Genetics and metabolic cardiomyopathies
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- Wicks, E. & Elliott, P. Herz (2012) 37: 598. doi:10.1007/s00059-012-3659-0
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Metabolic disorders encompass a heterogeneous group of conditions that commonly affect the heart and contribute adversely to cardiovascular outcomes. As the heart is a metabolically active organ, inborn errors in metabolism (IEMs) often present with cardiac manifestations such as cardiomyopathy, arrhythmia, and valvular dysfunction. More than 40 IEMs are reported to cause cardiomyopathy, including fatty acid oxidation defects, glycogen, lysosomal and perioxisome storage diseases, mitochondrial cardiomyopathies, organic acidaemias, aminoacidopathies and congenital disorders of glycosylation. Studies suggest that IEM account for only 5% of cardiomyopathies; however, their diagnosis is imperative to enable the effective institution of disease-specific management strategies. This review describes the more common genetic defects that affect metabolic pathways and give rise to heart muscle disease.
Genetik und metabolische Kardiomyopathien
Metabolische Störungen üben in der Regel einen negativen Einfluss auf das Herz-Kreislauf-System aus. Dies gilt für angeborene Störungen umso mehr. Sie zeigen sich klinisch als Kardiomyopathien, Rhythmusstörungen oder Herzklappenerkrankungen. Mehr als 40 angeborene Stoffwechselstörungen sind inzwischen bekannt. Zu ihnen gehören Störungen der Fettsäureoxidation, Glykogen-, lysosomale und peroxisomale Speichererkrankungen, mitochondriale Kardiomypathien, Azidämien, Aminoazidopathien sowie Störungen der Glykosylierung. Obgleich die angeborenen metabolischen Störungen nur 5% der Kardiomyopathien ausmachen, ist es unverzichtbar, sie zu erkennen, damit eine krankheitspezifische Behandlung vorgenommen werden kann. Die häufigsten Formen werden in diesem Beitrag beschrieben.
SchlüsselwörterGenetikAngebore metabolische StörungenStoffwechselKardiomyopathien
More than 40 inborn errors in metabolism (IEM) are known to cause myocardial abnormalities (Tab. 1). They can present with cardiovascular disease at any time during life but commonly present in infancy or early childhood with signs and symptoms of multi-organ system dysfunction. Although individual disorders are rare, the overall prevalence of IEM in the general population is between 1 in 1,000 and 1 in 2,500. Moreover, up to 5% of paediatric cardiomyopathy is caused by primary disturbance of myocardial metabolism . Common presenting cardiac manifestations include hypertrophic, dilated or restrictive cardiomyopathy, tachyarrhythmia, conduction disease, valvular dysfunction and sudden cardiac death. Disease pathophysiology is complex, but includes impaired energy production, infiltration of cardiac myocytes with stored substrate and the production of toxic intermediary metabolites that can lead to apoptosis.
Tabulation of metabolic cardiomyopathies according to accumulated substrate or the affected organelle. (Adapted from )
GENETIC METABOLIC CARDIOMYOPATHIES
Disorders of fatty acid metabolism
Carnitine transport defects
Arrhythmias, heart failure
- Systemic primary carnitine deficiency
- Muscle carnitine deficiency
- Carnitine–palmitoyl transferase deficiency (CPT types I&II) 
Cardiac arrest post exercise
- Carnitine acylcarnitine translocate deficiency (CACT)
- Carnitine transporter defect (CTD)
Low carnitine levels
Fatty acid oxidation defects
- Very long-chain acyl-CoA dehydrogenase deficiency (VLCHAD)
Arrhythmias, HCM, weakness
- Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)
HCM, DCM, HELLP, AFLD in pregnancy, arrhythmia, conduction disease
- Long-chain 3-ketoacyl-CoA thiolase deficiency (LKAD)
- Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (SCHAD)
- Medium chain acyl CoA dehydrogenase deficiency (MCADD)
- Multiple acyl-CoA dehydrogenase deficiency (MADD)
- Mitochondrial trifunctional protein deficiency (TFP)
Disorders of glycogen metabolism (GSD)
- GSD II (Pompe disease, acid α-glucosidase/acid maltase deficiency)
- GSD III (Cori disease, debranching enzyme)
- GSD IV (Anderson disease, branching enzyme)
- GSD IX (cardiac phosphorylase kinase)
- GSD 0 (glycogen synthase deficiency)
- PRKAG2 deficiency
HCM with WPW
- Danon disease (GSD Type IIb, pseudo-Pompe disease with normal acid maltase; LAMP2 gene defect)
- Phosphorylase B kinase deficiency
Lysosomal storage diseases
Disorder of glycosphingolipid, ganglioside, mucopolysaccharide, and oligosaccharide metabolism (sphingolipidoses)
Cherry red spot
- Anderson-Fabry disease (α-galactosidase deficiency)
HCM*, arrhythmias, short PR
- Gaucher disease (glucocerebrosidase deficiency)
HCM*, valve calcification
- Niemann-Pick disease
- GM1 ganlgiosidosis (β-galactosidase deficiency)
- GM2 gangliosidosis (Tay-Sachs and Sandhoff disease)
Rare cardiac involvement
- Metachromatic leucodystrophy
- Krabbe disease
Disorders of mucopolysaccharide (glycosaminoglycan) metabolism
ENT infections, sleep apnoea
- MPS I (Hurler, Hurler-Scheie, Scheie syndromes) (iduronidase enzyme deficiency)
HCM, DCM, valve disease
- MPS II (Hunter syndrome)
HCM, valve disease 
- MPS III (Sanfilippo syndrome)
- MPS IV (Morquio syndrome)
HCM, valve disease
- MPS VI (Maroteux-Lamy syndrome)
DCM, valve disease
- MPS VII (Sly syndrome)
HCM, hydrops fetalis
Disorder of glycogen metabolism
- GSD II (Pompe disease, acid α-glucosidase/acid maltase eficiency)
HCM, massive hypertrophy
- Danon disease (pseudo-Pompe disease with normal acid maltase; LAMP2)
- Mucolipidosis type II (I-cell disease)
HCM, DCM, valve disease
- Mucolipidosis type III (pseudo-Hurler polydystrophy)
- Mucolipidosis type II/III
Severe mental retardation
Disorders of glycoprotein and glycosylation metabolism
- Congenital disorders of glycosylation
- Galatosialidosis (defective protective protein/cathepsin A giving rise to functional loss of β-galactosidase and neuraminidase)
- Schindler disease
- Sialidosis (infantile sialic acid storage disease, ISSD)
Cardiomyopathy, conduction disease
Disorders of amino acid and organic acid metabolism
- Propionic acidaemia (propionyl-CoA carboxylase deficiency) 
- Barth syndrome (3-methylglutaconic aciduria type II)
HCM, DCM, mixed, myopathy conduction defects, arrhythmia, neutropenia 
- Sengers syndrome
- Methylmalonic aciduria
- β-ketothiolase deficiency
- Mevalonic acidaemia
- Alkaptonuiria (homogentisate 1,2-dehydrogenase deficiency)
Valvular heart disease
- Homocystinuria (cystathionine βsynthase deficiency)
Cholesterol biosynthesis defects
- Smith-Lemli-Opitz syndrome (3- β-hydroxysterol-Δ7-reductase deficiency) (DHCR7 gene on 11q)
ASD, endocardial cushion defects, APVD, PDA
- Mevalonate kinase deficiency
Ipsilateral hypolastic lesions
- CHILD syndrome
- Desmosterolosis (3-β-hydroxysterol-Δ 24-reductase deficiency)
- X-linked dominant chondrodysplasia punctata (CDPX2)
- Hydrops-ectopic calcification-moth-eaten skeletal dysplasis (HEM)
- Pyruvate dehydrogenase deficiency (Leigh disease)
- Complex I deficiency
- Complex II deficiency
- Complex III deficiency (histiocytoid cardiomyopathy)
- Complex IV deficiency (muscle and Leigh disease forms)
- Complex V deficiency
- Cytochrome-c reductase coenzyme deficiency
- Cytochrome-c oxidase deficiency
- Cytochrome-c oxidase deficiency with ‘histiocytoid’ cardiomyopathy
- Kearns-Sayre syndrome (mitochondrial DNA deletions/duplications)
HCM, conduction defects, progressive opthalmoplegia
- MELAS (mitochondrial transfer RNA mutation)
- MERRF (mitochondrial transfer RNA mutation)
- Refsum disease (phytanic acid oxidase deficiency)
OTHER GENETIC (AND METABOLIC) CARDIOMYOPATHIES
- Duchenne muscular dystrophy
- Becker muscular deficiency
- Nemaline myopathy
- Malignant hyperthermia
- Familial periodic paralysis
- Friedreich ataxia
- Kugelberg-Welander syndrome
- Myotubular myopathy
- Connective tissue disorders
- Marfan syndrome
- Ehlers-Danlos syndrome
- Osteogenesis imperfect
- Pseudoxanthoma elasticum
Other metabolic disorders
- Tyrosinemia type 1
- D-2-Hydroxyglutaric aciduria
- Multisystem triglyceride storage disease
- Disseminated lipogranulomatosis (Farber disease)
- Tangier disease
- Alcohol-induced cardiomyopathy
- Diabetes-induced cardiomyopathy
Disorders of metal and pigment metabolism
- Wilson disease
- Dubin-Johnson syndrome
- Menkes kinky hair syndrome
Neonatal effects of maternal disorders
- Infant of diabetic mother
- Thyrotoxic cardiomyopathy
- Catecholamine cardiomyopathy
- Lupus erthematosus
- Maternal phenyketonuia
Diagnosis of a metabolic cardiomyopathy has major clinical implications. Many disorders respond to lifestyle measures including dietary modification and vitamin supplementation, and for some there are effective specific treatment strategies such as enzyme replacement therapy, organ transplantation, stem cell and gene therapy. The diagnosis of an IEM also has significant implications for families. Genetic counselling and cascade genetic screening of families to provide presymptomatic and timely diagnoses, and utilisation of disease-specific therapies to preempt the development, natural history and progression of disease are important. For optimal care, all management should be delivered by expert multidisciplinary teams.
Normal heart metabolism
Each day, the normal adult heart must pump approximately 10 tons of blood and adapt almost instantaneously to rapid changes in loading conditions and energy demand. This is achieved through a complex regulation of gene expression, enzyme activity, and signalling pathways that allow the heart to utilise a range of different substrates including glucose, free fatty acid, pyruvate and ketone bodies to produce high energy phosphates.
Before birth, energy is generated by mitochondrial acetyl-CoA, produced from pyruvate via cytosolic glycolysis. In the normal adult heart, adenosine triphosphate (ATP) is produced primarily by the metabolism of free fatty acids (FFAs) and carbohydrates, with FFAs accounting for approximately 70% of ATP production. In health, FFA oxidation is directly related to plasma FFA concentration, whereas glucose and lactate uptake are inversely related to plasma FFA levels. Importantly, FFAs are less efficient as a source of myocardial energy as they require approximately 10% more oxygen than glucose in order to produce an equivalent amount of ATP [2, 3].
Inherited or acquired alterations within this closely regulated metabolic-function relationship can lead to adaptive and maladaptive alterations in ATP production and subsequent dysregulation of cardiac cellular processes which can lead to disordered embryogenesis, structural cardiac defects, cardiac hypertrophy and heart failure.
Genetic metabolic cardiomyopathies
Most genetic metabolic cardiomyopathies (Tab. 1) are inherited as autosomal recessive traits, but a few, such as Barth syndrome, Anderson-Fabry and Danon disease are X-linked [4, 5, 6]. Mitochondrial DNA disorders typically show matrilineal inheritance with DNA mutations being distributed variably among tissues leading to heterogeneous disease manifestations and severity.
Cardiovascular manifestations of IEMs include cardiomyopathy, arrhythmia, valvular heart disease, congenital heart disease and atherothrombotic disease. Whilst cardiac involvement may dominate the clinical picture in some conditions (such as Pompe disease, fat oxidation defects and respiratory chain disorders), it may be an incidental or minor finding in others (e.g. mucopolysaccharridoses, organic acidaemias, some glycogen storage disorders), discovered during multisystemic evaluation. Rarely the heart is the only affected organ (e.g. phosphorylase deficiency and some mitochondrial disorders). Diagnosis requires a high index of suspicion and a systematic clinical and metabolic assessment (Fig. 1). Clinical history, including a detailed family pedigree and details of the maternal obstetric history may provide pointers towards a diagnosis . Hypoglycaemia suggests fat oxidation defects, glycogen storage disorders and mitochondrial cytopathies. Multi-systemic questioning for symptoms of neuromuscular involvement, acroparaesthesiae, deafness, cataracts, renal or other organ involvement is important. Clinical examination may be entirely normal, but a number of diagnostic clues suggest particular disorders. For example, angiokeratomata and cornea verticillata (dystrophy) are typical of Fabry disease; coarse facies, corneal clouding and dysostosis multiplex are found in storage disorders such as Hurler syndrome; and inverted nipples, oedema and abnormal fat distribution in disorders of glycosylation. However, as metabolic cardiomyopathies often present with a paucity of clinical signs, specific metabolic investigations should be performed to aid diagnosis (Tab. 2). Whilst the detection of particular metabolites are suggestive of a diagnosis, analysis of enzyme activity in white blood cells, serum, or plasma or through the culture of fibroblasts from a skin biopsy, remains the gold standard investigation .
Diagnostic correlation of metabolic investigations with aetiologies
Giant complexes, short PR interval
Fat oxidation defects, mitochondrial, storage disorders, Barth syndrome
Congenital disorders of glycolysolation
Pseudo infarct pattern
Cardiopulmonary exercise testing
Mitochondrial disorders, fat oxidation defects, organic acidaemias
Cardiac magnetic resonance imaging
Biochemical investigations (fasting)
Full blood count + differential
Barth syndrome, organic acidaemias
Pompe, mucopolysaccharridosis, mucolipidoses
Fat oxidation defects, GSDs
Plasma lactate (lactate/pyruvate ratio)
Mitochondrial disorders, fat oxidation defects, organic acidaemias
Pompe, GSD III, Fat oxidation defects
Organic acidaemias, fat oxidation
Plasma pyruvate, free fatty acids
Plasma ketones (B-hydroxybutyrate/acetoacetate ratio)
Serum creatinine kinase
Plasma cartinine (total and free)–fetal long chain fat oxidation defects
Fat oxidation and carnitine defects
Urine organic acids
Organic acidaemias, mitochondrial disorders, fat oxidation defects
Second line tests
Muscle biopsy: morphology, histochemistry, histoenzymology
Fat oxidation studies
White cell enzymes
Storage disorders (e.g. Fabry disease)
Molecular genetics (DNA)
Point mutation, deletion
Malnutrition, TPN, IBD, cystic fibrosis
Fibroblasts cultures for enzyme assays
Fatty acid oxidation disorders
Fatty acids are the predominant substrate for energy production during periods of fasting. The fatty oxidation pathway comprises four components: the carnitine cycle (necessary for long chain fatty acid entry into mitochondria); β-oxidation cycle (production of acetyl CoA from activated fatty acylcarnitines); electron transfer (transfer of acetyl CoA from the β-oxidation cycle to the respiratory chain for ATP synthesis) and ketone synthesis (to convert acetyl CoA to ketone bodies for and oxidation particularly by the brain, sparing glucose utilization). Fatty acid oxidation deficiency disorders, which are inherited in an autosomal recessive manner, are listed in Tab. 1. Defective fatty acid oxidation leads to impaired fat metabolism and utilisation resulting in decreased ketone production and glucose consumption without gluconeogenesis resulting in hypoketotic hypoglycaemia and encephalopathy. Fat accumulation (steatosis) contributes to organ dysfunction. Fatty acid oxidation defects present at any age of life with cardiac, muscle, neurological and renal abnormalities. Cardiomyopathy (hypertrophic and dilated), conduction abnormalities, arrhythmias, hypoketotic hypoglycaemia coma, skeletal muscle weakness, pain or acute myositis (long chain disorders) are typical . Biochemical analysis for confirmatory diagnosis should include measurement of plasma carnitine (total and free) and acylated cartinine levels, an acylcarnitine profile, urinary organic acids and assessment of fatty acid oxidation in skin fibroblasts. Each condition has an individual carnitine profile. DNA analysis for autosomal recessive mutations should also be performed. Treatment of these conditions includes avoidance of fasting to prevent utilisation of fat stores and production of toxic intermediates, and dietary restriction of fatty acids. The use of carnitine supplementation remains controversial, yet some authors report the favourable use of riboflavin  and triheptanoin .
Carnitine cycle, β-oxidation and electron transfer defects
The carnitine cycle consists of three enzymes that transport long chain fatty acids into mitochondria. Defects of this system (carnitine transporter defects (CTD), carnitine-palmitoyl transferase 1 and 2 deficiencies (CPT-1 and 2), and carnitine acylcarnitine translocate deficiency (CACT)) are associated with cardio-metabolic disease [11, 12]. The β-oxidation cycle, comprising four steps (acyl-CoA dehydrogenase, enoyl-CoA hydratase, L-3-hydroxy acyl-CoA dehydrogenase and 3-keo-acyl-CoA thiolase), reduces the fatty acid chain length (by two carbons with each cycle) to produce acetyl-CoA at the inner mitochondrial membrane, whilst generating electrons for ATP synthesis within the respiratory chain. Electron transfer defects such as multiple acyl-CoA dehydrogenase deficiency (MADD) result in a block of electron transfer and oxidation from fatty acids and branched chain amino acids. The carnitine cycle, β-oxidation and electron transfer defects with cardiac involvement are shown in Tab. 3.
Key aspects of carnitine transport and cycle, β-oxidation and electron transfer defects associated with metabolic cardiomyopathies
Carnitine transporter defect. 5q mutation
AR disorder of fatty acid oxidation due to the lack of carnitine transporters
Progressive heart failure, muscle weakness, cardiomyopathy between 1–7 years . Hepatomegaly, hypoglycaemic hypoketotic encephalopathy
Carnitine supplementation 
Carnitine palmitoyl transferase deficiency (CPT-1)
Fasting or viral illness triggers deficiency, preventing fatty acid conjugation to carnitine and their transfer into mitochondria
Affected children normally present within 18 months of life with altered mental status and hepatomegaly. Features: non-ketotic hypoglycaemia, hyperammonia, deranged LFTs, elevated free fatty acids and carnitine levels
Carnitine-acylcarnitine translocase deficiency (CACT). 3p21 mutation
Deficiency or loss of carnitine/acylcarnitine exchange on inner mitochondrial membrane leads to mild or rapidly progressive disease, respectively.
Fasting, infections, fever or physiological stress present in neonatal period with hypokinetic hypoglycaemia, encephalopathy, seizures, cardiomyopathy, arrhythmia and premature death (< 1 year of age) 
Medium chain tryclyceride (MCT), low fat diet, carnintine supplementation 
Carnitine palmitoyl transferase-2 deficiency (CPT-2). 1p32 mutation
Neonatal and infantile forms: rapidly fatal with respiratory distress, seizures, altered mental status, hepato and cardiomegaly, arrhythmia, cardiomyopathy, conduction disease, dysmorphism, congenital renal dysgenesis and brain defects [11, 64]. Adults present with rhabdomyolosis, cardiac arrest (post exercise) 
Avoid fasting and sodium valproate (triggers rhabdomyolisis), glucose polymer, MCT supplementation. Triheptanoin, benzafibrate 
Very long chain acyl-CoA dehydrogenase deficiency (VLCAD)
Severe lethal neonatal presentations, a milder later onset form with hypokinetic hypoglycaemia (nil cardiac) and adult form with cardiomyopathy (hypertrophic), muscle symptoms and weakness, rhabdomyolysis, arrhythmias, cardiac arrest
Avoid fasting, long chain fat restriction, use of MCT and frequent feeds. Triheptanoin therapy 
Long chain hydroxyl acyl-CoA dehydrogenase deficiency (LCHAD) and mitochondrial trifunctional protein deficiency (TFP)
G1528C mutation on exon 15 of HADHA gene
Phenotypic variation: cardiomegaly, cardiac dysfunction, dysrhythmias, conduction disease, metabolic decompensation, cardiorespiratory arrest, sudden death . Chronic liver disease, feeding difficulties, growth delay, hypotonia, retinopathy, peripheral neuropathy
Multiple acyl-CoA dehydrogenase deficiency (MADD). 4q32 mutation
Electron transfer from fat and branched chain amino acids oxidation is blocked. Severe disease associated with nonsense mutations/deletions, milder disease missense mutations
Hypoketotic hypoglycaemia and metabolic acidosis, hypotonia, cardiomyopathy, coma. Congenital abnormalities (facial dysmorphism, polycyctic kidneys, genitalia anomalies, anterior abdominal wall defects are associated. Premature death (< 1 year). C14 and C16 are mainly cardiomyopathic
Respiratory chain disorders
Beyond mitochondrial fatty acid oxidation, glucose oxidation and TCA cycle ATP-generating pathways, the mitochondrial electron transport chain and oxidative phosphorylation (OXPHOS) system drives ATP synthesis [13, 14]. This system is comprised of five main multi-subunit complexes encoded by nuclear and mitochondrial DNA, located at the inner mitochondrial membrane (MIM). Electrons pass along this system on the MIM (via coenzyme Q10 and cytochrome c) and react-with oxygen releasing protons in the intermembrane space (IMS) creating a proton gradient across the MIM. This gradient allows reentry of protons via complex 5, which drives ATP production. Mitochondrial cardiomyopathies arise from inherited or sporadic mutations in mitochondrial (mtDNA) or nuclear DNA. mtDNA mutations have a population prevalence of in 1 in 8,000 and account for 70% of mitochondrial disease. Nuclear DNA mutations occur in 1 in 50,000 and are more frequently seen in children. mtDNA mutations are inherited as a matrilinear trait, but nuclear DNA mutations are transmitted by any manner (autosomal dominant, recessive or X-linked) .
Disease onset and clinical presentation are highly variable as a result of hetero/polyplasmy of mutant mtDNA. Cardiac involvement is a major component of specific mitochondrial DNA defects and often presents earlier and has a worse prognosis than non-cardiac disease . HCM (commonly concentric LVH but without outflow tract obstruction) is common in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) and myoclonic epilepsy with red-ragged fibres (MERRF). DCM and LV noncompaction with rapid progression to LV dilatation, systolic dysfunction and heart failure and occasionally sudden arrhythmic death are also described . Certain conditions such as Kearns-Sayre syndrome are associated with AV conduction defects and accessory pathways (including WPW in m.3243A >G mutations) sometimes necessitating cardiac pacing or radiofrequency ablation [14, 15].
Assessment of mitochondrial conditions requires enquiry and examination for muscle weakness, hearing and ocular abnormalities (ptosis, nystagmus, external opthalmoplegia, pigmentary retinopathy and cataract), breathing or neurological disturbance and detailed (especially maternal) family history. Biochemical investigation may reveal high blood lactate levels. Skeletal muscle biopsy may be necessary in some cases in order to demonstrate ‘ragged red fibres’ and to perform respiratory chain enzyme analysis and mutation analysis. The management of mitochondrial disorders is mainly supportive with secondary prevention measures, drug avoidance (sodium valproate, barbiturates, gentamicin, ciprofloxacin, chloramphenicol, tetracycline and zidovudine) and treatment of complications.
Lysosomal storage disorders
The presence of lysosomes within most living cells explains the wide range of abnormalities seen with these disorders. There are approximately 40 lysosomal storage disorders (LSDs) in which enzyme deficiencies within these membrane-bound intracellular organelles leads to the storage of partially degraded macromolecules. LSDs are categorized into mucopolysaccharidoses (MPS), mucolipidoses (ML), glycoproteinoses and sphingolipidoses by their primary storage product. The prevalence of LSDs is approximately 1 in 7,000. All are autosomal recessively inherited except Anderson-Fabry, Danon and Hunter’s diseases which are X-linked. Patients often have characteristic skeletal dystosis multiplex (large skull, spinal deformities and short, thick tubular bones), hepatosplenomegaly and coarse facial features, but the clinical picture is often dominated by neurodevelopmental regression. Cardiac involvement, whilst rarely being the reason for presentation except in Pompe and Anderson-Fabry disease, is characterized by substrate accumulation within the myocardium and heart valves causing rhythm and structural abnormalities.
Diagnosis of LSDs is made using specific enzyme assays in leucocytes or fibroblasts and urine analysis for glycosaminoglycans and oligosaccharides (MPS, ML, manosidosis, sialidosis), peripheral blood smears for vacuolated cells (GM1 gangliosidosis, Pompe disease), skeletal survey for dystosis multiplex (MPS, GM1 gangliosidosis, ML), bone marrow aspiration for foam cells (GM1 gangliosidosis) and DNA analysis. Management of these chronic, progressive conditions requires a multidisciplinary approach incorporating supportive treatment, cardiovascular investigation (ECG, echocardiography), substrate inhibition therapy, surgical intervention (valvular replacement) if indicated, bone marrow transplantation (BMT) to replace enzyme deficiencies  and targeted enzyme replacement therapy (ERT; for MPS I, II, VI, Pompe, Gaucher and Fabry) . Newer substrate deprivation therapies that reduce production of storage components, and chaperone therapies preventing enzyme destruction have the potential to alter disease pathophysiology and slow disease progression [1, 20, 21, 22, 23].
Mucopolysaccharidoses (MPS) are a hetergeneous family of inherited, progressive, multisystem disorders caused by a deficiency of lysosomal enzymes that degrade glycosaminoglycans. They are grouped according to the enzyme deficiency and are predominantly autosomal recessively inherited, except MPS type II which is X-linked. MPS commonly affect connective tissue giving rise to the characteristic coarse facial thickening, but specific cardiovascular problems include valvular disease (particularly mitral incompetence ), myocardial thickening, systemic and pulmonary hypertension and coronary artery narrowing precipitating ischaemia, heart failure and sudden cardiovascular death. Other systemic features consist of ENT infections, corneal clouding, obstructive sleep apnoea, herniae, spinal cord compression and skeletal dysplasia. The extent of clinical features (facial dysmorphism, physical disability and neurodegeneration) can aid classification in different MPS subtypes (see Tab. 1).
MPS type I (Hurler, Hurler-Scheie and Scheie syndrome)
MPS I arises due to a deficiency of the lysosomal enzyme iduronidase. Clinical features often present by the age of 9 months and endocardial fibroelastosis has been reported . MPS IH (Hurler syndrome) is classically associated with gradual progression of skeletal and cardiopulmonary disease with death by the age of 10 years; however, the use of bone marrow transplantation can reduce disease severity for all but the skeletal features . MPS IH/S (Hurler Scheie syndrome) has an intermediate iduronidase deficiency that presents with joint pain and stiffness with generally normal intellect and similar feature described above. MPS I/S (Scheie syndrome) is later in onset but presents with corneal clouding and joint problems but importantly systolic and diastolic dysfunction . Available therapies for MPS I include ERT, which reverses organomegaly and cardiomyopathy, improves joint involvement and remodels facial features but does not reverse valvular disease [28, 29, 30].
MPS II (Hunter syndrome)
MPS II is an X-linked disorder with more than 150 described mutations that give rise to the deficiency of iduronate-2-sulfatase . Disease onset is characteristically later than type I (between 2 and 4 years of age) with clinical features similar to MPS type I except for differing facial appearances. Some patients develop neurological degeneration by the age of 6 but others have an attenuated form maintaining normal intellect . Cardiomyopathy and valvular heart disease are similar to that seen in MPS type I, but sudden death due to AV block is an additional feature [24, 32]. ERT prolongs longevity and life expectancy for non-neurological phenotypes is into adulthood, but the impact upon neurological phenotypes remains unknown.
MPS III (Sanfillipo syndrome)
MPS IVA (Morquio disease)
MPS IVA is a heterogeneous condition caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulphate sulfatase causing the build up of keratin sulfate. Skeletal dysplasia with short stature dominates this condition alongside restrictive cardiopulmonary disease secondary to fixed chest deformities and valvular heart disease. Death ensues normally by the age of 30 as no specific therapies currently exist.
MPS VI (Maroteau-Lamy disease)
MPS VI is an extremely rare condition caused by N-acetylgalactosamine-4-sulfatase deficiency. It is associated with cardiomyopathy and valvular disease, skeletal dysplasia, short stature, hepatosplenomegaly, corneal clouding and retinal disease. Treatments (ERT and BMT) stabilize cardiac involvement.
MPS VII (Sly disease)
MPS VII, due to β-glucuroidase deficiency, causes progressive valve disease but is extremely rare. It has, however, stimulated the development of many of the MPS therapies following its early purification.
Mucolipidoses (ML) are rare autosomal recessively inherited diseases caused by deficiency of UDP-N-acetylglucosamine-1-phosphotransferase, which prevents the intracellular uptake of lysosomal enzymes. ML type II (‘I-cell disease’) is similar to Hurler disease, but with severe, rapidly progressive neurological impairment, cardiomyopathy, valve disease and death within early childhood. ML III is slower in progression with survival into adulthood. Valvular involvement is common alongside joint stiffness, normal/low IQ, mild coarse facial features and carpel tunnel syndrome. Whilst there is no specific ERT for these conditions, regular surveillance for symptomatic valvular and other pathology is required.
Defects/deficiencies of degradative enzymes involved in glycoprotein breakdown results in the accumulation of oligosaccharides (glucose, galactose, mannose and fucose) within lysosomes, causing six extremely rare disorders that are frequently overlooked [α-mannosidosis, aspartylglucosaminuria, β-mannosidosis, fucosidosis, galactosialidosis, Schindler disease and sialidosis (ISSD)]. They present with classical lysosomal features [neurdogenerative disease, coarse facies, skeletal dysplasia, angiokeratoma, cardiomegaly in fucosidosis, cardiomyopathy and conduction defects (ISSD)].
Sphingolipids are intricate membrane-bound lipid complexes that form an integral part of cerebral membranes. Thus when deranged, the sphingolipidoses are often associated with relentless neurodegeneration. Two subgroups of sphingolipidoses exist; the neurodegenerative subgroup rarely characterised by cardiac involvement (including GMS2 ganlgiosidosis (Tay-Sachs and Sandhoff disease), metachromatic leucodystrophy and Krabbe disease), and a second group characterised by β-galactosidase deficiency in which cardiac involvement (dilated or hypertrophic cardiomyopathy) is common (GM1 gangliosidosis) (see Tab. 1). Somatic symptoms often develop early in life with hypotonia from birth, neurodevelopmental deterioration, coarse facial features, dysostosis multiplex and often death by 2 years. No curative treatment is available. Juvenile and adults forms of GM1 gangliosidosis are recognised and characterised by neurological deterioration.
Gaucher’s disease is the most common lysosomal storage disease and is caused by glucocerebrosidase deficiency. It normally presents with haematopoeitic system and/or neurological (bulbar) involvement. Cardiac involvement is rare, but cardiomyopathy, valvular calcification and pulmonary hypertension are reported .
Anderson-Fabry disease (AFD, ‘Fabry disease’)
AFD is the second commonest X-linked lysosomal storage disorder (after Gaucher’s disease) with a population prevalence of 1 in 40,000–117,000 live births. It commonly affects hemizygous males whom often experience severe symptoms as opposed to heterozygous female carriers that tend to be less severely affected. It is caused by a mutation in the gene for α-galactosidase A located in Xq22 region of the X chromosome. More than 400 mutations have been described, the majority missense, often ‘private’ point mutations, with N215S, R112H, R301Q and G328R mutations most frequently being detected in ‘cardiac’ AFD. The enzyme deficiency results in an inability to catabolise glycosphingolipids causing progressive accumulation of globotriasylceramide throughout the body causing multi-system disease and an array of cardiac and extra-cardiac manifestations mainly neuropathy (and acroparesthesia), hypertrophic cardiomyopathy, renal and cerebrovascular disease with characteristic angiokeratoma in the bathing trunk region (Tab. 4, [36, 37]). Infrequently, cardiac manifestations are the sole feature; these include concentric left ventricular hypertrophy (LVH), diastolic function, valvular and conduction disease. Diagnosis in men relies on the detection of low or absent levels of α-galactosidase A activity (0–4%) in serum, leucocytes. In women, X- α-galactosidase A activity may be normal. Gene sequencing to identify the causative gene mutation is therefore used for confirmatory analysis. Cardiac management comprises symptomatic control with anti-anginal therapies, and treatment of heart failure and arrhythmia. ERT with recombinant enzyme improves cardiac function, LVH, milder forms of renal disease and possibly cerebrovascular complications [5, 38].
Cardiac and extracardiac features of Anderson-Fabry disease
Left ventricular hypertrophy ± septal hypertrophy in 5–15% of cases
Valvular heart disease
Vascular endothelium abnormalities
- Angiokeratoma (40%) (swimming trunk distribution)
- Hypohidrosis (50% men, 25% women)
- Coarse facial features
- Acroparaethsiae (chronic pain in hands and feet)
- Fabry’s crisis (severe pain precipitated by stress, exertion or illness)
- Transient ischaemic attack or stroke
- Substantial hearing loss (16–54% men)
- Tinnitus, vertigo, headache
- End-stage renal failure
- Nausea and vomiting
- Abdominal pain and diarrhoea
- Airways obstruction
- Decreased diffusion capacity
- Corneal opacities (cornea verticellata)
- Opacities posterior lens
- Retinal vascular tortuosity
- Occlusion retinal vessel infarction (rare)
- Decreased bone mineral density
- Reduced saliva, reduced tear production
Congenital disorders of glycosylation
Glycosylation is central to effective biological and cellular functions (signalling, protein targeting and folding). Congenital disorders of glycosylation (CDG; types I and II), comprising N- and O-glycosylation pathway defects, lead to decreased bio-cellular activities and degradation and severe multisystem diseases . Cardiac involvement may present with dilated or hypertrophic cardiomyopathy and pericardial effusion. Cardiomyopathy is associated with considerable risk of sudden death. Other multisystemic features include hypotonia, abnormal fat distribution, seizures, psychomotor retardation, liver dysfunction, endocrine defects and haematological complications (thrombosis and bleeding risks). Diagnosis and treatment involve enzyme assay or mutation analysis and cardiac monitoring for prevention of sudden death.
Cholesterol biosynthesis defects (CBD)
Glycogen storage disorders (GSDs)
Glycogen, the main storage form of carbohydrate, provides a steady supply of energy during fasting. Defects in glycogen storage, synthesis and breakdown make up more than 14 types of metabolic GSDs that mainly affect the liver and muscle with an overall prevalence of between 1: 20,000 and 43,000. GSDs confined to the liver are associated with hepatomegaly and hypoglycaemia, whereas those that affect muscle glycogen metabolism present with muscle cramps, weakness, exercise intolerance and cardiomyopathy . Those directly affecting the heart with manifestations such as left ventricular hypertrophy, restrictive cardiomyopathy, dilated cardiomyopathy and conduction disease, are GSD types II, III, IV and VI. GSD IX (phosphorylase kinase deficiency) and glycogen synthase deficiency (GSD 0) are rarely associated with HCM, reduced exercise capacity and sudden death but are successfully treated with β-blockers [41, 42].
Pompe disease (GSD type II)
Pompe disease (also known as GSD type II, acid α-glucosidase deficiency or acid maltase deficiency) is inherited in an autosomal recessive manner and caused by mutations in the gene GAA on chromosome 17 . It gives rise to a deficiency of acid α-glucosidase, which normally degrades glycogen to glucose, thus causing accumulation of glycogen within the lysosome. Pompe disease has two forms, infantile and adult onset. The infantile form (prevalence 1 in 100,000, with acid maltase levels < 1% or normal) usually presents within 6 weeks of age with hypotonia, failure to thrive and frequent cardiac involvement comprising a short PR interval, QT dispersion and extreme left ventricular hypertrophy on the ECG, with severe concentric biventricular hypertrophy, small left ventricular cavity, outflow tract obstruction and diastolic dysfunction on echocardiography. Creatine kinase levels are markedly elevated and vacuolated lymphoocytes in blood films are seen. The diagnosis is confirmed by enzyme assay of white cells, skin fibroblasts, or muscle fibres . Untreated the prognosis is particularly poor, being generally fatal within the first year of life due to cardiorespiratory failure. The juvenile or adult form is milder in severity perhaps due to residual acid enzyme activity and presents later in life with limb girdle pattern of myopathy and few cardiac features, such as conduction abnormalities (Wolff-Parkinson-White syndrome (WPW)). Early diagnosis by neonatal screening and treatment with ERT improves cardiomyopathy, ECG abnormalities and prognosis [45, 46].
Danon disease (LAMP-2, GSD IIb)
Danon disease is an extremely rare X-linked GSD caused by mutations in the lysosomal-associated membrane protein-2 (LAMP-2) leading to glycogen accumulation in lysosomes with normal maltase activity [6, 47]. Clinical features include muscle weakness, dilated cardiomyopathy and learning disability . The diagnosis is suggested by normal acid maltase levels, vacuolation and glycogen deposition on muscle. There remains no specific treatment but some patients with progressive heart failure require cardiac transplantation.
GSD type III
GSD type III, also known as Cori disease, Forbes disease or glycogen brancher deficiency, is caused by autosomal recessively inherited mutations in the AGL gene on chromosome 1 which lead to deficiency in glycogen debrancher enzyme (amylo-1,6-glucosidase) activity and an excessive intracellular accumulation of partially broken down glycogen molecules (limit dextrin). It accounts for 24% of all GSDs with a prevalence of approximately 1:83,000 in Europe. Eighty percent of patients have GSD IIIa which has liver and muscle involvement and a generalised debrancher deficiency affecting the liver, muscle, fibroblasts, erythrocytes and cardiac muscle (notably causing hypertrophy) [49, 50]. Those with GSD IIIb (20% of patients) have debrancher deficiency confined to the liver. Liver fibrosis in GSD IIIa is universal and studies have strongly suggested the presence of myocardial fibrosis . Variations in tissue expression lead to phenotypic heterogeneity, which includes hepatomegaly and liver symptoms which tend to resolve after puberty. Hypoglycaemia, small stature, dyslipidaemia, progressive skeletal myopathy and slight mental retardation are seen together with cardiac features resembling hypertrophic or dilated cardiomyopathy, arrhythmias, conduction disease, heart failure and sudden death. Diagnosis relies upon enzyme assay or biopsy demonstration of enzyme deficiency. Treatment comprises maintaining normoglycaemia through dietary measures.
GSD type IV
GSD type IV (brancher deficiency or amylopectinosis) accounts for only 0.3% of GSDs and is highly heterogeneous. It is due to an autosomal recessively inherited chromosomal abnormality resulting in deficiency of amylo-1,4–1,6-transglucosidase and accumulation of amylopectin (abnormal glycogen) within liver and muscle resulting in cirrhosis and hepatic failure in childhood. Cardiac involvement usually manifests as cardiomyopathy and congestive cardiac failure and has been successfully treated with transplantation [52, 53].
PRKAG 2 disease (AMP kinase)
The diagnostic clues for PRKAG 2 disease, caused by mutations in the γ-subunit of the AMP-activated protein kinase, are massive left ventricular hypertrophy > 30 mm (sometimes biventricular pseudohypertrophy), the presence of high-grade conduction system disease and ventricular pre-excitation . Post-exertional chest and skeletal muscle pains and myopathy are commonly seen. Thirty-eight percent require pacing for progressive conduction disease by the age of 40 years and syncope and sudden death is reported .
Dramatic advances in genomic medicine are driving change in the diagnosis and management of rare genetic disorders. Genetic and non-genetic metabolic cardiomyopathies represent a heterogeneous group of rare diseases that are recognised increasingly in everyday paediatric and adult cardiology practice. A high index of suspicion coupled with early referral for specialist investigation facilitates diagnosis and the initiation of therapy for patients and potentially helps to prevent disease in their relatives. Further research into the natural history and progression of disease in these disorders will enhance diagnostic strategies and lead to the development of disease-specific treatments that will improve quality of life and prognosis.
Conflicts of interest
On behalf of all authors, the corresponding author states that there are no conflicts of interest.