Causes of Ventricular Dysfunction
■ INTRODUCTION
■ CARDIOMYOPATHY PHENOTYPES
Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
Restrictive Cardiomyopathy
Noncompaction of the Left Ventricle
■ ETIOLOGY OF CARDIOMYOPATHY
Genetic Syndromes
Inborn Errors of Metabolism
Infants of Diabetic Mothers
■ OTHER CAUSES OF VENTRICULAR DYSFUNCTION
Myocarditis
Perinatal Asphyxia
Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery
Systemic Hypertension
Reversible Metabolic and Electrolyte
Disturbances
Arrhythmias
Cor Pulmonale
■ CLINICAL PRESENTATION AND DIAGNOSTIC APPROACH
■ SUGGESTED READINGS
■ INTRODUCTION
The term “cardiomyopathy” is used to indicate myocardial dysfunction in the absence of an obstructive lesion or sustained hypertension. Cardiomyopathy can occur either in isolation or as a manifestation of a multisystem disease. Neonates who have an unrecognized cardiomyopathy may come to medical attention with a life-threatening decompensation associated with an otherwise minor illness, such as a viral upper respiratory infection. Alternatively, evidence of cardiomyopathy may be noted on an echocardiogram performed for evaluation of an unrelated problem. Other conditions cause ventricular dysfunction but may not have a long-term impact on cardiac muscle function, such as myocarditis or anomalous origin of the left coronary artery from the pulmonary artery, and will be discussed at the end of the chapter.
Mutations in multiple genes encoding proteins of the sarcomere, cytoskeleton, sarcoplasmic reticulum, nucleus, and cell membrane of the myocardial cell are now known to cause cardiomyopathy (Figure 9-1). More information regarding the structure and function of these proteins is presented in Chapter 2.
Classification of cardiomyopathies is challenging and has evolved as new information has become available regarding causation. Classification based on phenotype (ventricular morphology and physiology) is practical because these characteristics are typically defined at the initial evaluation of the patient (Table 9-1). Phenotypic groups can be subdivided based on etiology (Tables 9-2, 9-3, 9-4). Unfortunately, specific causes of cardiomyopathy can present with different phenotypes in different patients or be associated with different phenotypes during the evolution of the disease in a specific patient, making classification by phenotype imperfect.
FIGURE 9-1. Myocyte cytoarchitecture. Various forms of cardiomyopathy may result from mutations in genes encoding multiple proteins within the cardiac myocyte. Different mutations in the same gene may cause different forms of cardiomyopathy. Abbreviations: EYA4, eyes absent homolog 4; MLP, cardiac LIM domain protein; MyBPc, myosin binding protein C; T-cap, telethonin; ZASP, muscle LIM-binding protein 3 (cypher).
The clinician should first perform a careful assessment of the disease phenotype (cardiac and extracardiac) and then proceed in a logical manner to elucidate the etiology. Genetic defects and abnormal proteins have been identified for many forms of cardiomyopathy that were thought previously to be idiopathic. Identification of a specific cause will facilitate genetic counseling and may lead to specific therapy and possibly to prevention in family members. This chapter reviews the varied clinical presentations and many associated disorders and provides a rational approach to the array of available diagnostic tests and biochemical assays. Many forms of cardiomyopathy do not present in the neonatal period; as such, they are included for informational purposes in tables but are not discussed further. The reader is referred to several excellent recent reviews listed in “Suggested Readings.”
■ CARDIOMYOPATHY PHENOTYPES
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is characterized by a hypertrophic, nondilated left ventricle in the absence of systemic disease (eg, hypertension) or structural abnormalities (eg, aortic stenosis) that can result in left ventricular hypertrophy. The hypertrophy may be asymmetric, affecting the interventricular septum more than the left ventricular free wall. In infants, the right ventricle may also be involved.
This phenotype may be present in many conditions discussed in the following text, including idiopathic, familial hypertrophic cardiomyopathy, inborn errors of metabolism (usually involving multiple organs), genetic and other malformation syndromes, neuromuscular disease, and infants of diabetic mothers (Table 9-2). The age of presentation and clinical course are highly dependent on etiology.
The Pediatric Cardiomyopathy Registry has published information regarding epidemiology and outcomes in groups of children with the phenotype of hypertrophic cardiomyopathy. Of the 855 patients from North America, 328 (38%) presented before 1 year of age. Of these, 15% had an inborn error of metabolism, 15% had a malformation syndrome, 1% had neuromuscular disease, and 69% were unclassified or idiopathic. Children with an inborn error of metabolism or malformation syndrome (mostly Noonan syndrome) presenting with hypertrophic cardiomyopathy before 1 year of age have a particularly poor prognosis, with a 5-year survival after diagnosis of 26% and 66%, respectively. The 1-year survival from the time of diagnosis in patients in the idiopathic group who were diagnosed at younger than 1 year of age was 86% compared with 99% in those diagnosed older than 1 year of age. However, no difference in annual mortality was observed between these age-groups for those patients who survived beyond 1 year of age. Similar outcomes were reported in a registry of Australian patients. Other presenting findings associated with a worse prognosis were lower weight Z score and the presence of congestive heart failure.
In typical familial hypertrophic cardiomyopathy, histologic examination discloses cellular and myofibrillar disarray, interstitial fibrosis, and coronary arterial abnormalities. The genetic defect is heterogeneous; hundreds of different mutations, mostly missense, are described in more than 23 genes involving myofilament and Z-disc proteins. A smaller number have been substantiated through cosegregation and linkage analysis studies (Table 9-2 and Figure 9-1). Defects in myofilament (sarcomeric) proteins show an autosomal dominant pattern of inheritance and account for about 60% of cases. Mutations in β-myosin heavy chain (20% to 30%) and myosin-binding protein C (30% to 40%) are most common. Most disease-causing mutations are unique to a single family. Phenotypic expression within families is highly variable and is influenced by modifier genes and/ or environmental factors (epigenetic modifications).
The precise mechanism of how a gene defect leads to the anatomic and functional abnormalities observed in these patients is poorly defined and likely varies among the different defects. Possibilities include abnormal calcium cycling, increased or decreased sarcomeric calcium sensitivity, altered biomechanical stress sensing, and impaired ventricular energy homeostasis.
Clinical genetic testing is currently available for 9 to 18 genes, depending on the laboratory, and is useful primarily for diagnosis rather than for predicting outcome or for guiding therapy. Of those patients who undergo testing, a mutation is identified in 40% to 60% of sporadic and familial cases when testing is performed for these genes (http://www.genetests.org). Genetic testing may not be covered by an individual patient’s health insurance plan. Of the 855 patients with hypertrophic cardiomyopathy in the Pediatric Cardiomyopathy Registry, 74% had no associated illness, no family history, and no defined genetic defect. Given the lack of reproducible phenotype-genotype correlation, the results of genetic testing may not impact patient management. In contrast, genotyping of children of affected individuals may be helpful in determining who needs repeated screening for disease.
Left ventricular hypertrophy associated with familial hypertrophic cardiomyopathy is often not present until adulthood. However, if hypertrophy is present in infancy, this may be severe enough to produce obstruction of right or left ventricular outflow. These patients have a high probability of mortality in the first year of life, usually because of congestive heart failure. The usual medical therapies for congestive heart failure are contraindicated in these patients. Positive inotropic agents and diuretics may increase outflow tract obstruction and symptoms. Administration of β-blocking agents is the most widely accepted therapy. Oral administration of calcium channel blockers, such as verapamil and nifedipine, may also be beneficial. Given the poor prognosis for many of these infants, heart transplantation should be considered early in the course.
Dilated Cardiomyopathy
Dilated cardiomyopathy is characterized by dilation of the ventricles and decreased ventricular systolic function in the absence of abnormal loading conditions (eg, valve disease) or other conditions that can cause global systolic dysfunction, such as severe anemia, hypoglycemia, or acidosis. This is the most common phenotype of cardiomyopathy and is also the most common reason for cardiac transplantation in children. According to data from the Pediatric Cardiomyopathy Registry, the incidence of dilated cardiomyopathy is higher in infants younger than 1 year of age than in older children (4.40 vs. 0.34 per 100,000 per year; P < .001).
A number of conditions are known to cause dilated cardiomyopathy (Table 9-3). The etiology for 591 children younger than 1 year of age in the Pediatric Cardiomyopathy Registry was unknown (idiopathic) in 78%, myocarditis in 11%, inborn error of metabolism in 5%, familial in 4%, malformation syndrome in 1.7%, and neuromuscular disease in <0.1%.
Hereditary factors have been recognized recently to play a role in the etiology of idiopathic dilated cardiomyopathy in an increasing percentage of patients. In newly diagnosed adult patients, dilated cardiomyopathy can be identified in up to 20% to 35% of screened first-degree relatives, and these patients are then classified as having familial dilated cardiomyopathy. The pattern of inheritance is autosomal dominant in about 90% of adult cases. Penetrance and expression are frequently incomplete and age dependent. Affected family members with certain mutations may show different phenotypic patterns of cardiomyopathy. In some studies, at least 80% of mutation carriers under the age of 20 years are clinically well. Familial disease is much less common in young infants, but screening of all first-degree relatives by electrocardiography and echocardiography is recommended when the diagnosis is made.
Familial dilated cardiomyopathy is genetically heterogeneous (at least 50 genes) and is caused by mutations in genes encoding proteins of the nucleus, sarcoplasmic reticulum, sarcolemma, mitochondria, and the cytoskeleton (Table 9-3 and Figure 9-1). In general, these mutations result in diminished force generation or alterations in mechanotransduction or myocyte signaling. Mutations in the large sarcomeric protein titin account for about 25% of adult cases, but none of the other known mutations account for more than a few percent of cases. Clinical genetic testing is available for a variety of genes and will identify a pathologic mutation in 30% to 40% of patients. Most of the identified mutations are unique to the patient or family. Screening of family members is made difficult by the fact that genetic variants thought to be disease causing are often identified in the absence of clinical disease.
Of particular interest is the fact that different mutations in the same genes for sarcomeric proteins that are well known to be associated with hypertrophic cardiomyopathy are also associated with dilated cardiomyopathy. This suggests that the precise location of the mutation on the gene and the resulting consequences on protein structure and function play an important role in determining cardiomyopathy phenotype. The myofiber disarray seen in hypertrophic cardiomyopathy is absent in dilated cardiomyopathy caused by mutations in the same sarcomeric proteins. Interestingly, such mutations tend to increase calcium sensitivity of the cardiac myofilaments in hypertrophic cardiomyopathy, yet they tend to decrease calcium sensitivity in dilated cardiomyopathy. Further studies are needed to understand the molecular mechanisms by which these mutations result in alterations in calcium sensitivity and the pathways that lead to a dilated or hypertrophic phenotype.
Young infants with dilated cardiomyopathy typically present with signs and symptoms of congestive heart failure that should be treated using standard therapy (see Chapter 11). Age <1 year at diagnosis (especially <4 weeks of age), a family history of cardiomyopathy, and the severity of ventricular dysfunction are all independently associated with a higher risk of transplantation or death. Overall, the 5-year transplantation-free survival of children with dilated cardiomyopathy is about 50%. The need for transplantation is highest in children who have a familial form of dilated cardiomyopathy.
Restrictive Cardiomyopathy
Restrictive cardiomyopathy is the rarest form of cardiomyopathy in the developed world, representing 2% to 3% of cardiomyopathies diagnosed in patients less than 18 years of age. Ventricular volume is normal or reduced, whereas atrial volume is usually markedly increased in the absence of congenital valve defects. Ventricular filling is impaired, and systolic function is normal or only minimally diminished. The left ventricular wall thickness is normal, but the restrictive phenotype can overlap with hypertrophic cardiomyopathy if both ventricular hypertrophy and a restrictive physiology are present.
Multiple conditions are associated with the restrictive phenotype (Table 9-4). Worldwide, the most common etiology of restrictive cardiomyopathy is a condition known as endomyocardial fibrosis, which is estimated to affect 10 million people, occurring most commonly in children and adolescents in tropical and subtropical regions, especially in Africa. The etiology is poorly defined, and genetic, autoimmune, dietary, and environmental factors may play a role. Fibrosis of the endocardium involves primarily the left ventricular apex, the mitral valve apparatus, and the right ventricular apex. Clinical manifestations vary with the site of involvement.
In the developed world, a specific etiology for restrictive cardiomyopathy cannot be identified in most cases. As described in the section above for both hypertrophic and dilated forms of cardiomyopathy, multiple mutations in both sarcomeric and nonsarcomeric proteins are associated with the phenotype of restrictive cardiomyopathy, and familial forms occur (Table 9-4). Additionally, some of the mutations are noted to cause both hypertrophic and dilated phenotypes in some family members.
Patients often present with respiratory complaints that are most prominent at times of exertion. The overall prognosis is poor and sudden cardiac death is common even in patients with only mild symptoms. Cardiac transplantation provides definitive therapy.
Noncompaction of the Left Ventricle
Noncompaction of the left ventricle is characterized by deep trabeculae with deep intertrabecular recesses involving most commonly the left ventricular apex and lateral wall, progressive impairment of ventricular function, and early death. Isolated forms may be inherited and are associated with mutations in a number of genes, many of which are known also to cause cardiomyopathy with hypertrophic or dilated phenotypes. This morphologic pattern is seen sporadically in association with a large number of disorders, including mitochondrial myopathies, Barth syndrome, neuromuscular disease, and various forms of congenital heart disease. In newborn infants, noncompaction is thought to be caused by a developmental arrest of unclear etiology resulting in insufficient compaction of the noncompacted myocardium during embryogenesis. The exact cause of the developmental arrest is not clear and is likely caused by different mechanisms in patients with different genetic disorders. In children, noncompaction cardiomyopathy is variably associated with ventricular hypertrophy, ventricular dilation, decreased systolic function, and arrhythmias. The risk of death or transplantation is highest in patients with ventricular dysfunction or arrhythmias and in those presenting in infancy.
■ ETIOLOGY OF CARDIOMYOPATHY
A wide variety of disease entities are associated with cardiomyopathy. Many cause dilated cardiomyopathy, but others lead to hypertrophic, noncompaction, or restrictive phenotypes. Below is a presentation of some of the many causes.
Genetic Syndromes
As noted above, many genetic mutations of various components of the myocardial cell are specifically associated with cardiomyopathy, and the phenotype and expression can vary within the family. In addition to these myocyte-based genetic causes of familial cardiomyopathy, certain genetic syndromes are associated with cardiomyopathy unrelated to myocardial cell mutations. Some are associated with known inborn errors of metabolism (eg, Pompe disease and Barth syndrome) and will be discussed below. Malformation syndromes, such as Noonan syndrome, have a known genetic defect, but the etiology of the cardiomyopathy is unknown; these conditions are discussed in Chapter 15.
Inborn Errors of Metabolism
Mitochondrial Disease
Disorders of fatty acid oxidation (Table 9-5) These disorders, although relatively rare, can cause catastrophic complications, including sudden death. Arriving at a correct diagnosis is imperative because the prognosis is often favorable once appropriate treatment is provided. A working knowledge of these disorders is essential for anyone caring for young infants because a high index of suspicion is often necessary to recognize patients who have these defects.
Pathophysiology Fats are an important source of fuel in the body and are the only substrate for oxidation during fasting or increased energy demand after depletion of hepatic glycogen. Decreasing blood glucose concentration causes lipid mobilization from fat stores. Stored fat is broken down into short-, medium-, long-, and very long chain fatty acids. Although skeletal and cardiac muscles metabolize fatty acids to generate ATP, the brain cannot metabolize fatty acids directly; ketone bodies synthesized by the liver are used for cerebral energy production.
The heart is critically dependent on adequate energy generation. The fetal heart relies on anaerobic glycolysis and lactate as energy sources. Among the many adjustments necessary during the transition to extrauterine existence is the use of fat as the main energy substrate for the heart. Up to 80% of the energy for cardiac function is produced by fatty acid oxidation in the mature heart.
Fatty acid oxidation, the process by which ATP is generated, occurs only within the mitochondria (Figure 9-2). A specific transporter facilitates movement of long- and very long chain fatty acids across the cell membrane into the cytosol. Long- and very long chain fatty acids are then activated by binding to coenzyme A (CoA) to form fatty acyl-CoA. This complex can then cross the outer mitochondrial membrane. At this point, the enzyme carnitine palmitoyl transferase I (CPTI) catalyzes transfer of the fatty acid from CoA to carnitine, forming acylcarnitine. The activity of this enzyme in the liver increases during fasting, which preferentially directs fatty acids to the liver. Acylcarnitine is then transferred across the inner mitochondrial membrane by an enzyme called carnitine acyl translocase. Once inside the mitochondria, the enzyme CPTII transfers the fatty acid from carnitine back to CoA. Short- and medium-chain fatty acids move across the plasma membrane (sarcolemma) and the outer and inner mitochondrial membranes without the aid of the carnitine-dependent transporter. Within the mitochondria, all fatty acids undergo β-oxidation, forming acetyl CoA (Figure 9-2). Acetyl CoA is metabolized by the tricarboxylic acid (Krebs) cycle, producing electrons that pass through the respiratory chain and generating ATP through oxidative phosphorylation (see following text). In fasting states, when glucose is relatively unavailable, acetyl CoA is metabolized to ketone bodies in the liver. Ketone bodies then circulate in the blood, where they are used preferentially by the brain for energy generation during fasting states.
FIGURE 9-2. Oxidation of fatty acids. The trifunctional protein is composed of the enoyl-CoA hydratase, the long-chain 3-hydroxyacyl dehydrogenase (LCHAD) enzymes, and the 3-ketoacyl-CoA thiolase enzymes. Abbreviations: CPT, carnitine palmitoyl transferase; LCAD, long-chain acyl-CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; TCA, tricarboxylic acid.
Carnitine plays a pivotal role in fatty acid oxidation. Carnitine can be obtained from the diet but is also synthesized from lysine and methionine in the liver, kidney, and brain but not in muscle. Carnitine is actively transported across the cell membrane by a carrier-mediated transport process. The carnitine concentration within the myocardial cell is 40 to 100 times above the concentration in plasma.
Disorders of fatty acid oxidation include abnormalities in carnitine-dependent transport or in mitochondrial β-oxidation of fatty acids. Defects may occur in any of the enzymes or transport proteins involved in fatty acid oxidation. Accumulation of substrates proximal to the specific enzyme defect explains many clinical findings in these patients:
• Hypoketotic hypoglycemia—Partial oxidation of fatty acids by the liver produces ketones. Patients who have these βdefects cannot produce ketones, and therefore glucose becomes the only available fuel. During times of stress, for example, fasting, glycogen, and glucose stores become depleted, and hypoglycemia develops.
• Encephalopathy or Reye-like syndrome—The brain is completely dependent on glucose and ketone bodies for energy generation. Neurological dysfunction results from failure to deliver these substrates to the brain during fasting.
• Hepatic dysfunction and hyperammonemia—Hepatic dysfunction results from the toxicity of accumulating metabolites and ammonia concentrations increase because acetyl CoA is required for hepatic synthesis of urea.
• Organ steatosis—Free fatty acids, which are released during fasting but cannot be metabolized, are often stored as triglycerides in various tissues. This may result in a hypertrophic or dilated cardiomyopathy, fatty liver, and/or lipid storage myopathy.
• Abnormal urine organic acids—Fatty acids within the mitochondria that cannot undergo β-oxidation can be diverted to the endoplasmic reticulum for omega oxidation, which generates dicarboxylic acids and 3-hydroxydicarboxylic acids. These are excreted in the urine in an amount equal to or greater than the amount of ketones when the patient is fasting. Abnormal urine organic acids are generally not seen in patients who have defects involving the transport of fatty acids into the mitochondria.
• Decreased plasma carnitine concentration—Carnitine concentrations are decreased in patients with many of these disorders, but this is a primary defect only in patients who have carnitine transporter deficiency. Carnitine concentrations are <5% of normal in these patients. In most other patients, carnitine deficiency (10% to 50% of normal) is secondary. Free fatty acids that accumulate because of the metabolic block are toxic, so excess fatty acids usually are conjugated to carnitine and glycine. These acylcarnitines compete with free carnitine during reabsorption in the renal tubules. Free carnitine is excreted preferentially because the affinity of the renal carnitine transporter is higher for longer chain-length acylcarnitines. Thus decreased carnitine concentrations are secondary, and the ratio of acylcarnitines to total carnitine usually is increased.
• Cardiovascular dysfunction—A large percentage of symptomatic patients show signs of cardiomyopathies, cardiogenic shock, arrhythmias, and/or sudden death; these conditions are more common in patients who present at a younger age. The exact mechanisms by which these defects lead to the development of cardiovascular manifestations are unknown. As discussed earlier, excess fatty acids may be stored as triglycerides in the cytosol of the myocardial cells. In addition, an inadequate supply of ATP may result in contractile dysfunction and subsequent development of hypertrophic cardiomyopathy. Finally, accumulation of intermediary metabolites, such as long-chain acylcarnitines, may cause myocardial injury and rhythm disturbances.
Clinical features All disorders of fatty acid oxidation are inherited in an autosomal-recessive manner. Considerable clinical heterogeneity exists within families. The estimated incidence of these defects is 1 in 6000, making these conditions among the more common of the inherited metabolic diseases.
These disorders usually become apparent during the first 2 to 3 years of life. The heart, skeletal muscle, and liver in particular are dependent on mitochondrial oxidation of fatty acids during periods of fasting. Clinical features of these disorders therefore include hypoketotic hypoglycemia, encephalopathy, or Reye-like syndrome associated with increased transaminase concentrations and possibly hyperammonemia, cardiogenic shock, cardiac arrhythmias, and sudden death, particularly during fasting stress. Cardiomyopathy, either dilated or hypertrophic, is present in nearly 50% of patients. Some infants show both ventricular hypertrophy and decreased systolic function. Skeletal lipid-storage myopathy is also seen. The pattern of symptoms in patients who have any specific defect, clinical course, and severity is often unpredictable. Symptoms often appear precipitously. Any situation that increases reliance on fatty acids for generation of ATP may precipitate heart failure or ventricular arrhythmias. In older infants and toddlers, an episode of infection, such as gastroenteritis or pneumonia, may precipitate acute decompensation. In other patients, cardiomyopathy and associated myocardial dysfunction may develop over time. Because these conditions are inherited as autosomal-recessive traits, a family history of sudden death in siblings is relatively common.
An important proportion of patients who have these disorders experience hypoglycemia, hepatic failure, and severe metabolic acidosis within the first 48 to 72 hours after birth. Defects in fatty acid oxidation are estimated to cause about 5% of all cases of sudden infant death. A newborn infant who is breast-fed may be vulnerable until the mother’s milk supply is plentiful. Breast-fed infants may receive little nutrition during the first days of life, and this may result in significant and undue fasting stress, precipitating the acute and sometimes fatal presentation.
Specific defects (Table 9-5) More than 20 different specific defects have been described, and those associated with cardiac pathology and/or sudden death in young infants are described as follows.
DEFECTS IN CARNITINE-DEPENDENT TRANSPORT LONG-
AND VERY LONG CHAIN FATTY ACIDS
Systemic primary carnitine deficiency (plasma MEMBRANE CARNITINE TRANSPORTER DEFICIENCY OR carnitine uptake defect) Impaired renal absorption of carnitine is present, and plasma carnitine concentrations are 1% to 5% of normal. About 50% of patients show symptoms in infancy. This defect is often associated with cardiomyopathy, usually dilated, and at times the clinical picture resembles endocardial fibroelastosis. Skeletal muscle weakness may also be present. Acute hepatic encephalopathy superimposed on the cardiomyopathy has been associated with sudden death in infants. Serum carnitine may be normal in the early neonatal period because carnitine is transferred across the placenta. These patients respond very well to carnitine administration and may have complete reversal of cardiomyopathy.
Carnitine-acylcarnitine translocase deficiency This enzyme shuttles acylcarnitines and carnitines between the cytosol and the intramitochondrial matrix space. Most of these patients present in the newborn period with hepatic dysfunction, hypotonia, arrhythmias, and cardiomyopathy, often resulting in sudden death. This is a rare condition with a fairly high mortality. Administration of medium-chain triglycerides, which do not require carnitine for transport into the mitochondria matrix, may be beneficial. The efficacy of carnitine therapy, which is often recommended because of low serum carnitine concentration, is not proven.
Infantile carnitine palmitoyltransferase II (CPTII) deficiency Infants who have <20% of normal enzyme activity present early in life with hypoketotic hypoglycemia, hepatic dysfunction, and cardiovascular collapse associated with hypertrophic cardiomyopathy, often with decreased systolic function and arrhythmias. Life expectancy is very short. Extensive fatty infiltration of the heart, liver, and kidneys is seen at autopsy. These infants usually often have null mutations that result in a complete lack of enzyme activity.
Defects in fatty acid b-oxidation These patients often develop a Reye-like syndrome with associated hyperammonemia, cardiomyopathy, arrhythmias, and sudden death. Serum and urine concentrations of dicarboxylic acids usually are increased.
Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency The majority of patients affected in infancy have cardiac disease. The specific gene defect is heterogeneous and results in variable loss of enzyme activity that is correlated with severity of disease. Patients with markedly decreased enzyme activity present in the newborn period with typical signs and symptoms, and most die within a few months. The cardiomyopathy can be dilated or hypertrophic and may be associated with pericardial effusion and arrhythmias. Long-term survival has been reported in some infants in whom the diet is strictly controlled.
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency This is one of the most common of the fatty acid oxidation disorders, especially in Caucasians from northern Europe, in whom the predicted incidence (1:6500 to 1:17000) is similar to that of phenylketonuria. This defect is associated with sudden death. Patients do not usually present with symptoms until 3 months of age, but neonatal presentation in association with poor feeding after birth is described. Cardiomyopathy and arrhythmias are less common. Fatty infiltration of the myocardium is seen at autopsy. The prognosis is good with appropriate therapy once the diagnosis is established, especially if the condition is detected by newborn screening before the onset of symptoms.
Trifunctional protein deficiency Trifunctional protein is a multienzyme complex composed of four a units containing the enoyl-CoA hydratase and long-chain 3-hydroxyacyl dehydrogenase (LCHAD) enzymes and four P subunits containing the 3-ketoacyl-CoA thiolase enzyme. Mutations in any of the subunits can result in reduced activity of all three enzymes, though this is much less common than isolated LCHAD deficiency (see following discussion). In addition to typical symptoms, sudden infant death is common, as are cardiomyopathy and arrhythmias.
Isolated long-chain 3-hydroxyacyl dehydrogenase (LCHAD) deficiency This is one of the most severe fatty oxidation disorders. Affected infants are frequently growth retarded and delivered prematurely. They may present with profound liver failure. Cardiomyopathy, either hypertrophic or dilated, may result in severe myocardial dysfunction and death. Dietary management is effective. Isolated LCHAD deficiency in children (but not trifunctional protein deficiency) is associated with severe maternal liver disease during pregnancy with affected fetuses. Acute fatty liver of pregnancy also may occur during the third trimester and is characterized by anorexia, nausea, vomiting, abdominal pain, and jaundice. The HELLP syndrome (hypertension or hemolysis, elevated liver enzymes, and low platelets) is also reported in as many as 30% of the mothers of these infants. The mothers are obligate heterozygotes for the condition. It is speculated that abnormal fetal fatty acid metabolites may be toxic to the maternal liver. Offspring from pregnancies complicated by these conditions may benefit from screening for LCHAD deficiency.
Multiple acyl-CoA dehydrogenase deficiency ETF dehydrogenase and ETF are enzymes involved in electron transport between the acyl-CoA dehydrogenase and the respiratory chain (Figure 9-2). Multiple acyl- CoA dehydrogenase deficiency (also known as glutaric acidemia type 2) is the result of electron transfer flavoprotein (ETF) dehydrogenase deficiency or deficiency of a or β subunits of ETF. Patients who have these defects excrete large amounts of organic acids, including glutaric acid. Sudden death and arrhythmias have been reported. Neonatal onset disease may be associated with congenital anomalies, including dysmorphic facies, enlarged or cystic kidneys, rocker bottom feet, and abnormal external genitalia. Cardiomyopathy is common, and fatty infiltration of the myocardium is present. These infants, who are described as having an abnormal “sweaty-feet odor,” are often severely symptomatic within 24 to 48 hours of life and usually do not survive the neonatal period. Another group of patients also has neonatal onset disease but does not have congenital anomalies. These infants also present with acute decompensation during the first few days of life and often have severe cardiomyopathy. Most die in infancy. A third group of patients who have mild or late- onset disease may not present until several months of age or possibly until adulthood. Riboflavin administration in addition to the usual supportive measures may improve the clinical course for these patients.
Diagnosis Evaluation of multiple diagnostic criteria is necessary to diagnose a fatty acid oxidation disorder, and consultation with a metabolic specialist knowledgeable about these disorders is essential. A protocol for evaluating patients suspected of having these disorders must rely on multiple independent factors. For example, the absence of fatty infiltration of the liver does not completely exclude these disorders. Routine laboratory evaluation should include serum glucose, electrolytes, liver function tests, lactate, ammonia, and creatine kinase as well as urine ketones. If possible, a complete metabolic evaluation needs to be obtained, including plasma carnitine, acylcarnitine and free fatty acid concentrations, 3-hydroxy fatty acids, and urine organic acids and acylglycines. Metabolic abnormalities are often detected only during an acute crisis, and biochemical screening may be uninformative when the patient is well. Thus, obtaining blood and urine samples at the time of the acute illness is very important. Tandem mass spectrometry can determine the concentration of many different fatty acids and fatty acylcarnitine compounds in a dried blood spot. Thus, obtaining a portion of the blood spots collected for newborn screenings may be helpful for patients in whom no other samples are available. Metabolic flux studies by use of cultured skin fibroblasts and direct enzyme analysis may also be useful for some disorders. Direct analysis of DNA for mutations can be performed on blood cells, cultured fibroblasts, and liver or skeletal muscle.
A comprehensive autopsy must be done in all infants who die suddenly. Unfortunately, testing all infants who die suddenly for fatty acid oxidation disorders is not practical, but the following patients certainly merit further attention: (1) those who are thought to be normal and die unexpectedly after a period of fasting, (2) those who have a family history of sudden death in an infant or young child, and (3) those in whom the autopsy shows fatty infiltration of the liver or other organs. Frozen postmortem liver specimens and samples of bile and urine are saved from all autopsies. Skin biopsies are obtained for fibroblast culture.
Newborn screening for many of these disorders has been implemented in many states. The National Newborn Screening and Genetics Resource Center website (http:// genes-r-us.uthscsa.edu/resources/consumer/statemap. htm) provides information regarding specific conditions screened and genetics programs in each state. Identification of presymptomatic newborns may allow prevention of sudden clinical deterioration and death. Early identification of affected individuals by expanded newborn screening using tandem mass spectrometry should improve understanding of the natural history of these disorders. The specificity and sensitivity of early detection as well as long-term benefits remain to be defined.
Therapy Diet is the mainstay of therapy. In general, fat restriction and a high-carbohydrate diet are recommended. These patients must avoid prolonged fasting. Dextrose solutions must be administered intravenously when oral intake is poor. Infusion of glucose at 8 to 10 mg/kg/min (10% dextrose at 1.5 times greater than maintenance) will prevent mobilization of free fatty acids. Young infants should receive nighttime feedings. Older infants and children need to be fed frequent meals and a high-carbohydrate snack at bedtime and be fed early in the morning. Cornstarch, which provides a sustained release source of glucose, can be added to the diet after 8 months of age when pancreatic enzymes are sufficient for full absorption. Supplementation of the diet with medium-chain triglycerides is often recommended, but published studies demonstrating clinical benefit are limited. A minimum intake of long- and very long chain triglycerides is necessary to prevent essential fatty acid deficiency.
Carnitine therapy clearly is indicated for those patients who have a defect in the carnitine transport protein. Treated patients show a dramatic reversal of cardiomyopathy. For patients who have other defects, therapy with carnitine has not shown consistent benefit.
Because these disorders are autosomal recessive, prenatal or presymptomatic screening needs to be done in siblings. Improved awareness, understanding, and treatment of fatty acid defects by clinicians should improve outcomes for patients and families.
Disorders of mitochondrial oxidative phosphorylation (Table 9-6)
Respiratory chain diseases Although neuromuscular and ocular abnormalities usually dominate, all morphologic forms of cardiomyopathy may be present in patients with respiratory chain diseases, and some defects are also associated with conduction disturbances. The frequency of cardiac involvement is 17% to 40%. Patients who present with cardiac manifestations have a poorer outcome.
PATHOPHysiOLOGy The respiratory chain is a series of five enzyme complexes within the mitochondria that produce ATP by a metabolic process called oxidative phosphorylation (Figure 9-3). Complexes I and II collect electrons generated from the metabolism of fats, carbohydrates, and proteins. These electrons are transferred sequentially to coenzyme Q (ubiquinone), complex III, and complex IV. The energy generated by these electron transfers is used by complexes I, III, and IV to pump protons from the mitochondrial matrix into the intermembrane space located between the inner and outer mitochondrial membranes. Complex V (ATP synthetase) then uses this proton gradient to generate ATP from ADP and inorganic phosphate.
Mitochondria are unique organelles in that they have their own DNA (mtDNA) as well as nuclear DNA. Nuclear genes encode most of the mitochondrial proteins. Mutations in nuclear DNA show Mendelian inheritance and can cause abnormalities in the following:
• Respiratory chain subunits
• Ancillary proteins for respiratory chain subunits (abnormalities in proteins necessary to synthesize or direct assembly of respiratory chain subunits)
• Mitochondrial lipids
• Communication between the nuclear and mitochondrial genomes (abnormalities in control of mitochondrial replication, maintenance, and translation)
Mitochondrial DNA genes encode several essential subunits of the respiratory chain complexes and the transfer and ribosomal RNAs responsible for their translation. Mutations in mitochondrial DNA, which are usually point mutations or small or long DNA deletions, can therefore cause abnormalities in respiratory chain subunits or in genes responsible for protein synthesis.
The unique molecular and genetic properties of the mitochondrial genome account for some of the unusual features of mitochondrial disorders. The mitochondrial genome has a relatively high rate of spontaneous mutation, and each cell contains many mitochondrial DNA copies that are distributed randomly among daughter cells during cell division. Mutant and normal DNA often occur together within cells (heteroplasmy). A minimum “mutation load” (usually >80%) is necessary to cause mitochondrial dysfunction (threshold effect) and the resulting clinical disease. The proportion of mutant DNA per cell varies among tissues and may shift as the cells divide. This latter fact explains why clinical characteristics may change as the patient ages. Point mutations usually show a maternal rather than a Mendelian pattern of inheritance because the mtDNA in the fertilized egg is derived from the oocyte. The disease will be expressed in both sexes but will show only maternal transmission. Large-scale rearrangements (single deletions, duplications, or both) are usually sporadic.
FIGURE 9-3. The mitochondrial respiratory chain. I, NADH: ubiquinone oxidoreductase (NADH reductase); II, succinate: ubiquinone oxidoreductase (succinate dehydrogenase); Q, ubiquinone (coenzyme Q10); III, ubiquinol: ferrocytochrome c oxidoreductase (ubiquinol-cytochrome c reductase); IV, ferrocy- tochrome c: oxygen oxidoreductase (cytochrome c oxidase); V, ATP synthetase. NAD+ and FAD are necessary for fatty acid β-oxidation.
The precise mechanism for cardiomyopathy in these disorders is not defined. The rarity of these disorders, the lack of a reliable animal model, and poor genotype-phenotype correlation complicate investigation of pathophysiology.
Clinical features Disorders of oxidative phosphorylation may affect nearly every organ in the body because ATP is vital to cell function. Atypical clinical presentations with an unexplained association of symptoms and involvement of seemingly unrelated organ systems should prompt consideration of oxidative phosphorylation disorders. Brain, heart, and skeletal muscle are typically involved because of their relatively high energy demands. Severely affected infants present immediately after delivery or in the first few days of life.
Many neonates with respiratory chain disease are diagnosed with Leigh syndrome. Affected infants have severe psychomotor regression and lactic acidosis. Cerebellar and pyramidal signs are present. Magnetic resonance imaging shows focal symmetric lesions in the basal ganglia and brain stem. These findings are thought to be the result of damage to the developing brain because of impaired oxidative metabolism. Pathologic examination shows necrosis with gliosis and vascular proliferation. Leigh syndrome is genetically heterogeneous; mutations have been identified in mitochondrial respiratory chain complexes I, II, III, IV, and V and components of the pyruvate dehydrogenase complex. Although cardiomyopathy occurs in a few patients, the heart is not typically involved.
Some neonates present with cardiovascular collapse immediately after delivery. Other neonates may present with cardiomyopathy and skeletal myopathy or isolated skeletal myopathy. Mutations in both mitochondrial and nuclear-encoded genes are reported. The cardiomyopathy is most often hypertrophic, but dilated forms also occur. Arrhythmias, including ventricular tachycardia and, more rarely, Wolff-Parkinson-White syndrome, occur less commonly. Apnea, poor feeding, vomiting, and hepatomegaly may also be seen.
Older children usually have generalized hypotonia and weakness, psychomotor retardation, lactic acidemia, and often cardiorespiratory insufficiency. The older patients most often come to attention because of a skeletal myopathy that results from the mitochondrial myopathy.
Classical histologic abnormalities include abnormal skeletal muscle fibers (ragged-red fibers) and abnormal mitochondria, but this is not always present and is not required for diagnosis. The ragged-red fibers result from accumulation of abnormal mitochondria under the plasma membrane and may not be present in infants. Laboratory manifestations are variable but may include an increased ratio of lactate to pyruvate and a normal molar ratio of serum glucose to ketone.
Description of selected disorders Complex I (NADH-ubiquinone reductase) deficiency may occur as an isolated defect or together with other respiratory chain defects. This complex consists of at least 36 nuclear- encoded and seven mitochondrial-encoded subunits. Deficiency can be caused by mutations in several different nuclear- or mitochondrial-encoded genes. The majority of cases are caused by mutations in nuclear-encoded genes. The fatal infantile form (lethal mitochondrial disease) is a multisystem disorder characterized by severe lactic acidosis, hypertrophic or dilated cardiomyopathy, hepatomegaly, apnea, and feeding difficulties. Severe cardiac dysfunction often results in death within a few weeks after birth. Muscle biopsies show ragged-red fibers. Measurement of enzyme activity in affected organs or cultured skin fibroblasts establishes the diagnosis.
Complex IV or cytochrome c oxidase (COX) deficiency can result in an encephalopathy (Leigh syndrome) or myopathy. Deficiency of this complex is caused by mutation in multiple nuclear-encoded and mitochondrial- encoded genes. Leigh syndrome usually does not present until after early infancy when psychomotor regression is noted. The fatal infantile myopathy (lethal mitochondrial disease or fatal cardio-encephalomyopathy) is characterized by diffuse hypotonia associated with respiratory insufficiency, lactic acidosis, and hypertrophic cardiomyopathy and/or renal dysfunction. These patients do not respond to treatment and usually die from respiratory insufficiency. In contrast, the benign infantile form presents similarly, but these patients do respond to aggressive supportive therapy and improve spontaneously. Both lactic acidosis and ragged-red fibers gradually regress.
Sengers syndrome is characterized by abnormal mitochondria in cardiac and skeletal muscle, cataracts, and lactic acidosis with exertion. Loss-of-function mutations in the gene for acylglycerol kinase, which is involved in mitochondrial lipid metabolism, cause this condition. In the fatal neonatal form, these findings are present at birth.
These patients have severe hypertrophic cardiomyopathy that causes death within the first month of life. In the more benign form, cataracts may be the only symptom in childhood; cardiomyopathy develops during adult life.
Barth syndrome (cardioskeletal myopathy with neutropenia and abnormal mitochondria) is a rare disorder caused by abnormalities in the mitochondrial lipids. This is an X-linked disorder in which mitochondrial abnormalities are present in cardiac muscle, neutrophil bone marrow cells, and occasionally skeletal muscle. Typical findings include cardiomyopathy (>90%) often characterized by dilated cardiomyopathy and/or left ventricular noncompaction, cyclical neutropenia, skeletal myopathy, and growth retardation. Ventricular tachycardia is seen in 10% to 20% of patients. Blood and urine concentrations of 3-methyl glutaconic acid are increased. Some patients die or need cardiac transplantation within the first few months to years of life from cardiac failure or sepsis, but aggressive and proactive supportive care increases life expectancy. A high frequency of male fetal death is present in maternal carriers and can be associated with hydrops.
This condition is caused by mutations in the tafazzin gene (TAZ), which is located on the long arm of the X chromosome and encodes a family of phospholipid acyltransferases called tafazzins. Tafazzin is required for normal synthesis of cardiolipin, an acidic phospholipid that is the major component of the inner mitochondrial membrane. The respiratory chain complexes are embedded in this membrane; mutations in TAZ alter the concentration and composition of cardiolipin, leading to membrane destabilization and abnormalities in electron transport. High-performance liquid chromatography/electrospray mass spectrometry shows decreased total cardiolipin and alterations in cardiolipin subclasses in fibroblasts from affected patients. TAZ mutation analysis establishes the diagnosis.
Disorders related only to mitochondrial genome mutations include mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), which is characterized by recurrent neurologic events. This condition is most often caused by a point mutation in the tRNA for leucine, but other mitochondrial DNA point mutations have been described. Myoclonus, epilepsy, and redragged fiber disease (MERRF) is associated with a point mutation in the tRNA for lysine. These patients usually develop normally during the first few years of life, but neonatal onset has been reported.
Kearns-Sayre syndrome is a sporadic condition that results from a large single deletion of mitochondrial DNA. Patients have progressive external ophthalmoplegia and frequently develop high-degree atrioventricular conduction defects in the second or third decade. They are usually asymptomatic as infants. Some patients have another manifestation of a large mitochondrial DNA deletion, Pearson syndrome (sideroblastic anemia with pancytopenia and exocrine pancreatic insufficiency), and eventually develop Kearns-Sayre syndrome.
Diagnosis The patient phenotype must be assessed carefully. A complete family history is important to determine whether Mendelian or maternal inheritance is present. Standard metabolic testing including assay of blood and urine for organic acids and amino acids is done. A muscle biopsy is often necessary for histologic and biochemical analyses. Biochemical studies in particular are difficult because a variety of laboratory errors can produce false-positive results. Genetic testing, including comprehensive mitochondrial DNA analysis, is also necessary if indicated. A fully integrated multidisciplinary approach is necessary to reach a correct diagnosis. Determining whether a patient’s phenotype is the result of abnormal nuclear DNA or mitochondrial DNA is important for genetic counseling of the family.
THERApy Treatment of mitochondrial oxidative phosphorylation defects is difficult. Isolated publications report beneficial effects of cofactor substitution in a few cases, but at this time, there is no evidence supporting the use of any intervention in these disorders. Further research is needed to establish the role of a wide range of proposed therapeutic approaches.
Storage Disorders (Table 9-7)
Glycogen storage disease Glycogen is present in large quantities in muscle and liver cells and serves as a reservoir for glucose. The glycogen storage diseases (GSD) make up more than 10 different inherited disorders caused by abnormalities of the enzymes regulating the synthesis and degradation of glycogen, but only a few of these affect the heart.
aIndicates cardiomyopathy usually not present in infancy.
OMIM, Online Mendelian Inheritance in Man. Latest updates regarding gene(s) and loci can be obtained from this website: http://www.ncbi.nlm. nih.gov/omim.
D, dilated cardiomyopathy; H, hypertrophic cardiomyopathy.
GSD II is caused by decreased activity of the lysosomal glycolytic enzyme acid alpha-1,4-glucosidase (acid maltase) and is transmitted as an autosomal-recessive trait. The main purpose of this lysosomal pathway is to degrade the glycogen that is taken up in autophagic vacuoles during times of cellular turnover. The enzyme deficiency causes glycogen to accumulate in the lysosomes of cardiac, smooth, and skeletal muscle cells, resulting in cellular hypertrophy and lysosomal rupture.
Complete deficiency causes a severe infantile form of GSD II called Pompe disease. Pompe disease is unique among the GSDs because glycogen accumulates within the lysosomes (rather than in the cytoplasm) of cells in the heart, liver, skeletal muscle, and central nervous system. Symptoms such as poor feeding, respiratory distress related to loss of diaphragm contractile strength, decreased spontaneous movement, failure to thrive, and delayed development are frequently present. Physical examination shows hypotonia, macroglossia, and marked hepatomegaly. Cardiomegaly is always prominent. The electrocardiogram typically shows a short PR interval and markedly increased precordial voltages (Figure 9-4). The echocardiogram shows massive hypertrophy of the entire left ventricle, interventricular septum, and papillary muscles (Figure 9-5). The left ventricular cavity size and ventricular function are decreased. The serum creatine kinase concentration is always increased. Muscle biopsy shows vacuoles filled with glycogen within all muscle fibers. With supportive care only, the average age of death is 8 months because of impaired ventilation and heart failure. These patients are now commonly treated with enzyme replacement therapy with recombinant human alglucosidase alfa. Affected infants who begin therapy before 6 months of age and before ventilator support is needed show improved survival, decreased ventricular mass, improved ejection fraction, improved motor skills, and prolonged ventilator-free survival. The response is variable in that some patients improve, but many develop chronic disability. Lifelong therapy is needed, and efficacy is often compromised by development of antibodies.
FIGURE 9-4. Electrocardiogram in a patient with Pompe disease. All leads are recorded at one-fourth standard (2.5 mm/V) because of the markedly increased voltage. The PR interval is short (80 ms).
FIGURE 9-5. Echocardiogram from an infant with Pompe disease. Four-chamber view shows marked concentric left ventricular hypertrophy. Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
Patients who have mutations that result in no production of acid alpha-1,4-glucosidase recognize the replacement enzyme as a foreign protein and rapidly develop neutralizing antibodies. Immunomodulation often improves response. Long-term neurodevelopmental outcomes are unknown at this time.
GSD III (debrancher deficiency, amylo-1,6-glucosidase, Cori disease) usually does not affect young infants, but a rare infantile form occurs that is associated with severe hypertrophic cardiomyopathy.
Another condition associated with excess intracellular glycogen, familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome, is caused by mutations in the Prkag2 gene, which encodes a regulatory subunit of an AMP-activated protein kinase. The activity of this enzyme is critical in regulating cellular glucose and fatty acid metabolic pathways and recently has been found to regulate myocardial proliferation and growth in a mouse model.
Affected patients most commonly present in late adolescence with supraventricular tachycardia. Their electrocardiograms show ventricular pre-excitation and may progress to advanced atrioventricular block. The echocardiograms often show varying degrees of ventricular hypertrophy that may progress to dilated cardiomyopathy. A much less common severe neonatal variant, previously attributed to deficiency of a cardiac variant of phosphorylase kinase, is thought to be related to a mutation in Prkag2 that causes higher levels of enzyme activity than described for less severely affected older patients. These neonates show hypertrophic cardiomyopathy and ventricular pre-excitation; they die of cardiorespiratory failure within a few weeks to months of birth. Interestingly, transgenic mice with mutations in this enzyme show that accumulating glycogen disrupts the normal development of the annulus fibrosis, explaining the pre-excitation.
Other lysosomal storage diseases Lysosomal disorders, which include Pompe disease (discussed earlier), are the most common causes of metabolic cardiomyopathy in children. Lysosomes contain several hydrolytic enzymes and are responsible primarily for intracellular digestion of macromolecules. Lysosomal storage diseases are caused by genetic defects that affect one or more of these hydrolases, resulting in accumulation of undigested substrates within the lysosome. The severity of the condition depends in part on the number of enzymes affected.
Mucopolysaccharidoses Glycosaminoglycans (mucopolysaccharides) are high-molecular-weight carbohydrate chains (eg, heparin, hyaluronic acid) located on the surface of the cell and in the extracellular matrix. These molecules are involved in cell communication, migration, and adhesion. Deficiencies in lysosomal enzymes involved in degrading glycosaminoglycans result in mucopolysaccharidoses (MPS). Excess glycosaminoglycans are stored in tissues and excreted in the urine. More than 10 different disorders have been described, and they are transmitted as both autosomal and X-linked traits. In most cases, valve dysfunction secondary to deposition of glycosaminoglycans develops. This is uncommon in neonates. Mitral valve regurgitation is most frequent, but aortic valve regurgitation is also seen. Systemic hypertension is the result of arterial narrowing secondary to medial and intimal thickening. Myocardial ischemia is sometimes seen secondary to circumferential coronary arterial narrowing, which tends to occur throughout the length of the vessel rather than in a discrete region and is therefore more difficult to identify. Cardiomyopathy, specifically in a pattern of endocardial fibroelastosis, may be seen. These problems usually develop over the first two decades of life, but a few patients who have Hurler (MPS I) and Marote- aux-Lamy (MPS VI) syndromes have been reported who developed dilated cardiomyopathy with congestive heart failure in infancy.
Enzyme replacement therapy does not prevent central nervous system deterioration because the administered enzyme does not cross the blood-brain barrier. The treatment of choice therefore is hematopoietic cell transplantation. Long-term outcome is more favorable in patients who undergo transplantation at younger ages.
GM1 gangliosidosis GM1 gangliosides (sphingolipid plus >1 sialic acid residue) accumulate in multiple tissues in patients with this disorder because of decreased activity of β-galactosidase, a lysosomal enzyme involved in degradation of gangliosides. Enzyme activity is absent in the severe infantile form. Affected infants resemble those with Hurler syndrome. Radiographic studies of the skeletal bones show characteristic abnormalities. Echocardiography shows hypertrophic cardiomyopathy with asymmetric septal hypertrophy and mitral regurgitation. These patients usually die before age 5 years.
Type II mucolipidosis (I-cell disease) I-cells are fibroblasts with multiple inclusion bodies composed of acid hydrolases that accumulate because of deficiency of N-acetyl-glucosamine-1 -phosphotransferase. Patients who have this autosomal-recessive disorder resemble those with Hurler syndrome. Cardiomegaly and congestive heart failure may occur in early infancy. Left ventricular hypertrophy is present and is associated with aortic and mitral valve stenosis secondary to thickened valve leaflets. Cytoplasmic inclusions are seen in myocardial cells. Death in untreated patients occurs before age 5 years. Outcomes after hematopoietic stem cell transplantation are poor because of cardiac and neurologic complications.
X-linked vacuolar cardiomyopathy and myopathy (Danon disease) This condition was previously classified as a glycogen storage disease but is no longer classified as such because intracellular glycogen is not always increased. This is an X-linked dominant condition caused by a defect in the gene encoding lysosome-associated membrane protein-2 (LAMP-2). Skeletal myopathy, cardiomyopathy, conduction defects, and mental retardation are common. Males often develop symptoms in childhood or adolescence, and females may not present until adolescence or adulthood. These patients show ventricular pre-excitation and cardiomyopathy that is most commonly hypertrophic in males and dilated in females. Histopathology shows clusters of vacuolated myocytes suggestive of impaired autophagy.
Congenital Disorders of Glycosylation
Congenital disorders of glycosylation (CDG) are a genetically heterogeneous group of autosomal-recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans. Glycans are important components of cell membranes and play critical roles in metabolism, cell recognition, and adhesion. Multiple disorders have been described, but CDG 1A is the most common. It is caused by phosphomannomu- tase-2 deficiency and is also called PMM2-CDG. The most severe form presents in neonates and is characterized frequently by nonimmune hydrops fetalis, neurologic abnormalities, dysmorphic features (including inverted nipples and abnormal subcutaneous fat distribution), hypotonia, seizures, liver dysfunction, and coagulation abnormalities. Pericardial effusions and cardiomyopathy, often hypertrophic but sometimes dilated, may be present.
Disorders of Amino Acid and Organic Acid Metabolism Propionic acidemia results from a defect in propionic- CoA carboxylase. Neonates have poor suckling, respiratory distress, emesis, and hypotonia. Some patients have cardiomyopathy and/or arrhythmias, and some have died from congestive heart failure or sudden death. Liver transplantation has been reported to reverse cardiomyopathy in isolated case reports. Laboratory abnormalities include metabolic acidosis with an increased anion gap, ketosis, and hyperammonemia. Urine organic acid analysis confirms the diagnosis.
Methylmalonic acidemia is caused by a deficiency in methylmalonyl-CoA mutase activity or impaired transport or synthesis of its cofactor, cobalamin. The most common type (cblC, >80%) is associated with homocys- tinuria. All of these disorders can present at any age, but neonates with fatal disease are characterized by intrauterine growth retardation, microcephaly, and multisystem failure, including ventricular dysfunction.
Infants of Diabetic Mothers
Cardiorespiratory distress is common in infants born to diabetic mothers. This may be the result of congenital heart defects and/or a transient form of severe ventricular hypertrophy that has an echocardiographic appearance very similar to that of hypertrophic cardiomyopathy. This is the most common etiology of marked ventricular hypertrophy in newborn infants; true hypertrophic cardiomyopathy is much less common at birth.
The incidence of congenital heart defects is two to four times higher in infants born to diabetic mothers than that in the general population. Of note, structural defects are likely the result of an embryopathy in long-standing diabetic mothers with increased hemoglobin A1c in the first trimester, whereas ventricular hypertrophy is more commonly seen in infants of mothers with gestational diabetes who have persistent hyperglycemia later in gestation.
Pathophysiology
Maternal hyperglycemia results in fetal hyperinsulin- ism and increased leptins, which likely lead to high birth weights and enlarged viscera. The mechanism(s) responsible for the congenital heart defects is undefined.
Clinical Features
These large-for-gestational-age infants are nearly always plethoric and edematous. Tachypnea and cyanosis are seen in symptomatic infants. Systolic murmurs may indicate structural malformations, such as ventricular septal defects, tetralogy of Fallot, or left ventricular outflow tract obstruction related to hypertrophic cardiomyopathy. Hepatomegaly is common. Hypoglycemia, hypocalcemia, and polycythemia may be present.
Ventricular hypertrophy with marked thickening of the interventricular septum is seen frequently. This may be relatively mild in asymptomatic infants, but if more severe hypertrophy is present, diastolic dysfunction secondary in part to poor ventricular compliance results in heart failure. Ventricular hypertrophy can result in right ventricular outflow tract obstruction, thereby causing cyanosis. Alternatively and more frequently, left ventricular obstruction causes left heart failure with poor pulses and perfusion.
Noninvasive Evaluation
Cardiomegaly is present in up to 30% of infants and is more common in symptomatic infants. In one study, the degree of cardiomegaly was not related to echocardiographic findings, including ventricular chamber diameter or wall thickness. This may be explained in part by the fact that hypoglycemia, hypocalcemia, and polycythemia, which are also present frequently in these infants, may cause cardiomegaly. Evidence of pulmonary venous congestion may result from impaired left ventricular filling.
Generally, a consistent relationship between hypertrophy on the electrocardiogram and echocardiographic findings is not present. The electrocardiogram may be normal, but right ventricular or biventricular hypertrophy is seen frequently. The ST segments and T waves are normal for age.
FIGURE 9-6. Echocardiogram from an infant of a diabetic mother. Subcostal four-chamber view shows marked left ventricular hypertrophy (septum greater than the left ventricular free wall). Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
An echocardiogram will define congenital heart defects if present and is essential for evaluating ventricular hypertrophy and ventricular outflow tract obstruction. All ventricular walls are usually thickened, but disproportionate enlargement of the interventricular septum is often seen (asymmetric septal hypertrophy) (Figure 9-6). Left ventricular outflow tract obstruction is seen less frequently. Asymptomatic infants have milder degrees of hypertrophy.
Natural History
Even when hypertrophy is severe and causes symptoms in the newborn, it always resolves, usually within the first 6 months of life.
Management
All infants born to infants of mothers with pregestational diabetes should have a screening echocardiogram. Symptomatic infants with ventricular hypertrophy benefit from supportive care, including aggressive management of hypoglycemia, hypocalcemia, and polycythemia. Mechanical ventilation may be necessary. Digoxin and intravenous positive inotropic agents are contraindicated unless the echocardiogram shows poor systolic function (eg, associated with concomitant perinatal asphyxia). These agents, as well as afterload-reducing agents, may decrease end-systolic ventricular cavity size and thereby cause or worsen left or right ventricular outflow tract obstruction. Although these infants appear edematous and have large livers, this does not often indicate excess total body water. Diuretics must be used cautiously, as decreased intravascular volume may also adversely affect ventricular output. P-adrenergic antagonists reportedly have been administered to a few severely symptomatic patients. Follow-up is indicated until ventricular hypertrophy is resolved. Rarely, ventricular hypertrophy in an infant who was thought to have hypertrophy related to maternal diabetes does not resolve; these infants have true hypertrophic cardiomyopathy.
■ OTHER CAUSES OF VENTRICULAR DYSFUNCTION
Myocarditis
Myocarditis is an inflammatory disorder involving the myocardium and is characterized by lymphocytic infiltration of the myocardium often associated with myocyte necrosis. Myocardial injury is caused by direct pathogen- induced damage and an autoimmune response to myocytes transformed by viral infection.
Although rare in neonates, myocarditis should always be suspected in any infant with congestive heart failure in whom structural heart disease has been excluded. Hepatitis and encephalitis may also be present. Overwhelming sepsis may be the initial diagnosis in many of these infants who are acutely ill. Almost any infectious agent can cause myocarditis. Enteroviruses, especially Coxsackie B and ECHO viruses, are the most common etiologic agents; however, disease secondary to adenovirus, parvovirus B19, and toxoplasmosis also occurs. The initial symptoms are nonspecific and may include lethargy, poor feeding, emesis, and respiratory distress. Older infants may have had a preceding respiratory infection. Some infants come to medical attention having signs and symptoms of cardiovascular collapse. Congestive heart failure is present on physical examination, and the chest radiograph shows cardiomegaly often with pulmonary edema. The electrocardiogram may show low-voltage QRS complexes and diffusely abnormal (often flat) T waves (Figure 9-7). Arrhythmias are common. Echocardiography shows ventricular dilation and decreased function. Hypertrophy is not present.
FIGURE 9-7. Electrocardiogram in a 10-month-old patient with acute myocarditis. Tachycardia, decreased QRS voltages, and diffuse ST-segment and T-wave abnormalities are present.
Congenital defects, such as coarctation of the aorta and anomalous left coronary artery arising from the pulmonary artery, must be excluded. Cardiac magnetic resonance imaging may be helpful for diagnosis in the acute stage of the disease process.
Viral, bacterial, and fungal cultures should be obtained from nasopharyngeal and stool specimens. Serologic identification requires a threefold to fivefold increase in antibody titers, but even this does not prove causation. Polymerase chain reaction is used to analyze nasopharyngeal specimens for specific viral sequences. This process allows identification of a presumptive etiologic virus in at least one-third of patients but does not prove causation.
Supportive measures are the principal form of therapy (Chapters 11 and 12). The use of immunosuppression and immunomodulation remains controversial; evidence-based data are lacking, especially in young infants. Administration of intravenous immunoglobulin may be beneficial; however, efficacy has not been validated. Extracorporeal membrane oxygenation and ventricular assist devices have been used with success, especially in those patients who have malignant arrhythmias unresponsive to antiarrhythmic therapy. Nearly two-thirds of infants with myocarditis will recover substantially, some of the rest will die or need immediate cardiac transplantation, and the others will develop dilated cardiomyopathy and have chronic congestive heart failure, eventually requiring transplantation.
Perinatal Asphyxia
Severe perinatal asphyxia may occasionally cause ventricular dilation and dysfunction in newborn infants that is likely the result of myocardial ischemia. Myocardial oxygen delivery is impaired because cardiac output and arterial oxygen content decrease while oxygen demand is increased because of asphyxia-induced increases in pulmonary and systemic vascular resistances (afterload). The clinical features are variable and range from mild bradycardia to cardiovascular shock. These infants typically have low Apgar scores and metabolic acidosis at birth. Poor perfusion and poor pulses are present, as are hepatomegaly and cardiomegaly. Sepsis must be excluded as well as other causes of neonatal cardiomyopathy and certain congenital heart defects, such as critical aortic stenosis.
Hypoxemia may be more prominent than shock in some asphyxiated infants. Tricuspid regurgitation, characterized by a systolic murmur at the lower left sternal border, is frequently present and may result from ischemia or even necrosis of the anterior papillary muscle of the tricuspid valve. Tricuspid regurgitation is exacerbated by pulmonary hypertension. The degree of hypoxemia is related to the amount of right-to-left shunting through the patent foramen ovale and/or ductus arteriosus. Cyanotic heart disease such as Ebstein anomaly of the tricuspid valve must be excluded.
The chest radiograph shows cardiomegaly. Typical electrocardiographic findings include ST-segment abnormalities and inversion of T waves. Echocardiography should exclude congenital defects and will often show ventricular dilation, global ventricular dysfunction, and tricuspid valve regurgitation. The laboratory tests routinely used to evaluate myocardial ischemia in adult patients are not always reliable in newborn infants. Both creatine kinase (CK)-MB isozyme and cardiac troponin T concentrations are higher in healthy neonates than in normal adults. Supportive care results in dramatic improvements in many of these infants over several days with normalization of cardiac function, but those with extensive myocardial necrosis may not survive.
Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery
Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is an uncommon congenital defect that often results in severe congestive heart failure related to infarction of the anterolateral left ventricular free wall. During fetal life and at birth, desaturated blood flows from the pulmonary artery into the left coronary artery. As pulmonary vascular resistance and pulmonary arterial pressure decrease after birth, blood in the left coronary artery reverses direction and flows into the pulmonary artery. If collateral blood supply from the right to the left coronary artery is inadequate, myocardial ischemia and infarction may occur in early infancy. Collateral vessels between the abnormal left coronary artery and the normal right coronary artery gradually enlarge, and eventually pulmonary to coronary arterial steal develops because blood in the collateral vessels flows preferentially into the pulmonary artery rather than into the higher resistance coronary arteries. This also may cause myocardial ischemia.
Many infants show episodic agitation, especially during feeding or crying. This may be attributed to “colic” or gastroesophageal reflux, but it is actually related to myocardial ischemia that occurs during times of stress. Other infants present with signs and symptoms of congestive heart failure, and some are critically ill with cardiogenic shock. Physical examination may show a gallop rhythm and a murmur of mitral regurgitation. The chest radiograph shows marked cardiomegaly and often pulmonary edema. The electrocardiogram often shows findings compatible with an anterolateral myocardial infarction (Figure 9-8).
This anomaly can usually be diagnosed by careful echocardiographic examination. The abnormal attachment of the left coronary artery to the pulmonary artery can be visualized in about 50% of patients by two-dimensional echocardiography alone. Color Doppler flow shows retrograde flow in the left coronary artery because flow passes from the coronary artery to the pulmonary artery rather than from the aorta to the coronary artery. This is an important differentiating point between patients with ALCAPA and those with dilated cardiomyopathies of other etiologies. In addition, diastolic turbulent flow is seen in the pulmonary artery at the site of the connection with the anomalous left coronary artery. The right coronary artery is often dilated. Global left ventricular dilation and dysfunction are present, and mitral regurgitation is often seen. If the echocardiographic examination is not diagnostic, cardiac catheterization and coronary angiography are indicated in all patients who have clinical findings consistent with ALCAPA.
FIGURE 9-8. Electrocardiogram in a 5-month-old patient with anomalous origin of the left coronary artery from the pulmonary artery. Prominent Q waves are present in leads I and aVL.
Most children with ALCAPA present in infancy, and about 75% will die before age 1 year if not treated surgically. Various surgical procedures have been tried, and for many years the mortality rate was relatively high, especially in infants who were critically ill. Direct reimplantation of the origin of the left coronary artery into the aorta is now the procedure of choice in most centers. The long-term results are encouraging. Ventricular function and mitral regurgitation most often improve dramatically, and signs and symptoms of congestive heart failure resolve in many patients. If the lesion is discovered late, there may be long-term ischemic cardiomyopathy, leading to chronic congestive heart failure and possible transplantation.
Systemic Hypertension
Acute increases in systemic blood pressure may result in severe left ventricular hypertrophy and dysfunction in the neonate. In full-term infants, systolic pressures >90 mm Hg and diastolic pressures >60 mm Hg are cause for concern. Nomograms are available to facilitate interpretation of blood pressure measurements in premature infants. Causes of hypertension in neonates include renal and renovascular abnormalities, descending aortic thrombosis, and adverse effects of medications such as dexamethasone.
Symptomatic infants have gallop rhythms, poor peripheral pulses, and poor perfusion. Somewhat paradoxically, the blood pressure is increased. Aortic coarctation must be excluded because some infants with this defect have upper extremity hypertension. Echocardiographic examination shows left ventricular hypertrophy and poor myocardial function. Treatment with an angiotensin-converting enzyme inhibitor is often efficacious.
Reversible Metabolic and Electrolyte Disturbances
Hypocalcemia may cause decreased ventricular function and congestive heart failure in neonates. The electrocardiogram shows prolongation of the corrected QT interval. Cardiomyopathy is reversed with administration of calcium.
Hypoglycemia may also cause cardiomegaly, decreased ventricular function, and congestive heart failure in neonates. This is most frequently seen in infants of diabetic mothers but also occurs in low-birth-weight infants, critically ill infants, and infants who have certain metabolic disorders. Ventricular function usually normalizes after administration of glucose.
Polycythemia is sometimes associated with cardio- megaly and decreased ventricular function in neonates. Often, concomitant electrolyte abnormalities are present (eg, in infants of diabetic mothers), so cause and effect are sometimes difficult to define. Treatment results in resolution of cardiac abnormalities.
Arrhythmias
Certain sustained tachyarrhythmias and third-degree atrioventricular heart block may cause decreased ventricular function and congestive heart failure. These disorders are discussed in Chapter 10.
Cor Pulmonale
Cor pulmonale is characterized by right ventricular dysfunction related to increased right ventricular afterload caused by hypoxic pulmonary vasoconstriction. Chronic lung disease and upper airway obstruction are the most common causes of hypoxic pulmonary vasoconstriction in neonates.
Clinically, these infants may have hepatomegaly and peripheral edema related to right heart failure. The chest radiograph shows cardiomegaly. The electrocardiogram may show right axis deviation, right atrial enlargement, and/or right ventricular hypertrophy. Echocardiography first shows right ventricular dilation and then right ventricular hypertrophy often associated with pulmonary arterial hypertension. Tricuspid regurgitation occurs in more advanced cases. Severe right ventricular dilation and hypertrophy may adversely affect left ventricular function because of ventricular interdependence.
Aggressive treatment of chronic lung disease and/or upper airway obstruction is the most important component of therapy. Exacerbations of chronic lung disease are often associated with increased right heart failure. Adequate oxygenation and pH must be maintained. In some infants, polysomnography is useful for assessing obstructive and central apnea, seizures, hypopnea, and so on. Diuretics are frequently used in patients who have chronic lung disease. These agents alleviate pulmonary interstitial edema and fluid overload related to right heart failure. Digoxin has not been shown to be beneficial. Cor pulmonale may improve if lung disease resolves, but chronic pulmonary artery hypertension and associated sequelae cause long-term morbidity. The benefit of therapies known to be efficacious in older patients, including intravenous epoprostenol, aerosolized prostacyclin, oral endothelin receptor blockers, and sildenafil, remains to be defined in this population.
■ CLINICAL PRESENTATION ANDDIAGNOSTIC APPROACH
Many disorders are associated with cardiomyopathy in infancy. As such, the list of possible diagnostic tests and biochemical assays is lengthy (Table 9-8). Clues from the history and physical examination should assist in focusing the diagnostic evaluation. Comprehensive newborn screening with appropriate confirmatory studies may provide a diagnosis of some metabolic disorders before symptoms are seen, though some infants become ill before these results are available. Of note, routine newborn screening does not diagnose glycogen and lysosomal storage disorders or oxidative phosphorylation defects.
Those infants who have dilated forms of cardiomyopathy usually have signs and symptoms of congestive heart failure because of systolic and diastolic ventricular dysfunction. The initial findings may be subtle, but some infants become acutely ill within a short period of time. The differential diagnosis includes structural heart disease, bacterial or viral sepsis, respiratory infection, metabolic and electrolyte derangements, and arrhythmias. Patients with hypertrophic forms of cardiomyopathy may have symptoms related to right or left ventricular outflow tract obstruction as well as from diastolic dysfunction.
A careful history must be taken, including information regarding prenatal and perinatal events. A complete family history, including history of recurrent fetal loss and parental consanguinity (as a marker for a recessively inherited condition), must be obtained to assess for the presence of familial inheritance.
In addition to evaluating cardiorespiratory status, the infant is examined for signs of systemic disorders associated with cardiomyopathy. Dysmorphic features are often distinctive for certain malformation syndromes and other genetic disorders associated with cardiomyopathy (Table 9-9). Hypotonia is present in several disorders (Figure 9-9). Encephalopathy associated with cardiomyopathy is suggestive of a mitochondrial oxidative phosphorylation disorder or a defect in fatty acid oxidation, and appropriate laboratory investigation must be done.
TABLE 9-8. Available Diagnostic Tests for Infants with Cardiomyopathya
General
Chest radiograph
Electrocardiogram
Echocardiogram
Cardiac catheterization
Endomyocardial biopsy
Skeletal muscle biopsy
Skeletal bone X-ray studies
Magnetic resonance imaging of the head
Nasopharyngeal and stool for viral cultures,
PCR for viral genome
Skin fibroblast culture for enzyme assays
Ophthalmologic examination
Laboratory
Blood
Electrolytes, Ca2+, Mg2+, PO4-2
Arterial blood gas (pH, anion gap) Liver function tests
Ammonia
Lactate, pyruvate
Glucose, ketones
Insulin
Creatinine, blood urea nitrogen
Carnitine, acylcarnitine profile
Cholesterol
Uric acid
Creatine kinase and myocardial specific enzyme
(CK-MB)
Troponin I
Lactate dehydrogenase
Amino acids
Free fatty acids
Complete blood count with differential
Erythrocyte sedimentation rate
C-reactive protein
Viral serologies
Blood for cell lines
Cytogenetics
Genetic testing
Urine
Urinalysis
Amino acids
Organic acids
Acylglycines
aTesting must be guided by clinical presentation and initial screening laboratory data.
PCR, polymerase chain reaction.
TABLE 9-9. Abnormal Features Found in Patients with Genetic Disorders Associated with Cardiomyopathya
|
Organ system |
Feature |
Disorder |
|
Growth |
Short stature Macrosomia/overgrowth |
Noonan syndrome Multiple lentigenes Mucopolysaccharidoses Beckwith-Weidemann syndrome Costello syndrome |
|
Facies |
Distinctive Coarse |
Noonan syndrome Cardio-facio-cutaneous syndrome Monosomy 1p36 syndrome Mucopolysaccharidoses Pompe disease Costello |
|
Other craniofacial |
Cataracts Macroglossia Neck webbing |
Sengers syndrome Beckwith-Weidemann syndrome Costello syndrome Noonan syndrome |
|
Skeleton |
Hemihypertrophy Kyphoscoliosis Pectus |
Beckwith-Weidemann syndrome Proteus syndrome Noonan syndrome LEOPARD Mucopolysaccharidoses Noonan syndrome |
|
Skin/hair |
Sparse, curly hair Hirsutism Hyperkeratosis/ichthyosis Lentigines Cutislaxa, loose skin Deep palmar and plantar creases |
Cardio-facio-cutaneous syndrome Naxos disease Mucopolysaccharidoses Cardio-facio-cutaneous syndrome LEOPARD Naxos disease Costello syndrome Costello syndrome |
|
aPagon RA, Adam MP, Ardinger HH, et al., eds. Gene Reviews. http://www.ncbi.nlm.nih.gov/books/NBK1116. Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim). |
||
The chest radiograph often shows cardiomegaly. Evidence of pulmonary venous congestion and possibly pulmonary edema are also often present.
The electrocardiogram frequently shows tachycardia and left ventricular hypertrophy. ST-segment and T-wave abnormalities are also fairly common but are relatively nonspecific. Some electrocardiographic features are relatively specific for certain diseases (Table 9-10). Arrhythmias are seen but are much less common than in older children and in adults.
FIGURE 9-9. Algorithm for evaluation of cardiomyopathy associated with hypotonia. Adapted from Schwartz ML et al. Circulation. 1996;94:2021.
The echocardiogram provides important information. First, structural heart disease must be excluded. For some lesions, such as ALCAPA, careful scanning must be done by persons knowledgeable about congenital heart disease. Even with the most careful scanning, ALCAPA may be missed, so a second imaging technique, such as magnetic resonance imaging or angiography, should be considered when there is any doubt. The ventricles are evaluated for dilation and hypertrophy, and the cardiomyopathy is classified as dilated, hypertrophic, or restrictive. In patients with dilated cardiomyopathy, the left atrium and left ventricle are dilated. Mitral regurgitation may be present. Left ventricular function is decreased. Patients with hypertrophic cardiomyopathy may have hypertrophy of the left ventricle, right ventricle, and/or interventricular septum. The left and right ventricular outflow tracts are assessed for obstruction. Right ventricular outflow tract obstruction is common in neonates. Mitral regurgitation may be present. Measures of left ventricular dimension and wall thickness must be normalized for body surface area. Other findings, such as isolated asymmetric hypertrophy of the interventricular septum, left ventricular noncompaction, and endocardial fibroelastosis, are also suggestive of cardiomyopathy.
Signs and symptoms of multiple organ dysfunction may reflect profound cardiovascular insufficiency, but inborn errors of metabolism should also be considered. The presence of hypoglycemia, metabolic acidosis with an increased anion gap, or hyperammonia is consistent with metabolic disorders, and further evaluation is necessary (Figures 9-10, 9-11). Metabolic abnormalities are sometimes detected only during an acute clinical decompensation, so blood and urine samples need to be obtained at the time of the acute illness and saved for analyses as indicated.
In most centers, cardiac catheterization is reserved for those patients in whom the echocardiographic diagnosis is uncertain and those being considered for cardiac transplantation. Myocardial biopsy is done in some cases, but interpretation of results is complicated by frequent sampling error and specificity. For this and other reasons, the role and value of the information obtained are not clear. For patients suspected of having metabolic myopathy, a skeletal muscle biopsy is equally informative and is less invasive. Skin fibroblasts can be obtained for enzyme assays as indicated.
Genetic testing is available for some disorders as discussed earlier (http://www.genetests.org) (Chapter 15).
FIGURE 9-10. Algorithm for evaluation of cardiomyopathy associated with hypoglycemia. Adapted from Schwartz ML et al. Circulation. 1996;94:2021.
FIGURE 9-11. Algorithm for evaluation of cardiomyopathy associated with metabolic acidosis and an increased anion gap. Adapted from Schwartz ML et al. Circulation. 1996;94:2021.
SUGGESTED READINGS
Bharucha T, Lee KJ, Daubeney PE, et al. Sudden death in childhood cardiomyopathy: results from a long-term national population-based study. J Am Coll Cardiol. 2015;65(21):2302-2310.
Cahill TJ, Ashrafian H, Watkins H. Genetic cardiomyopathies causing heart failure. Circ Res. 2013;113(6):660-675.
Restrictive Cardiomyopathy
Denfield, SW, Webber SA. Restrictive cardiomyopathy in childhood. Heart Failure Clin. 2010;6(4):445-452.
Webber SA, Lipshultz SE, Sleeper LA, et al. Outcomes of restrictive cardiomyopathy in childhood and the influence of phenotype: a report from the Pediatric Cardiomyopathy Registry. Circulation. 2012;126(10):1237-1244.
Hypertrophic Cardiomyopathy
Bos JM, Towbin JA, Ackerman MJ. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009;54(3):201-211.
Colan SD, Lipshultz SE, Lowe AM, et al. Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation. 2007;115(6):773-781.
Frey N, Luedde M, Katus HA. Mechanisms of disease: hypertrophic cardiomyopathy. Nat Rev Cardiol. 2012;9(2):91-100.
Lipshultz SE, Oray EJ, Wilkinson JD, et al. Risk stratification at diagnosis for children with hypertrophic cardiomyopathy. Lancet. 2013;382(9908):1889-1897.
Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381(9862):242-255.
Dilated Cardiomyopathy
Alexander PMA, Daubeney PEF, Nugent AW, et al. Longterm outcomes of dilated cardiomyopathy diagnosed during childhood. Results from a national populationbased study of childhood cardiomyopathy. Circulation. 2013;128(18):2039-2046.
Hershberger RE, Hedges DJ, Morales AM. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10(9):531-547.
Jefferies JL, Towbin JA. Dilated cardiomyopathy. Lancet. 2010;375:752-762.
McNally EM, Golbus J, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 2013;123(1):19-26.
Pietra BA, Kantor PF, Bartlett HL, et al. Early predictors of survival to and after heart transplantation in children with dilated cardiomyopathy. Circulation. 2012;126(9):1079-1086.
Weintraub RG, Nugent AW, Davis A, et al. Presentation, echocardiographic findings, and long-term outcomes in children with familial dilated cardiomyopathy. Prog Pediatr Cardiol. 2011;31(2):119-122.
Left Ventricular Noncompaction
Brescia ST, Rossano JW, Pignatelli R, et al. Mortality and sudden death in pediatric left ventricular noncompaction in a tertiary referral center. Circulation. 2013;127(22):2202-2208.
Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008;117(22):2893-2901.
Disorders of Fatty Acid Oxidation
Baruteau J, Sachs P, Broue P, et al. Clinical and biological features at diagnosis in mitochondrial fatty acid betaoxidation defects: a French pediatric study of 187 patients. J Inherit Metab Dis. 2013;36(5):795-803.
Baruteau J, Sachs P, Broue P, et al. Clinical and biological features at diagnosis in mitochondrial fatty acid betaoxidation defects: a French pediatric study of 187 patients. J Inherit Metab Dis. 2014;37(1):137-139.
Bennett MJ. Pathophysiology of fatty acid oxidation disorders. J Inherit Metab Dis. 2010;33:533-537.
Exil VJ, Boles MA, Atkinson J, et al. Metabolic basis of pediatric heart disease. Prog Pediatr Cardiol. 2005;20(2):143-159.
Hill KD, Hamid R, Exil VJ. Pediatric cardiomyopathies related to fatty acid metabolism. Prog Pediatr Cardiol. 2008;25(1):69-78.
Houten SM, Violante S, Ventura RV, Wanders RJ. The biochemistry and physiology of mitochondrial fatty acid P-oxidation and its genetic disorders. Annu Rev Physiol. 2016;78:23-44.
Strauss AW, Andersen BS, Bennett MJ. Mitochondrial fatty acid oxidation defects. In: Sarafoglou K, Hoffman GF, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. New York, NY: McGraw-Hill; 2009:51-70.
Disorders of Mitochondrial Oxidative Phosphorylation
Bates MG, Bourke JP, Giordano C, et al. Cardiac involvement in mitochondrial DNA disease:
clinical spectrum, diagnosis, and management. Eur Heart J. 2012;33(24):3023-3033.
Clark SLN, Bowron A, Gonzalez IL, et al. Barth syndrome. Orphanet J Rare Dis. 2013;8:23.
Gibson K, Halliday JL, Kirby DM, et al. Mitochondrial oxidative phosphorylation disorders presenting in neonates: clinical manifestations and enzymatic and molecular diagnoses. Pediatrics. 2008;122(5):1003-1008.
Jefferies JL. Barth syndrome. Am J Med Genet Part C Semin Med Genet. 2013;163C(3):198-205.
Pfeffer G, Majamaa K, Turnbull DM, Chinnery PF. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2012;(4):CD004426.
Schiff M, Ogier de Baulny H, Lombes A. Neonatal cardiomyopathies and metabolic crises due to oxidative phosphorylation defects. Semin Fetal Neonatal Med. 2011;16(4):216-221.
Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet. 2012;13(12):878-890.
Yaplito-Lee J, Weintraub R, Jamsen K, et al. Cardiac manifestations in oxidative phosphorylation disorders of childhood. JPediatr. 2007;150(4):407-411.
Storage Diseases
Braunlin EA, Harmatz PR, Scarpa M, et al. Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management. J Inherit Metab Dis. 2011;34(6):1183-1197.
Burwinkel B, Scott JW, Buhrer C, et al. Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated
protein kinase (PRKAG2), not by phosphorylase kinase deficiency. Am J Hum Genet. 2005;76(6):1034-1049.
Byrne BJ, Falk DJ, Clement N, Mah CS. Gene therapy approaches for lysosomal storage disease: next-generation treatment. Hum Gene Ther. 2012;23(8):808-815.
Maron BJ, Roberts WC, Arad M, et al. Clinical outcome and phenotypic expression in LAMP2 cardiomyopathy. JAMA. 2009;301(12):1253-1259.
Muenzer J, Wraith JE, Clarke LA. Mucopolysaccharidosis I: management and treatment guidelines. Pediatrics. 2009;123(1):19-29.
Prater SN, Banugaria SG, DeArmey SM, et al. The emerging phenotype of long-term survivors with infantile Pompe disease. Genet Med. 2012;14(9):800-810.
Staretz-Chacham O, Lang TC, LaMarca ME, Krasnewich D, Sidransky E. Lysosomal storage disorders in the newborn. Pediatrics. 2009;123(4):1191-1207.
Miscellaneous
Baker, CD, Abman SH, Mouranai PM. Pulmonary hypertention in preterm infants with bronchopulmonary dysplasia. Pediatr Allergy Immunol Pulmonol. 2014;27(1): 8-16.
Canter CE, Simpson KP. Diagnosis and treatment of myocarditis in the current era. Circulation. 2014;129(1): 115-128.
Romano S, Valayannopoulos V, Touati G, et al. Cardiomyopathies in propionic aciduria are reversible after liver transplantation. JPediatr. 2010;156(1):128-134.
Schwartz ML, Cox GF, Lin AE, et al. Clinical approach to genetic cardiomyopathy in children. Circulation. 1996;94(8):2021-2038.