy, RCM restrictive cardiomyopathy, ARVC arrhythmogenic right ventricular cardiomyopathy, PRKAG2 protein kinase, AMP-activated, gamma 2 noncatalytic subunit

Echocardiography/cardiac magnetic resonance: hypertrophy pattern, pericardial effusion, valve thickening, bulging, sacculations, sparkling myocardium texture, late gadolinium enhancement (LGE) (Table 2.5). Some typical features are described, such as LGE localized to the inferolateral wall in patients with Anderson–Fabry disease or dystrophinopathies and to the circumferential subendocardial wall in cardiac amyloidosis. The echocardiogram remains the first-line imaging tool in patients with suspected CMP. It has a central role in defining the morphological and functional phenotype and in guiding treatment decisions. As with all imaging modalities, echocardiography rarely suggests a specific etiology, but it can be helpful in the context of a number of features in directing further investigation.
Table 2.5

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