Cardiologic Aspects of Systemic Disease





Cardiac involvement in systemic disease can broadly be divided into those conditions where the heart is involved in the disease process itself and those where a structural or functional cardiac abnormality is associated with other anomalies, usually in a recognizable syndrome. Many of the conditions in the latter group have received attention in the sections of this book dealing with etiology and genetics. They are not dealt with again here, although they may be mentioned or the discussion amplified as necessary. A vast number of systemic diseases, nonetheless, can involve the heart during childhood. Cardiac aspects of the latter diseases are the focus of this chapter.


Metabolic Disorders: Storage Diseases


Glycogen Storage Diseases


Glycogen Storage Disease Type I (Von Gierke Disease, Glucose 6-Phosphatase Deficiency [Type Ia], Glucose 6-Phosphatase Translocase Deficiency [Type Ib])


Von Gierke disease is an autosomal recessive disorder. Clinical manifestations of type I glycogen storage disease are profound hypoglycemia associated with hyperlipidemia, hyperuricemia, and lactic acidosis. It presents in childhood and primarily involves the liver, kidneys, and small intestinal mucosa. Pulmonary hypertension in association with type Ia glycogen storage disease has been described; when present, the prognosis is very poor. Postulated mechanisms include chronic stimulation of the smooth muscle of the pulmonary arterioles by the persistent hepatic metabolism of circulating catecholamines such as serotonin. Indeed, serotonin levels have been shown to be markedly elevated in some patients with glycogen storage disease type I. However, elevated serotonin levels alone do not appear to confer pulmonary vascular disease on these patients. Rather, it is hypothesized that other mediating factors in concert with persistently elevated serotonin levels increase the risk for pulmonary vascular changes. Gene therapies are being developed to treat glycogen storage disease type I and initial results appear promising.


Glycogen Storage Disease Type II (Pompe Disease)


Pompe disease is a generalized glycogen storage disease in which glycogen of normal structure accumulates in the myocardium, skeletal muscle, and liver. The disease is progressive and is associated with deficiency of lysosomal α-1,4-glucosidase. There are four subtypes based on age at onset of clinical symptoms: infantile (classic Pompe disease), childhood, juvenile, and adult. The age at onset correlates inversely with the measured activity of lysosomal α-1,4-glucosidase in muscle cells or fibroblasts. In the infantile form, which generally has more severe cardiac involvement than the forms with later onset, there is generalized accumulation of glycogen in the heart (including in the conduction tissues), in skeletal muscle (notably the tongue and diaphragm), and in the liver. Central and peripheral neurons and smooth muscle are also affected. The results are cardiomegaly, hepatomegaly, a thickened diaphragm, and macroglossia. In the heart, the glycogen is deposited mainly in ventricular muscle. There is gross thickening of the ventricular walls, with impairment of both diastolic and systolic performance. The infants typically appear normal at birth, although cases of severe neonatal ventricular hypertrophy have been reported. The median age at onset of clinical symptoms is 1.6 months. Muscle weakness and hypotonia along with loss of motor milestones are noted during the first 6 months of life, and signs of CHF become evident. Although there is excess glycogen in the liver, hepatomegaly is not commonly present until heart failure is apparent. The disease is progressive, and most affected babies die before the age of 1 year. The clinical course may be complicated by arrhythmias. Since patients with Pompe disease appear very sensitive to digoxin, this drug must be used with extreme caution. Irritability and poor feeding often draw attention to the disease. The cardiac physical signs are not characteristic, with variable murmurs being heard. Unexplained cardiomegaly and CHF in a generally “floppy” baby should suggest the diagnosis.


The chest radiograph may be normal at birth, but in all affected infants the heart becomes enlarged within a few weeks. There is no specific pattern to the cardiac silhouette but rather a generalized smooth enlargement of the contour. The characteristic electrocardiographic features are a short PR interval, wider than normal QRS complexes, and voltage evidence of left or biventricular hypertrophy, which can be severe ( Fig. 59.1 ). In addition, in the majority there are Q waves and inverted T waves in leads I, II, and the left chest leads. Electrophysiologic studies have shown a short A-H interval. Both M-mode and cross-sectional echocardiography demonstrate gross increase in the thickness of the ventricular free walls and the ventricular septum ( Fig. 59.2 ). Impaired diastolic filling is frequent, together with reduction of the rate and extent of systolic shortening. Cardiac catheterization is rarely performed as it adds little to the diagnosis or management.




Fig. 59.1


Typical electrocardiogram of a patient with Pompe disease demonstrates striking biventricular hypertrophy.



Fig. 59.2


Typical echocardiographic findings in glycogen storage disease type II. (A) Diastolic frame in long axis reveals severe concentric left ventricular hypertrophy, while the systolic frame from the same child (B) shows the absence of subaortic obstruction.


The complete clinical picture together with the characteristic electrocardiographic and echocardiographic findings will lead immediately to the definitive diagnostic investigation. This is the demonstration of deficiency of lysosomal α-1,4-glucosidase in fibroblasts grown from a skin biopsy. Sometimes the skeletal muscle abnormalities are less evident. The presentation is then as a cardiomyopathy alone. Pompe disease should be considered in any such case and skin biopsy performed. Until recently there was no specific treatment available, and supportive and decongestive measures failed to improve outcomes. However, recent studies using recombinant human lysosomal acid α-glucosidase show promise in improving survival. Early diagnosis, typically via standardized newborn screening in developed countries, and early initiation of enzyme replacement therapy shows the most benefit. Since the disease appears to be inherited in an autosomal recessive fashion, parents should be advised of the availability of prenatal diagnosis via culture of amniocytes obtained by amniocentesis.


Danon disease is included in this section because it was previously considered to be a variant of Pompe disease known as glycogen storage disease type IIb, with normal acid maltase. The disease is due to a deficiency of lysosome-associated protein 2 (lamp-2) and manifests as a progressive hypertrophic cardiomyopathy with skeletal myopathy. Other similar diseases in this family of autophagic vacuolar myopathies are still being studied. Some demonstrate autosomal recessive inheritance, whereas others are x-linked, and the degree of cardiac and skeletal involvement is variable.


Glycogen Storage Disease Type III (Cori Disease, Amylo-1,6-Glucosidase [Debrancher] Deficiency)


In Cori disease, an autosomal recessive condition, glycogen accumulates in skeletal muscle, the liver, and cardiac muscle due to a deficiency of amylo-1,6-glucosidase, the enzyme necessary for breaking down branch points in glycogen chains. There are three subtypes, which are dependent on the primary site of abnormal glycogen storage (IIIa, liver and muscle; IIIb, liver; IIIc, muscle). A fourth subtype (IIId) involves normal debrancher enzyme activity but a deficiency of debrancher enzyme transferase activity. Patients with types IIIa and c have a tendency to develop skeletal muscle weakness and left ventricular hypertrophy, which is progressive. A study found that 58% of patients with glycogen storage disease IIIa had some degree of ventricular hypertrophy. However, the clinical course appears to be less severe, with fewer symptoms, as compared with hypertrophic obstructive cardiomyopathy.


Glycogen Storage Disease Type IV (Andersen Disease, α-1,4-Glucan-6-Glucosyltransferase [Brancher] Deficiency)


Andersen disease is a rare heterogeneous glycogen storage disease characterized by the deposition of glycogen of abnormal structure in the liver, leading to cirrhosis. There may also be deposition of glycogen in the heart. Consequently, although liver dysfunction is the most common clinical manifestation, the disease can rarely present with dilated cardiomyopathy, which is typically severe.


Glycogen Storage Disease Type V (McArdle Disease, Muscle Phosphorylase Deficiency)


McArdle disease is an autosomal recessive condition that results from a deficiency of muscle glycogen phosphorylase. It is often not diagnosed until adolescence or adult life and is commonly misdiagnosed in childhood. Its main clinical features are muscle fatigability, muscle cramps, and myoglobinuria. Rare lethal variants have been reported in infants, but the heart is typically spared. This may be due to activity of a distinct cardiac phosphorylase isozyme that retains activity in patients with deficiency of the skeletal isozyme. No clinical cardiac manifestations have been reported, but on occasion the electrocardiogram (ECG) has features similar to those seen in Pompe disease.


Glycogen Storage Disease Type VI (Hers Disease, Phosphorylase B Kinase Deficiency, or Liver Phosphorylase Deficiency)


Hers disease involves both x-linked and autosomal recessive modes of inheritance and results from deficiency of liver phosphorylase. Both have involvement of the liver in childhood, whereas involvement of muscles occurs in young adults with the autosomal recessive form of the disease. Rare forms of phosphorylase b kinase deficiency have been described, in which deposition of glycogen is limited to the heart.


Glycogen Storage Disease Type VII (Tarui Disease, Muscle Phosphofructokinase I Deficiency)


Tarui disease is a rare form of glycogen storage disease that presents in early childhood or adult life with fatigability, muscular weakness, which can be progressive, muscle cramps, and myoglobinuria. Typically the heart is spared. However, an infantile form of the disease has been described in the members of one family. Cardiomyopathy occurred in addition to the progressive muscular weakness, and abnormal deposition of glycogen was noted in the cardiac muscle at autopsy. Progressive cardiomyopathy has also been reported in an adult.


Mucopolysaccharidoses


The mucopolysaccharidoses result from deficiency of lysosomal enzymes involved in the degradation of mucopolysaccharides. The incompletely degraded mucopolysaccharides then accumulate in the tissues. The substances accumulated are dermatan sulfate, heparan sulfate, or keratan sulfate. They can accumulate alone or in combination. There is skeletal involvement in all forms. In most, there is glaucoma and corneal clouding. Retinal pigmentation frequently occurs. Deafness is a feature of all types. In most, there is hepatosplenomegaly. Involvement of the central nervous system is common, usually with cervical myelopathy as a consequence of pachymeningitis or atlanto-occipital subluxation.


Cardiovascular involvement is a feature of all types. The mucopolysaccharides are deposited in arterial walls, including the coronary arteries, producing lesions similar to atherosclerosis. A dilated aortic root is also frequently seen. Deposition in cardiac valves leads to valvar stenosis and/or regurgitation. The various forms of these diseases are brought about by deficiencies of 10 identifiable lysosomal enzymes. Specific deficiencies can be demonstrated in cultured fibroblasts, and prenatal diagnosis from culture of amniocytes is possible. The availability of such diagnosis is important, since there is genetic variability within different forms of mucopolysaccharidoses.


Mucopolysaccharidosis Type I (α-L-Iduronidase Deficiency)


The three major clinical forms of α- l -iduronidase deficiency are Hurler syndrome, Scheie syndrome, and a syndrome intermediate between the two, Hurler-Scheie syndrome. These diseases are due to defects in the gene encoding α- l -iduronidase, and multiple defects have been elucidated. These include nonsense, missense, insertional, deletional, and splice-type gene defects. It was previously thought that the clinical severity of the disease was related to the level of de novo enzyme activity, but no biochemical differences have been identified to distinguish the subtypes.


Hurler Syndrome.


The defect in Hurler syndrome results in a virtual absence of lysosomal α- l -iduronidase. This enzyme is responsible for the breakdown of heparan sulfate and dermatan sulfate to heparan and hyaluronic acid, respectively. The enzyme is completely absent in fibroblasts but some activity is present in the liver. Consequently traces of the breakdown products of heparan and dermatan may be found in the urine. As a consequence of this enzyme deficiency, both heparan and dermatan sulfates accumulate in the lysosomes of many tissues. When in neurons, the lesions bear some resemblance to those found in Tay-Sachs disease. Deposition in the arterial walls is associated with proliferation of smooth muscle cells, and the lesions are described as “pseudoatheromatous.” There is proliferation of both elastic fibers and collagen accompanying the lysosomal accumulation of mucopolysaccharides.


The babies seem to be normal at birth, the clinical features appearing after the age of 1 year, when the facial features become coarse. Premature closure of the skull sutures and hydrocephalus as a consequence of pachymeningitis lead to cranial deformities. The characteristic lumbar lordosis develops because of stiff joints. Growth retardation then becomes evident after the age of 2 or 3 years; deafness, corneal clouding, and (sometimes) glaucoma subsequently develop. The liver and spleen are always enlarged. Although the heart is rarely spared, clinical evidence of cardiac involvement is seen only in half the patients. Angina pectoris is an occasional symptom because of coronary artery involvement, but more frequently attention is drawn by the finding of a cardiac murmur or systemic hypertension. The murmurs are variable and usually not loud. Rarely, the murmur of aortic or mitral insufficiency may be heard. Cardiac failure as the presenting feature associated with endocardial fibroelastosis has been reported.


There are typical skeletal radiologic features. The clavicles have wide medial ends. The lower thoracic and upper lumbar vertebrae have a flared and hook-shaped appearance. There are also changes in the skull and long bones, the latter being more severely affected in the upper limbs. The heart is usually enlarged but with no specific silhouette, although left atrial enlargement will occur with severe mitral regurgitation. Similarly, there are no specific electrocardiographic features, although combined ventricular hypertrophy is frequent. A long QT interval has been reported in some patients.


Pathologic findings in the heart include deposition of mucopolysaccharide in structures such as the sinus and atrioventricular nodes as well as in the myocardium and endocardium. The coronary arteries often demonstrate severe luminal narrowing, and care must be taken whenever these patients are subjected to general anesthesia or sedation, as hypotension can lead to coronary ischemia and death. The mitral valve is most frequently involved, followed by the aortic and tricuspid valves. Pulmonary valve involvement is only rarely reported. Valvar changes include nodular thickening along the free edges, which may lead to stenosis or regurgitation. Evidence suggests that the accumulation of dermatan sulfate leads to impaired elastogenesis, which may lead to some of the characteristic arterial and valvar deformities.


Thickening of the valve leaflets is characteristically seen echocardiographically. Left ventricular cavity enlargement will reflect the volume load resulting from valvar regurgitation, and left ventricular mass may be increased as a result of compensatory hypertrophy and deposition of mucopolysaccharide in the myocardium. Cardiac catheterization and angiocardiography add little to the diagnostic findings, which include systemic and mild pulmonary hypertension. If angiography is performed, the hemodynamics will reflect the severity of valvar insufficiency. The disease progresses inexorably, death occurring by the age of 10 years from heart failure, sudden death, or from chest infection. Hematopoietic stem cell transplantation has been beneficial in selected patients for many aspects of the disease. However, the valvar lesions remain progressive. Enzyme replacement therapy with human recombinant α- l -iduronidase has also proved beneficial, but, as with stem cell transplantation, the valvar lesions appear to remain and even progress.


Scheie Syndrome.


Patients with Scheie syndrome are less severely affected and have normal stature and intellect. They also have a near normal life span. The most striking features are corneal clouding and stiff joints. Typical cardiac manifestations are aortic stenosis and regurgitation or mitral regurgitation. These should be managed in a similar fashion to that employed in otherwise normal subjects. Scheie syndrome is inherited in autosomal recessive fashion.


Hurler-Scheie Syndrome.


Hurler-Scheie syndrome falls in severity between the two extremes of α- l -iduronidase deficiency. The patients have short stature with mental retardation and multiple bony defects. There is clouding of the cornea and stiff joints, claw-hand being particularly common. Aortic and mitral valve involvement is the primary manifestation, but asymmetric septal hypertrophy has also been reported. The clinical course is intermediate between Hurler and Scheie syndromes, patients living into adolescence or even to the third decade.


Mucopolysaccharidosis Type II (Hunter Syndrome, Iduronate Sulfatase Deficiency)


Deficiency of iduronate sulfate results in blocked degradation of dermatan sulfate. The difference in clinical profile between this and Hurler and Scheie syndromes (e.g., the absence of corneal clouding in Hunter syndrome) may result from specific variability in the degree of blockage of degradation of the mucopolysaccharide. Furthermore, it may be that the block to degradation caused by the accumulation of iduronate sulfate may be bypassed by hyaluronidase. The severe and mild forms of Hunter syndrome both have total (or near total) deficiency of iduronate sulfatase. However, as with mucopolysaccharidosis type I, the clinical phenotype may be representative of the degree of residual enzyme activity specific to certain gene mutations, of which more than 300 have been found for Hunter syndrome.


The condition can occur with a wide variation in severity, which tends to run true in any given family. Apart from the extreme rarity of corneal clouding in Hunter syndrome and the presence of hearing loss, the clinical features are those of Hurler syndrome, although usually less severe. A positive distinguishing physical sign pointed out by Hunter himself (1916) is the occurrence of pebble-like ivory-colored skin lesions. These are seen over the scapulae and occasionally on the pectoral regions.


Cardiac involvement produces all the manifestations so far mentioned, namely aortic and mitral regurgitation or stenosis, ischemic changes, and evidence of myocardial deposition and dysfunction. Echocardiography is a useful method for evaluating cardiac involvement in Hunter syndrome. The clinical course is extremely variable. Severely affected individuals may die in adolescence. At the opposite end of the spectrum, however, survival beyond the sixth decade has been reported. Death in younger patients is usually associated with progressive neurologic deterioration. The disease is inherited as an X-linked recessive trait, although cases in females have been reported. Since the reproductive fitness of the Hunter gene is low, a large proportion of cases result from new mutations.


Recently a new treatment for Hunter syndrome has emerged with the development of recombinant human iduronate-2-sulfatase. This is well tolerated and associated with improvement in several outcome parameters, including forced vital capacity, urinary excretion of glycosaminoglycans, liver and spleen volume, and 6-minute walk distance. However, the effect of enzyme therapy on the cardiac lesions remains to be determined.


Mucopolysaccharidosis Type III (Sanfilippo Syndrome)


The degradation of heparan sulfate and N -sulfated or N -acetylated α-linked glucosamine requires five enzymes: N -sulfoglucosamine sulfohydrolase (sulfamidase), α-2-acetamido-2-deoxy- d -glucoside acetamidodeoxyglucohydrolase (α- N -acetylglucosaminidase), heparan acetyl CoA:α-glucosaminide N -acetyltransferase, N -acetylglucosamine-6-sulfatase, and N -glucosamine-3-O-sulfatase. Deficiency of one of the five enzymes required for this degradation results in the Sanfilippo syndrome, which is an autosomal recessive disorder. Consequently there are five biochemically distinct types of the disease (designated a to e ), although they all present the same clinical features. Incidentally, type e has yet to be uncovered in humans, although it exists in animal models.


The onset is usually evident in the first few years of life with “behavioral” problems. Mental and neurologic deterioration are severe and lead to death in the first two decades. Bone, joint, and cardiac involvement is generally less severe than in Hurler syndrome. Corneal clouding is never seen.


There is wide variation in the severity and age at death in all four forms, but type a is likely to be the most severe. Inheritance is in autosomal recessive fashion. Cardiac involvement is similar to that of other mucopolysaccharidoses, with a number of patients reported to have mitral valve involvement. Although treatment is primarily supportive, animal studies have been undertaken to assess enzyme replacement therapy in a mouse model with mucopolysaccharidosis type III-b.


Mucopolysaccharidosis Type IV (Morquio Syndrome)


Morquio syndrome results from defective degradation of keratan sulfate. It occurs in two biochemically distinct forms. So-called type a is due to a deficiency of n -acetylgalactosamine-6-sulfate sulfatase, whereas type b results from deficiency of β-galactosidase. The two types have similar clinical features, but type b is less severe, sometimes being called the “long-legged” variant. Despite the generally increased severity of features with type a, more mild forms of type a can occur. Keratan sulfate is excreted in the urine in type a, but this is less evident in type b.


Keratan sulfate is found in cartilage, intervertebral discs, and the cornea. Thus skeletal involvement with dwarfism, pectus excavatum, and bowed legs are the most obvious manifestations. Corneal clouding is common. In contrast to the mucopolysaccharidoses described earlier, the joints in patients with Morquio syndrome are hyperextensible. Absence or severe hypoplasia of the odontoid process, together with laxity of its associated ligaments, leads to atlanto-occipital subluxation and consequent cervical myelopathy. Sinus tachycardia is a common feature of this disease, but the mechanism is unclear. Valves of the heart are often involved, with thickening of mitral and aortic leaflets, although significant valve dysfunction is less common. Aortic root dilation, concentric left ventricular hypertrophy and, rarely, asymmetric septal hypertrophy have all been described. Survival beyond the third or fourth decade is not unusual. The effects of the cervical myelopathy and respiratory problems are the usual cause of death. Experimentation with enzyme replacement therapy in animals has been undertaken and holds some promise.


Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome)


Deficiency of arylsulfatase b results in an inability to hydrolyze the sulfate groups in dermatan sulfate. The clinical picture is similar to that of Hurler syndrome, but normal intelligence is usual. Although severe in its classical form, milder variations exist. Affected infants can present acutely with cardiomyopathy. The mitral and aortic valves are frequently involved and the disease is typically progressive. Regurgitation is the primary valve disorder, but stenosis or a combination or stenosis and regurgitation will become more common over time. Valvar dysfunction severe enough to necessitate replacement has been noted in young adults. Left ventricular aneurysm has also been reported. Death usually occurs in the third decade. The condition is inherited in an autosomal recessive fashion, although some cases have been presumed to be X-linked. Enzyme replacement therapy with human recombinant arylsulfatase b has been studied and found to be effective in terms of arresting the progression of cardiac valve disease when started late in life, but it is postulated that it may have even better efficacy if started in early infancy.


Mucopolysaccharidosis Type VII (Sly Syndrome)


Deficiency of β-glucuronidase results in a clinical syndrome of extremely variable severity. Included in the features are coarse facies, corneal clouding, abdominal and inguinal hernias, puffy hands and feet, hepatosplenomegaly, and a small thoracolumbar hump. Cardiovascular manifestations include hypertension, aortic aneurysm, valve thickening, aortic regurgitation, obstructive arterial disease including coronary involvement, and cardiomyopathy. Fetal hydrops has also been reported. This extremely rare condition is inherited in autosomal recessive fashion. Duration of survival varies widely and depends on the severity of the disease. Death as early as 30 months has occurred in one child with severe disease. Animal studies involving enzyme replacement therapy have been performed and are encouraging in terms of improving the cardiovascular changes associated with this disease.


Mucolipidoses


The mucolipidoses present with clinical features similar to the mucopolysaccharidoses but are biochemically distinct. Leroy and Demars observed inclusions in cultured fibroblasts that occupied the whole cytoplasmic space apart from the Golgi apparatus. It was because of this that the name inclusion-cell, or i-cell, disease was coined. The cause of the lysosomal storage defect is deficiency of several acid hydrolases in the lysosome, but this is not the primary problem, since the plasma abounds in these acid hydrolases (albeit in unstable forms). The problem is failure to locate the hydrolases within the lysosome. Failure of phosphorylation of mannose residues of the hydrolases is the primary defect. Hydrolases without mannose 6-phosphate components are then not recognized by the lysosome and are not transported across the lysosomal membrane, particularly in connective tissue. In this way, inclusion-cell disease and pseudo-Hurler polydystrophy differ from sialidosis (previously called mucolipidosis type I), where there is a single lysosomal enzyme defect. Mucolipidoses types II (inclusion-cell disease) and III (pseudo-Hurler polydystrophy) result from a deficiency of uridine diphosphate (udp)-n-acetylglucosamine:lysosomal enzyme n-acetylglucosamine-1-phosphotransferase. The degree to which this enzyme is deficient determines the ultimate phenotype. Diagnosis is suggested by clinical features resembling mucopolysaccharidoses but without their biochemical abnormalities. Findings of high serum levels of β-hexosaminidases, iduronate sulfatase, and arylsulfatase are diagnostic. The characteristic enzymatic deficiencies in fibroblasts can be identified in cultured cells.


Mucolipidosis Type II (Inclusion-Cell Disease, I-Cell Disease)


Inclusion-cell disease is an autosomal recessive condition that results from a severe deficiency of the phosphotransferase enzyme due to specific gene mutations that result in a marked reduction in enzyme activity. Various defects in the gene encoding this enzyme have been discovered in patients with this disorder. Patients with inclusion-cell disease present with clinical features very similar to those of Hurler syndrome. Hepatosplenomegaly is not so obvious, whereas striking gingival hypertrophy is a feature not encountered in Hurler syndrome. Furthermore, the disease becomes evident earlier than does Hurler syndrome. Corneal clouding is the rule. The skeletal and joint abnormalities, together with myocardial infiltration, usually lead to death by the age of 5 years either from respiratory causes or cardiac failure. All children have cardiac involvement, frequently with thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Asymmetric septal hypertrophy has been reported. Treatment of the cardiac manifestations is usually supportive, although surgical management of valve involvement has been reported. Also, success with allogeneic stem cell transplantation in terms of disease progression has been reported in a small number of cases.


Mucolipidosis Type III (Pseudo-Hurler Polydystrophy)


Mucolipidosis type III is an autosomal recessive condition that is less severe, and also less common, than type II and is due to a deficiency of the same phosphotransferase enzyme. However, in this type the enzyme activity is less severely reduced and the manifestations are less severe. There is significant variability in the clinical severity of this disease. This is likely due to various genetic defects leading to different levels of enzyme activity. Patients are usually spared the joint manifestations early in life (unlike those with inclusion-cell disease) and often present with joint stiffness at the age of 4 or 5 years. Growth is moderately retarded and corneal clouding is present by the age of 7 or 8 years. The patients are disabled by carpal tunnel syndrome and destruction of the hip joints. Cardiac involvement, typically gradual thickening and eventual regurgitation of the mitral and aortic valves, does occur but is usually not sufficiently severe to cause clinical problems. Patients with pseudo-Hurler polydystrophy generally survive into the fourth decade. More recently, with advances in understanding of the genetics of the disease, mucolipidosis has been subcategorized into type III α/β and type III gamma as the deficient enzyme is the product of two genes. The first encodes the α and β subunits and the second encodes the gamma subunit. Despite this, the two subtypes have similar manifestations.


Disorders of Glycoprotein Degradation


Specific lysosomal enzymatic deficiencies result in failure of degradation of glycoproteins with consequent accumulation of glycoproteins in many tissues, especially the nervous system. They became recognized when patients with presentations similar to those with the mucopolysaccharidoses were found to have biochemically distinct diseases.


The five primary disorders of glycoprotein degradation, mannosidosis, fucosidosis, sialidosis, galactosialidosis, and aspartylglycosaminuria, can all be diagnosed by demonstration of the enzyme defect in cultured fibroblasts. Prenatal diagnosis is often possible.


Mannosidosis


Deficiency of α-mannosidase is a rare, autosomal recessive disorder that results in the accumulation of oligosaccharides, as their degradation is dependent on lysosomal activity of this enzyme. Oligosaccharides are excreted in the urine. Several defects in the gene encoding α-mannosidase have been discovered. The specific defect may result in decreased enzyme synthesis, decreased enzyme activity within the lysosomal environment, decreased localization of the enzyme within the lysosome, or faulty posttranslational modification of the enzyme. The patients present with features suggestive of mucopolysaccharidosis but have an increased susceptibility to infections. Progressive mental retardation is typical. Early onset of the disease categorized as type I is associated with increased severity. Death occurs between 3 and 10 years of age. Late-onset disease (type II) runs a more benign course. Cardiac manifestations are not frequently reported. However, a short PR interval has been reported in several patients. The mechanism for this is unknown. Treatment has been attempted with bone marrow transplantation, and strategies currently under investigation include various forms of enzyme replacement therapy.


Fucosidosis


Deficiency of α- l -fucosidase results in the accumulation of fucosylated oligosaccharides and glycolipids. Two clinical types are recognized. The first type presents in infancy with coarse facies, growth retardation, mental retardation, and neurologic deterioration. Convulsions and respiratory infections often occur. The second type has a more benign course and a later onset. Cardiomegaly, probably as part of a generalized visceromegaly, is the most common cardiac feature but is benign. These two types probably represent both ends of a continuum that is dictated by a patient’s specific enzyme activity as determined by his or her specific gene defect. Bone marrow transplantation has been performed with good results, and further experimentation with enzyme replacement therapy is ongoing.


Sialidosis


The basic defect in sialidosis is deficiency of α-neuraminidase, with accumulation of sialoglycoconjugates. Two forms exist. The first is of late onset and patients are of normal appearance but develop the cherry-red spot myoclonus syndrome. Decreased visual acuity is associated with a cherry-red spot in the macular region. Neurologic (and occasional renal) manifestations dominate the clinical picture. The second type has an early onset, even on occasion being obvious at birth. The patients have coarse features and enlargement of various organs including the heart. Echocardiography has shown an increased left ventricular wall thickness along with thickening of the mitral valve. There is great variability in the spectrum of severity, even in the group with early onset. Survival beyond 20 years is rare; occasionally, however, affected subjects are stillborn. Fetal hydrops has been reported as a presenting feature. Sialidosis is inherited in autosomal recessive fashion. Enzyme replacement therapy and gene transfer treatments are under investigation.


Galactosialidosis


In galactosialidosis, patients have a defect in the production of lysosomal protective protein/cathepsin A, which helps to form a stable and activated complex with β-galactosidase and α-neuraminidase. Thus the symptoms are a combination of those seen in sialidosis and Morquio syndrome, the severity of which is likely determined by the specific genetic defect and its overall effect on the production of functional levels of the protein. An infantile form has been described, and there appears to be a fair amount of clinical variation even in those diagnosed as infants. Structural congenital heart disease has been reported in patients with galactosialidosis, but the cardiac manifestations are usually similar to those seen in Morquio syndrome and sialidosis, with aortic and mitral valve thickening, which is progressive. Recently the role of these enzymes and protective protein/cathepsin A in elastogenesis has begun to be unraveled, helping to further explain the phenotype associated with these genetic disorders. Although no specific treatment yet exists, early work has begun on therapies involving enzyme replacement or gene transfer.


Aspartylglycosaminuria


Aspartylglycosaminuria is a lysosomal storage disease due to a defective or deficient glycosylasparaginase. This enzyme is required for complete breakdown of asparagine-linked glycoproteins within the lysosome. Accumulation of these glycoprotein residues leads to severe and progressive neurologic impairment. It is associated with coarse features, joint laxity, and early rapid somatic growth followed by a reduced adolescent growth spurt leading ultimately to short stature and mental retardation. Animal models demonstrate residue accumulation within the heart, but clinical cardiac involvement does not appear to predominate. Therapy via enzyme replacement is currently being studied in animal models.


Acid Lipase Deficiency (Wolman Disease and Cholesterol Ester Storage Disease)


Lysosomal acid lipase is necessary for the cleavage of triglycerides and cholesterol esters from lipoproteins delivered to the lysosome. Complete or partial deficiency of lysosomal acid lipase results in accumulation of cholesterol in most tissues of the body. The disease occurs in two forms. Wolman disease, with complete absence of enzymatic activity, is a disease of infancy presenting with vomiting, diarrhea, hepatosplenomegaly, failure to thrive, anemia, and calcification of the adrenal glands. Cardiac manifestations are not usually evident, but microscopic examination of the arteries shows excess fatty deposits. Hepatomegaly is frequently the only sign in the milder form of the disease, cholesterol ester storage disease, although premature atherosclerosis is also seen. The diagnosis of Wolman disease is suggested by the association of hepatosplenomegaly with adrenal calcification. Definitive diagnosis of either disease can be made by assessing acid lipase activity in cultured skin fibroblasts. The disease is inherited in autosomal recessive fashion. Successful treatment with hematopoietic stem cell, bone marrow, and cord blood transplantation has been reported.


Sphingolipidoses


Sphingomyelin Lipidosis (Niemann-Pick Disease)


In Niemann-Pick disease, there is accumulation of sphingomyelin in the cells as a result of deficiency of sphingomyelinase (type a and b). A second distinct form (type c) was recently discovered, which arises from the defective function of cholesterol transport. The primary cells affected are those of monocyte-macrophage lineage as they are frequently employed in the metabolic turnover of these substances. In type a, patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement. These individuals rarely survive beyond 3 years of age. Type b patients also have hepatosplenomegaly along with pathologic alterations in their lungs, but there are usually no central nervous system signs. In type c, psychosis predominates initially. Many of these patients are of Ashkenazi Jewish heritage. The disease is characterized by hepatosplenomegaly and the occurrence of foam storage cells in many tissues. The heart is not usually affected, but one infant with acute neuronopathic disease had endocardial fibroelastosis. Since there were no storage cells in the heart, however, this may have been a chance association. Lipid profile abnormalities have also been described in children with Niemann-Pick disease types a and b, possibly leading to premature atherosclerosis. Low levels of high-density lipoprotein cholesterol was the most consistent finding, whereas elevated triglycerides and levels of low-density lipoprotein cholesterol were seen in approximately two-thirds. These abnormalities were noted at an early age and may reflect deranged cholesterol metabolism in these cells as a result of sphingomyelin accumulation. Niemann-Pick disease in most of its forms is inherited in an autosomal recessive fashion.


Glucosylceramidosis (Gaucher Disease)


Gaucher disease is the most common inherited disorder of glycolipid metabolism. In his original description, Phillippe Gaucher ascribed the changes to a primary epithelioma of the spleen. There is excessive accumulation of glucosylceramide in cells of the reticuloendothelial system in organs throughout the body, resulting from deficiency of the enzyme glucocerebrosidase, which cleaves glucose from glucocerebroside. Although over 150 different mutations of the gene encoding glucocerebrosidase have been described, the disease occurs in three varieties based on the presence or absence of neurologic manifestations and their rate of progression. The first (type I, the chronic nonneuronopathic form) can be diagnosed at any age and is the most common form. It is characterized by hypersplenism, hepatomegaly (with evidence of abnormal liver function), and skeletal lesions (including aseptic necrosis of the femoral head). Other long bones and vertebrae may also be eroded. In patients with this type of disease, cardiac involvement may be seen, with myocardial infiltration or restrictive pericardial disease. The most frequently encountered cardiac problem, however, is cor pulmonale secondary to pulmonary involvement. Mitral and aortic stenosis and insufficiency can also be seen, and severe valvar and aortic arch calcification has been reported. The course is variable. Death may occur in early childhood or, particularly when the onset is late, there may be a normal life expectancy. Further variability is apparently the consequence of the nonneuronopathic form at onset changing to one of the other forms with poorer prognosis.


The acute neuronopathic form (type II) is usually recognized within the second half of the first year of life. Neurologic involvement is evident early, afflicting particularly the cranial nerves and extrapyramidal tracts. The mechanism of death is usually a respiratory infection, since—owing to incoordination of the nasopharynx—aspiration is common.


The subacute neuronopathic form (type III) falls between the acute and chronic forms. The neurologic involvement renders it less benign than the chronic variant, but its course usually stretches over many years.


Although describing Gaucher disease in terms of three distinct phenotypes is convenient, the actual observed behavior of this disease is much less well defined. Patients with the same genotype can have widely differing phenotypes, and patients even within a particular type can have markedly differing clinical courses. Thus, although the genetic defects leading to Gaucher disease are being elucidated and include over 150 specific mutations already identified, the genotype-phenotype link is still quite unclear.


The diagnosis of Gaucher disease is confirmed by the finding of typical storage cells in the bone marrow or by liver biopsy. The Gaucher cell is large and lipid-laden. The cytoplasm is described as having a “wrinkled tissue paper” or “crumpled silk” appearance. The nucleus is eccentric. These cells must be differentiated from cells found in multiple myeloma, leukemia, thalassemia, and congenital dyserythropoietic anemia. Demonstration of the enzymic deficiency in cultured skin fibroblasts or in leukocytes confirms the diagnosis. Treatment options include bone marrow transplantation and gene therapy in rare cases, but enzyme replacement therapy has become the standard of care in the majority of cases. In fact, type I Gaucher disease was the first lysosomal storage disorder for which, in 1991, an effective enzyme replacement therapy was developed. Improvement in the visceral organ involvement is common, but neurologic damage is generally not responsive to exogenous enzyme therapy. All three variants are inherited as autosomal recessive traits. Intrauterine diagnosis is available, and heterozygotes can be identified at least for the acute and chronic types.


α-Galactosidase a Deficiency (Fabry Disease)


Deficiency of α-galactosidase, a lysosomal enzyme, results in the accumulation of phosphosphingolipids in the lysosomes of many tissues and also in the body fluids. The most frequently affected tissue is the vascular endothelium. The disease is of X-linked inheritance, but heterozygous women can show severe manifestations of the disease. The gene locus for the enzyme is on the long arm of the X-chromosome.


The disease usually presents in childhood in the male homozygote, often with periodic crises of severe pain of burning character, which usually starts in the hands and feet. Crises occur most usually in the afternoon. Such crises, which become less frequent and severe with time, may, however, be followed by eruption of skin lesions, angiokeratomas, and typical opacities of the cornea and the lens. The angiokeratomas are clusters of dark-red to purple punctate lesions, which are usually flat or slightly raised. They occur most frequently between the umbilicus and the knees and do not blanch on pressure. Hyperkeratosis and hypohydrosis usually accompany the angiokeratomas. Ocular lesions include typical creamy whorl-like opacities in the cornea. They are frequently found in the female heterozygote as well as the male homozygote. Cardiac disease is manifest with increasing age. Myocardial ischemia and infarction are common and are secondary to the vascular lesions. Mitral regurgitation and aortic stenosis are the most frequently encountered valvar lesions. Infiltration of the conduction tissues also occurs. This results in progressive shortening of the PR interval, as in other storage diseases that affect the specialized atrioventricular conduction axis. Myocardial deposition can be detected echocardiographically by the demonstration of septal and left ventricular wall thickening. Progressive deposition of glycosphingolipid means that the cardiac problems themselves are also progressive. Since concomitant renal involvement occurs, the cardiac effects are exacerbated by, for example, renal hypertension. The clinical course in the male homozygote is one of steady deterioration during early adult life, death being due to cardiac or renal disease. The heterozygote female experiences little limitation of style and length of life. The diagnosis can be confirmed (and heterozygotes identified) by demonstrating the enzymic deficiency in leukocytes and by an abnormally high content of accumulated substrates in tears or urinary sediment. Prenatal diagnosis is available. Enzyme replacement therapy was first reported in 2002, and positive effects on cardiac involvement are evident. Fabry disease should be considered whenever unexplained left ventricular hypertrophy is discovered, as early diagnosis and initiation of enzyme replacement therapy has shown clear benefit.


Gangliosidoses


The gangliosidoses are lysosomal storage diseases characterized by accumulation of gangliosides gm 1 or gm 2 (or related conjugates) owing to deficiency of specific lysosomal hydrolases. The enzyme deficient in gm 1 gangliosidosis is acid β-galactosidase. Deficiency of hexosaminidase a or b (or both) or a deficiency of an enzyme activator results in gm 2 gangliosidosis.


Gm 1 Gangliosidosis


There are many enzymatic and clinical subdivisions of gm 1 gangliosidosis. The gene locus is on the short arm of chromosome 3. Mutation at this locus results in absence of enzyme activity for acid β-galactosidase, leading to accumulation of gm 1 ganglioside in the brain and viscera. The wide variation in clinical picture has resulted in a broad classification of infant, juvenile, and adult forms. All forms of gm 1 gangliosidosis are inherited as autosomal recessive traits.


The infant form is a rapidly progressive disease characterized by hypotonia, poor feeding, and failure to make motor or intellectual progress. Progressive neurologic deterioration results in spastic quadriplegia or decerebrate rigidity. Rarefied bones and beaked vertebrae are some of the skeletal lesions encountered. As in Tay-Sachs disease (see later), a cherry-red spot is seen in the macular region of the retina. Death usually occurs by the age of 3 years, frequently from bronchopneumonia. The heart is frequently involved. The spectrum from CHF with systolic dysfunction to isolated valve thickening has been observed. Neonatal ascites has also been reported. Cardiac involvement usually includes cardiomegaly on chest radiography, left ventricular hypertrophy on the echocardiogram, and CHF. Interestingly, patients with gm 1 gangliosidosis have a defect in the same enzyme that is involved in patients with Morquio syndrome type b. The clinical heterogeneity among patients with this enzymatic defect is unclear but is probably related to residual activity of the enzyme, postprocessing of the enzyme, and other proteins involved such as saposin b. A novel treatment strategy is under investigation involving molecular chaperones, substances that stabilize the configuration of defective enzymes and enable them to remain enzymatically active. Treatment in a mouse model demonstrated improved enzyme activity and a reduced quantity of substrate in neuronal tissues; however, no viable therapy for humans yet exists.


Gm 2 Gangliosidoses


The gm 2 gangliosidoses are autosomal recessive conditions that result in variable deficiency of hexosaminidase, the locus for which has been mapped to the q arm of chromosome 5. This enzyme, which is composed of two subunits (α and β), comes in two forms. Hexosaminidase a (found in the central nervous system) is composed of an α- and β-subunit, and hexosaminidase b (found in peripheral tissues) is composed of two β subunits. Thus the gm 2 gangliosidoses result from a defect in either the α-subunit (Tay-Sachs disease, severe deficiency of hexosaminidase a) or the β-subunit (Sandhoff disease, with severe deficiency of both types a and b of the enzyme). The juvenile and adult (chronic) gm 2 gangliosidoses result from less severe deficiencies of hexosaminidase type a. Treatment for these disorders is still under investigation using animal models. Efforts have included gene therapy, substrate reduction therapy, and bone marrow transplantation, although none of these treatments has yet to show clinic benefit in humans.


Tay-Sachs Disease.


Tay-Sachs disease is the most common of the gangliosidoses; it presents with motor weakness in the first 6 months of life. There is progressive motor and mental deterioration, with convulsions, spasticity and decerebrate rigidity. Death usually occurs by the age of 3 years, the most frequent cause being bronchopneumonia. The children have doll-like facies. Examination of the retina shows the typical cherry-red macula, which later becomes brown. Cardiac accumulation of substrate is usual; however, save for a prolonged QT interval and nonspecific T-wave changes, cardiac manifestations are rare. Although the hallmark of the disease is central nervous system accumulation of gm 2 ganglioside, evidence of peripheral and autonomic nervous system involvement has been reported in patients with chronic disease.


Sandhoff Disease.


Sandhoff disease is similar to Tay-Sachs disease in its presentation and course but is biochemically distinct. Clinically relevant cardiac involvement is rare, but a cardiomyopathy has been described, along with thickening of the mitral valve and its tension apparatus. Another separate report describes a case of CHF due to aortic and mitral valve thickening with severe mitral regurgitation. The coronary arteries may also be narrowed. As with gm 1 gangliosidoses, the inheritance is autosomal recessive.




Endocrine Disorders


Diabetes Mellitus


The annual incidence of types 1 and 2 diabetes mellitus (DM) diagnosed prior to age 19 years has been increasing over the last few decades. From 2011 to 2012, the incidence of type 1 DM was 21.7 cases per 100,000 youths per year, and the incidence of type 2 DM was 12.5 cases per 100,000 youths per year. There were significant variations across racial and ethnic groups for both types 1 and 2. Cardiovascular complications are usually manifest later in the disease, and they are exceedingly rare in childhood.


However, the pediatric cardiologist will encounter an increasing incidence of congenital cardiac malformations in the offspring of diabetic mothers. Congenital structural cardiac anomalies occur in 3% to 6% of pregnancies complicated by insulin-dependent diabetes, with a predominance of conotruncal abnormalities. Because these defects occur early in gestation and are associated with poorly controlled DM, with higher HbA1c increasing the risk, preconception counseling and treatment are very important.


The most frequent neonatal cardiac complication of maternal diabetes is hypertrophic cardiomyopathy, produced by elevated levels of insulin and insulin-like growth factor I. The most obvious complication, however, is macrosomia. Even in the absence of congenital cardiac disease, infants of diabetic mothers have a host of problems. This syndrome is seen both in mothers with established diabetes and in those who develop the disease during pregnancy. The babies have a characteristic appearance, with high birth weight, plumpness, and puffy plethoric facies. They are jittery, owing to hypoglycemia secondary to hyperinsulinism. The organs, including the heart, are enlarged. The babies are frequently tachypneic, but this may not be of cardiac etiology. Respiratory distress syndrome is quite common. Cardiac murmurs are frequent. Approximately one-third have radiologic cardiomegaly. The ECG is rarely diagnostic.


In diabetes-related cardiac hypertrophy, the ECG shows thickening of the right and left ventricular walls together with the septum. Indeed, the ventricular septum is usually thicker than the free walls. Septal thickness is generally most pronounced in those infants with CHF. Spontaneous improvement after birth is usual, and specific treatment of the hypertrophic cardiomyopathy is rarely needed. Diuretics must be used judiciously, as the thickened myocardium requires a high preload, and β-blockade is sometimes advised to help diastolic dysfunction, but the benefit has not been proven. The clinical and echocardiographic signs of hypertrophic cardiomyopathy usually resolve over the early weeks of life, but myocardial thickening can take up to 6 months to resolve. More important than diagnosis and treatment is prevention. It is suggested that the most severely affected newborns are those in whom maternal control of diabetes has been poor.


Pituitary Gigantism and Acromegaly


Adenomas of the pituitary that secrete growth hormones cause gigantism in growing children and acromegaly in adults. Cardiovascular complications are common and leading contributors to the morbidity and mortality of acromegaly. Hypertension, early coronary artery disease, valve disease, arrhythmias, and acromegalic cardiomyopathy have all been described. Acromegalic cardiomyopathy results from elevated levels of growth hormone and the resultant elevated levels of insulin-like growth factor 1. The cardiomyopathy is characterized by biventricular and concentric involvement, which is progressive and may lead to CHF with myocardial fibrosis. The severity of disease relates to the age of the patient. Treatment with surgery or somatostatin analogues, which reduce growth hormone levels, is beneficial in terms of clinical symptoms and indexes of myocardial morphology and physiology.


Disorders of Thyroid Function


Hypothyroidism


Congenital Hypothyroidism.


Congenital hypothyroidism has many etiologies. The most common cause is congenital thyroid dysplasia, present in approximately 1 in 6000 live births. There are rarer causes, including endemic deficiency of iodine, diminished responsiveness to thyrotrophin in familial goiter, and administration of antithyroid drugs to pregnant mothers. The cardiac features of cretinism are not dramatic. Normal to slow heart rates and radiologic cardiomegaly are usually the only manifestations. The enlarged cardiac silhouette is usually caused by pericardial effusion, which is an extremely common feature (affecting approximately half of these patients ), but it is rarely hemodynamically important. Cardiac performance is usually well preserved. Abnormalities of heart rate and the pericardial effusions resolve when substitution treatment of the hypothyroidism is successful.


Juvenile Hypothyroidism.


As with congenital forms, juvenile hypothyroidism has multiple etiologies. It is generally the result of autoimmune thyroiditis or Hashimoto disease. Growth retardation is the most common form of presentation and can lead to delayed sexual maturation. Cardiac signs and symptoms are few and cardiac failure is very rare. Bradycardia, low pulse pressure, poor peripheral circulation, and nonspecific murmurs may be present. Pericardial effusions with no evidence of pericarditis occur in some patients. Tamponade is rarely seen because of the slow rate of fluid accumulation. About half of the patients with pericardial effusions have associated pleural effusions. Establishment of a euthyroid state reverses the cardiac manifestations.


Hyperthyroidism


Juvenile Hyperthyroidism.


The most common cause of juvenile hyperthyroidism is diffuse toxic goiter, also known as Graves disease. This is an autoimmune disease in which IgG immunoglobulins, which stimulate excessive production of thyroid hormones, can be demonstrated. It is more common in girls, with a ratio of females to males of approximately 5 to 1. Its greatest incidence is between the ages of 11 and 19 years, and it is rarely seen in children under the age of 3 years. Cardiovascular issues are present at presentation in approximately one-quarter of these patients. Other presenting symptoms include restlessness, poor performance at school, irritability, loss of weight, and occasionally diarrhea. On examination, patients have warm skin and a fine tremor is visible in outstretched hands. Enlargement of the thyroid gland is always present, and bruits are often audible over the enlarged gland because of its increased vascularity. Exophthalmos is common but is not marked. Cardiovascular involvement is secondary to an increased adrenergic drive and to direct myocardial stimulation by thyroid hormones. The pulse is fast with a wide pulse pressure. The systolic blood pressure is increased, and the apical impulse is hyperdynamic. On auscultation, the first heart sound is accentuated, and nonspecific systolic murmurs may be present. A high incidence of mitral valve prolapse has been reported in adults with Graves disease but has not been demonstrated in children. This suggests that the appearance of the prolapse is related to the duration of the disease.


The ECG is atypical. Sinus tachycardia, first-degree atrioventricular block, and nonspecific ST-segment and T-wave changes may be present. Signs of atrial and left ventricular enlargement are more common in children than in adults. Although atrial fibrillation is quite common in adults, it is extremely rare in children. Radiographic cardiomegaly and a slight increase in pulmonary vascular markings may be seen, especially in the setting of CHF, although this is rare today. The echocardiogram reveals hyperdynamic ventricular contractions with a variable degree of chamber enlargement.


Evaluation of cardiac function by radionuclide angiography in the presence of hyperthyroidism has demonstrated a fall in left ventricular ejection fraction with exercise; however, upon restoration of a normal thyroid state, the ejection fraction shows its normal exercise-induced increase. In general the cardiovascular system in childhood tolerates the effects of hyperthyroidism well. In the presence of cardiac failure, however, concomitant cardiovascular lesions must be excluded. Cardiovascular manifestations of hyperthyroidism are reversible with treatment; but if the disease is of long standing or poorly treated, it may predispose to irreversible cardiac dysfunction.


Addison Disease


Adrenal insufficiency may occur at any age and demonstrates no predilection for gender. It usually results from autoimmune destruction of the adrenal cortex and is manifested by weakness, hyperpigmentation, nausea, vomiting, loss of weight, and hypotension. When acute in onset or when seen in patients who are metabolically stressed by a concomitant illness, the disease may present with shock or coma.


Cardiac involvement is due to the chronic hypotension and hypovolemia. Chest radiography may demonstrate diminished cardiac size. The ECG may demonstrate diffusely low voltages, sinus bradycardia, and first-degree atrioventricular block. Treatment involves replacement of mineralocorticoid hormones and must be carried out with caution as CHF can ensue. This complication is presumably due to the acute load of salt and water that is thrust upon the previously unloaded myocardium and is a readily treatable, generally transient condition.




Disorders of Energy Metabolism


Mitochondrial Myopathies


The mitochondrial myopathies are muscle and systemic disorders characterized by the presence of mitochondria with abnormal structure, number, and/or function. They are typically caused by deletions in mitochondrial deoxyribonucleic acid (DNA), although some are caused by defects in nuclear DNA. These disorders involve complexes of the respiratory chain and thus affect oxidative phosphorylation.


Chronic progressive ophthalmoplegia, or Kearns-Sayre syndrome, is frequently encountered among these diseases. It is associated with pigmentary degeneration of the retina, lack of coordination, facial and limb weaknesses, short stature, and endocrinologic anomalies. The disease appears in childhood and has a progressive course. The most frequently reported cardiac anomaly is progressive heart block. ECGs should be performed frequently for early recognition and appropriate implantation of a pacemaker. Cardiomyopathy, prolonged QT interval, torsades de pointes, atrial arrhythmias, and mitral valvar prolapse have also been described (see further on).


Myoclonic epilepsy with ragged red fibers and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes can present with a dilated cardiomyopathy. Patients with Leigh syndrome, or subacute necrotizing encephalomyelopathy, can develop hypertrophic cardiomyopathy and conduction system defects. Mitochondrial deoxyribonucleic acid is maternally transmitted. Inheritance, therefore, follows non-Mendelian patterns.


Barth Syndrome


Barth syndrome is an X-linked disorder due to a defect in the TAZ gene, encoding tafazzin, a phospholipid transacylase in the mitochondrial membrane. This defect leads to a deficiency of cardiolipin, causing disruption of mitochondrial structure and energy metabolism as well as a deficiency in adenosine triphosphate. The disease is characterized by a dilated cardiomyopathy, skeletal myopathy, cyclic neutropenia, and growth retardation. The heart typically displays poor contractility and is often hypertrabeculated, showing features of ventricular noncompaction. Hypertrophy has also been noted. Dilated cardiomyopathy is an early manifestation, with 70% of patients with Barth syndrome having cardiomyopathy before 1 year of age and evidence of cardiomyopathy related to Barth has been seen as early as 18 weeks’ gestation. Response to standard heart failure treatment is good, but cardiac transplantation has been reported in refractory cases. Sudden death has also been reported; this may be due to the increased risk of ventricular arrhythmias independent of the severity of cardiomyopathy and may require implantation of a defibrillator. Death typically results from infectious complications or from cardiac disease.


Propionic Acidemia


Propionic acidemia is a rare metabolic disorder due to a deficiency of propionyl-CoA carboxylase, an enzyme involved in the catabolism of valine, leucine, isoleucine, methionine, threonine, cholesterol, and fatty acids. Gene mutations mapped to chromosomes 3 and 13 have been described. Diagnosis is suspected by analysis of urinary organic acids, with elevations of propionate, propionylglycine, and methylcitrate. Confirmation of the diagnosis rests with demonstration of reduced activity of propionyl-CoA carboxylase in skin fibroblasts. There is a wide spectrum of clinical presentations, from severe early onset of the disease in the first days of life to relatively mild forms presenting in adulthood. Patients develop hypoglycinemia, hyperammonemia, hypoglycemia, and deficits in the central nervous system, particularly in times of metabolic stress such as occurs with minor infections. Cardiomyopathy and sudden death are relatively frequent late complications. The latter may be due to an increased prevalence of prolongation of the QT interval in these patients, a phenomenon seen more frequently with age. Because of this, regular electrocardiographic screening is necessary. When involved, the heart is typically dilated with depressed function, although hypertrophy is also seen. Poor ventricular contractility can complicate acute metabolic crises, and patients presenting with encephalopathy should be assessed for left ventricular systolic dysfunction. One series found that 23% of those surviving infancy developed dilated cardiomyopathy at an average age of 7 years. The development was independent of apparent disease severity and frequency of metabolic crises. In two patients treated with liver transplantation, the cardiomyopathy was reversed. The precise etiology of the cardiomyopathy is not known, but disordered carnitine metabolism and toxicity of byproducts in the metabolic pathway of propionyl-CoA carboxylase are leading suspects. Treatment consists of restriction of protein and supplementation with l -carnitine and antibiotics.


Methylmalonic Aciduria


Methylmalonic aciduria is clinically similar to propionic acidemia and is due to a deficiency of methylmalonyl-CoA mutase. It can also be due to defects in adenosylcobalamin, its cofactor. The enzyme is required for the metabolism of valine, leucine, isoleucine, methionine, and threonine and yields succinyl-CoA for the tricarboxylic acid cycle. Deficiency can lead to dilated cardiomyopathy, although the pathogenesis is not known. Some patients, who likely have residual enzymatic activity or whose disease is the result of defective or deficient cofactor, can respond favorably to supplemental cyanocobalamin. Those with deficiency of the enzyme itself are managed on a low-protein diet with carnitine supplementation. Despite therapy, however, the risk of metabolic crisis during acute illnesses remains high. Hepatocyte-directed gene delivery has been shown to correct the enzymatic activity in vitro and may hold promise as a future corrective therapy.


Disorders of Fatty Acid Metabolism


The heart utilizes fatty acids for energy production by converting long-chain free fatty acids to long-chain acyl-CoA via acyl-CoA synthetase. These acyl-CoA compounds are then transferred into the mitochondria, where they are degraded to produce acetyl-CoA for use in the tricarboxylic acid cycle.


Carnitine-acylcarnitine translocase mediates entry of fatty acyl-CoA compounds into mitochondria. Deficiency often results in early death due to severe metabolic collapse with encephalopathy and hypertrophic cardiomyopathy, although patients with milder variants can present later. Treatment with medium-chain triglycerides and carnitine supplementation can potentially avert the severe neurologic outcomes usually associated with this disease.


Carnitine palmitoyltransferase II converts acylcarnitine back to acyl-CoA for β-oxidation once it has crossed the inner mitochondrial membrane. Deficiency of this enzyme leads to nonketotic hypoglycemia with seizures, hepatomegaly, and hypertrophic cardiomyopathy. Milder forms can present later with fasting or during periods of metabolic stress. Treatment consists of a low-fat diet, supplementation with medium-chain triglycerides, carnitine supplementation, and avoidance of fasting.


The acyl-CoA dehydrogenases mediate the reactions yielding acetyl-CoA from acyl-CoA compounds of varying lengths. These enzymes are referred to as short, medium, long, and very long acyl dehydrogenases. Deficiency of any of these can yield a generalized myopathy along with nonketotic hypoglycemia and cardiomyopathy.




Disorders of Collagen Synthesis or Extracellular Matrix


The group of disorders of collagen synthesis includes several diseases with cardiac involvement. Included in this discussion are Ehlers-Danlos syndrome, cutis laxa, osteogenesis imperfecta, and Marfan syndrome. Alcaptonuria also comes into this general group but, as yet, cardiac disease has not become manifest in childhood. Direct cardiac involvement does not occur in epidermolysis bullosa, but the heart may be affected when the condition is complicated by amyloidosis.


Ehlers-Danlos Syndrome


Phenotypical features unite the biochemically and genetically heterogeneous group of disorders included in Ehlers-Danlos syndrome. The stigmas are hyperextensible skin and joints, easy bruising, and poor healing of wounds. A distinctive facial appearance includes epicanthic folds, a flat bridge of the nose, and prominent downward pointing ears. Apart from the palms and soles, the skin is smooth and rubbery. In later life it may hang in folds from the elbows. Premature death is common in the most severe form, and the babies have poor muscular tone. In addition to the epicanthic folds, ocular signs include easy eversion of the upper eyelid, known as the Metenier sign, blue scleras, and a dislocated lens. A variety of congenital cardiac malformations have been reported, being found in approximately one-eighth of patients in one study. Prolapse of the mitral valve had previously been reported to be common in these patients, but a more recent study shows an incidence similar to that of the general population.


More than 10 subtypes of Ehlers-Danlos syndrome have been described, but six major subtypes are recognized, comprising nine-tenths of individuals affected. Patients typically fall into the hypermobility, classical, or vascular type. Classic Ehlers-Danlos syndrome, incorporating types I and II, demonstrates the typical cutaneous findings. It most often results from defects in one or more of the collagen or procollagen genes. The hypermobility type is similar, with joint hypermobility the predominant clinical feature. Both of these types, though not characteristically demonstrating vascular changes, have been shown to be associated with dilation of the aortic root and valvar dysfunction. the vascular type, also known as Ehlers-Danlos syndrome type IV, results from mutations in the COL3A1 gene encoding type III collagen and accounts for 5% to 10% of all Ehlers-Danlos cases. These patients are at risk for arterial rupture, which typically occurs after the onset of the third decade of life. The median survival for patients with Ehlers-Danlos syndrome type IV is up to 48 years of age primarily due to arterial rupture and often without preceding aneurysms. Surgery may be needed for life-threatening complications, but a conservative approach is usually preferred owing to tissue characteristics, poor wound healing, and hemorrhage risk. A more severe recessive form has been reported, including both the cutaneous findings of the classic form coupled with cardiac valvar involvement.


Cutis Laxa


Cutis laxa is, again, a genetically heterogeneous group of conditions characterized in the phenotype by the skin being so loose that it appears too large for the body. Unlike the case in Ehlers-Danlos syndrome, the lax skin is slow to recoil after being stretched. Cutis laxa has some features in common with the Ehlers-Danlos syndrome, such as fragility of the skin, hypermobile joints, and easy bruising. There are characteristic facies, including a long upper lip, a hooked nose, and a short columella. The defect of connective tissue also results in a deep voice, owing to lax vocal cords. Hernias and rectal or vaginal prolapse can also be seen. The disease can be inherited in both autosomal dominant and autosomal recessive forms. From the cardiac standpoint, peripheral pulmonary stenosis and aortic dilation have been reported. These findings, coupled with reports of supravalvar aortic stenosis, have helped lead to the discovery that defects in the elastin gene are one cause of this disorder. Defects in other genes, including fibulin-4 and fibulin-5, have also been implicated in some forms. Another major complication is cor pulmonale, since the associated emphysema is frequently progressive and severe. Patients with the neonatal variant of cutis laxa can have severe mitral regurgitation with dysplastic valvar leaflets.


Osteogenesis Imperfecta


Osteogenesis imperfect is caused by mutations in genes for collagen type I. Bone fragility is the main clinical feature of this condition. Although the fractures are subperiosteal, with little displacement, the multiplicity of fractures leads to bowing of the long bones. Additionally, the vertebrae are biconcave, with the disc sometimes perforating the vertebral body to give the appearance known as Schmorl nodes. The skull is frequently made up largely of wormian bones and shows frontal and parietal bossing. The skeletal deformities lead to short stature. The skin is thin but not lax. The sclerae are blue in most types. In the so-called type III variant of the disease, they may become less blue with age. Despite collagen type I being an important cardiac protein clinically, significant cardiac disease is rare in children and young adults with osteogenesis imperfecta. The cardiovascular manifestations include aortic and mitral regurgitation owing to dilation of the valvar hinges or, in the latter, to prolapse from ruptured cords. It has been suggested that aortic root dilation may be present in a certain subset of patients with osteogenesis imperfecta and that it appears to be nonprogressive. In some patients, aortic or mitral valvar disease is severe and may require replacement surgery. This carries a higher than normal risk due to bleeding complications related to tissue friability. Administration of recombinant factor VIIa may be helpful in controlling bleeding in these patients. Aortic stenosis, defects of the oval fossa, and tetralogy of Fallot have also been reported.


Marfan Syndrome


Marfan syndrome is transmitted as an autosomal dominant disease with variable clinical expression. The prevalence is estimated at 2 to 3 per 10,000. The disease is due to defects in the FBN1 gene on chromosome 15q21, which encodes fibrillin-1, an important component of connective tissues. More than 600 mutations in the gene have been identified, and approximately one-quarter to three-tenths of cases represent new mutations. Although expression of the disease is highly variable, even among family members with the same genetic defect, some correlations between genotype and phenotype have been clarified. More than seven-tenths of those affected are diagnosed before the age of 10 years. Physical features of the syndrome may be present at birth. Affected persons are usually very tall, with an increase in the length of the limbs compared with the trunk. Their arm span exceeds their height ( Fig. 59.3A ). They have long thin fingers (see Fig. 59.3B–C ), hypermobile joints, kyphoscoliosis, and chest deformities. High arching of the palate, with dental crowding, is commonly seen, as are inguinal hernias. Ocular abnormalities occur in about three-quarters of patients. The most frequent are subluxation of the lenses and myopia. Because of the importance of identifying individuals with this disease, a multidisciplinary group of experts produced diagnostic criteria known as the Ghent nosology. The 2010 revised Ghent nosology is divided into those with a positive family history and those without a positive family history. For those without a positive family history, the definitive diagnosis can be made with aortic root dilation ( z -score plus 2 at the sinus of Valsalva or aortic root dissection) and one of the following; ectopia lentis, FBN1 mutations, and/or a systemic score of 7 or greater. In the absence of aortic root dilation the diagnosis can be made in the presence of ectopia lentis and an FBN1 mutation known to cause aortic root dilation. In the present of a positive family history the diagnosis can be made in the presence of ectopia lentis, systemic score of 7 or greater, or an aortic root z -score of 2 or greater if the patient is above age 20 years, or 3 or greater if the patient is younger than age 20 years ( Box 59.1 ). The addition of the systemic score allows for findings in multiple organ systems to be factored into the diagnostic criteria Table 59.1 . Adolescents and children may not meet the criteria. If clinical suspicion remains high, this group should still be monitored for aortic root dilation. a systemic score calculator with additional diagnostic details can be found at https://www.marfan.org/ .




Fig. 59.3


(A) Typical body habitus of a patient with Marfan syndrome shows how the arm span exceeds the height by more than 5%. (B) The positive wrist sign and (C) the positive thumb sign.


Box 59.1

2010 Revised Ghent Nosology for the Diagnosis of Marfan Syndrome


Absence of Family History of Marfan Syndrome




  • 1.

    Aortic root z -score ≥2 and ectopia lentis


  • 2.

    Aortic root z -score ≥2 and FBN1 mutation


  • 3.

    Aortic root z -score ≥2 and systemic score ≥7


  • 4.

    Ectopia lentis and an FBN1 mutation with known aortic root dilation



Presence of Family History of Marfan Syndrome




  • 1.

    Ectopia lentis


  • 2.

    Systemic score ≥7


  • 3.

    Aortic root z -score ≥2 if >20 years old and aortic root z -score ≥3 if <20 years old




Table 59.1

Systemic Scoring for Marfan Syndrome














































Feature Score
Wrist and thumb sign 3 points (1 point if either wrist or thumb sign)
Pectus carinatum 2 points (1 point for pectus excavatum or chest asymmetry)
Hindfoot deformity 2 points (1 point plain flat foot)
Spontaneous pneumothorax 2 points
Dural ectasia (CT or MRI) 2 points
Protusia acetabula (pelvic x-ray) 2 points
Reduced upper segment/lower segment ratio increased arm/height ratio a 1 point
Scoliosis or thoracolumbar kyphosis 1 point
Reduced elbow extension (angle <170 degrees) 1 point
Three of five facial features 1 point
Skin striae 1 point
Myopia >3 diopters 1 point
Mitral valve prolapse 1 point

Score is positive if it is ≥7 out of 20 possible points.

CT , Computed tomography; MRI , magnetic resonance imaging.

a US/LS ratio is abnormal if it is <0.85 in white adults and <0.78 in black adults. For children younger than 10 years the US/LS ratio is abnormal if it is <1 for ages 0 to 5 years, <0.95 for ages 6 to 7 years, <0.9 for ages 8 to 9 years, and <0.85 for age 10 years. Arm span/height ratio is abnormal if it is >1.05.



Cardiac manifestations in children are usually less severe than those in adults. Mitral valve disease in the form of prolapse and incompetence, present in approximately three-quarters of the patients, are the most frequent abnormalities. Dilation of the aortic root and fusiform aneurysms of the ascending aorta are also common, particularly in males. The major consequences of these aortic lesions are valvar regurgitation and aortic dissection. Aortic involvement is progressive, and the risk of aortic dissection increases with increasing diameter due to increases in mural stress. Histopathologic examination of the ascending aorta reveals degeneration of the elastic fibers, so-called cystic medial necrosis, which is most severe in patients with aneurysms. The leaflets of the aortic valves contain increased amounts of acid mucopolysaccharide. The mitral valvar annulus is dilated and may become calcified. Pulmonary arterial dilation and aneurysm formation have also been reported. The ECG may show signs of left ventricular and left atrial enlargement when there is significant valvar insufficiency. Disturbances of rhythm—such as first-degree atrioventricular block, atrial ectopic beats, atrial flutter, fibrillation, and tachycardia—are common. Ventricular arrhythmias are present in about one-third of the patients during childhood. Progressing with age, they appear to be closely related to mitral valve prolapse. Radiographic examination of the cardiac shadow is difficult in the presence of thoracic skeletal deformities. Cardiac enlargement may be seen in the presence of valvar insufficiency and dilation of the ascending aorta. Serial echocardiographic evaluation is essential. Mitral valve prolapse is a very frequent finding. Dilation of the aortic root, sometimes with paradoxical motion of the posterior aortic wall, is common. Mitral and aortic incompetence will lead to left atrial and left ventricular volume overload. Doppler echocardiography should increase the early diagnosis of the valvar abnormalities. Cardiac magnetic resonance studies have also become part of the regular assessment of patients with aortopathy to monitor the degree and extent of aortic dilation and associated vascular abnormalities. Such studies have also demonstrated decreased aortic distensibility and increased stiffness in children with Marfan syndrome. Imaging is recommended 6 months following diagnosis. If the aortic root size is stable and less than 4.5 cm, yearly imaging is recommended. If aortic root dimensions are greater than 4.5 or there is rapidly progressive dilation (>0.5 cm per year) more frequent imaging is likely needed.


The pathophysiology of dilation of the aortic root is likely due to a complex interplay between altered vascular mural composition and other destructive processes. The defective collagen renders the arterial walls less distensible, but this alone has not proven to lead to arterial dilation. The dilation itself may be related to apoptosis of vascular smooth muscle cells, which has been shown to be related to angiotensin II receptor signaling pathways. Additionally, defective microfibrils result in excessive activity of transforming growth factor (TGF)-β, which is normally regulated by latent TGF-β binding proteins bound to microfibrils. This excessive TGF-β signaling leads to disordered formation of the matrix and may be a principal cause of the vascular dilation found in these patients. Patients with Loeys-Dietz syndrome and other disorders similar to Marfan syndrome have been found to have defects in the gene encoding the TGF-β receptor. The complex interplay between fibrillin, microfibrils, latent TGF-β binding proteins, TGF-β, and the TGF-β receptor probably accounts for the wide clinical variability in Marfan syndrome and other related disorders.


Life expectancy is very variable. Death usually occurs in the fourth decade, mainly from cardiovascular causes. Cardiac failure, dissection or aneurysms of the aorta, and sudden death are the most frequent causes. Incompetence of both mitral and aortic valves carries a poor prognosis. There is no specific treatment for this condition. Cardiac failure is best treated with diuretics and vasodilators, since the positive inotropic effects of digoxin may further damage the aortic root.


Surgical replacement of the diseased valves and of the ascending aorta may be necessary. The timing of surgery for repair or replacement of valves or replacement of the aortic root must be decided in light of the known risks of surgery as well of the risks of not performing surgery. Elective replacement of the aortic root can be accomplished with a relatively low risk of mortality. On the other hand, replacing the aortic root emergently due to acute dissection carries a much higher risk of short- and long-term mortality. Early recommendations suggested elective replacement when the root reached an absolute diameter of 60 mm. Many patients suffer dissections at sizes significantly smaller than this, and an annual risk of mortality of nearly 5% has been described for patients with an aortic root greater than 50 mm. Surgery is currently recommended for an external root diameter greater than 5.0 cm. If there is rapid dilation, family history of earlier dissection, or clinically significant aortic regurgitation, prophylactic repair may be considered earlier. Due to the increased risk of dissection in pregnancy, prophylactic repair in women may be considered at an aortic root dimension greater than 4.0 cm. In addition, procedures that allow for replacement while maintaining the native aortic valve have been evaluated and appear to be satisfactory, potentially eliminating the need for chronic anticoagulation.


Prophylactic β-blockade has been used to slow the progression of aortic dilation and is recommended in all guidelines. More recently, angiotensin receptor blockers and angiotensin converting enzyme inhibitors have also been used alone or in combination with a β-blocker. However, in a recent randomized controlled study comparing atenolol with losartan there was no clinically significant difference in the progression of aortic root dilation over a 3-year period. In both groups the aortic root z -score decreased significantly over time, and this effect was more pronounced in younger patients.


Infantile Marfan Syndrome


An infantile variant of Marfan syndrome is seen on rare occasions. The skeletal and ocular manifestations are similar to the adult forms but the cardiovascular features are distinct. There is marked myxomatous thickening and redundancy of the leaflets of the mitral and tricuspid valves, with elongation of the tendinous cords leading to severe valvar insufficiency. Morbidity and mortality are primarily related to mitral and tricuspid valvar disease as opposed to aortic dissection and rupture, as seen in the adult form. Additionally, patients with the infantile syndrome frequently exhibit pulmonary emphysematous changes. Neonates with the infantile syndrome present with CHF that responds poorly to conventional therapy. Death often occurs within the first 2 years of life, although surgical repair of mitral valve disease at this age is feasible. A family history of Marfan syndrome is much less common in infants who present with severe cardiovascular symptoms early in life. Most mutations resulting in the infantile syndrome occur between exons 24 and 32 in the fibrillin gene.


Loeys-Dietz Syndrome


Loeys-Dietz syndrome was first described in 2005 in a cohort of 10 families caused by mutations in the TGFBR1 or TGFBR2 gene. It is characterized by hypertelorism, bifid uvula, and/or cleft palate as well as and generalized arterial tortuosity ( Fig. 59.4 ) with ascending aortic aneurysmal formation and dissection. There is some phenotypical overlap with Marfan syndrome, but the hypertelorism, palatal involvement, and widespread arterial changes help to differentiate this from Marfan syndrome and similar disorders. Recognition of this disease is critical, as early evaluation for aortic aneurysm formation may lead to operation at a young age. Because of the aggressive nature of root dilation and high risk for dissection at smaller aortic dimensions, replacement is recommended at diameters of 4.0 cm in adults and at even smaller diameters in children. Patients with Loeys-Dietz should have imaging at diagnosis and 6 months after diagnosis. Due to risk for aneurysms in other vessels not seen by echocardiography, they should also have yearly magnetic resonance imaging from the cerebrovascular circulation to the pelvis.




Fig. 59.4


Magnetic resonance angiogram showing distinctive tortuosity of the head and neck vasculature in a patient with Loeys-Dietz syndrome.


Homocystinuria


Homocystinuria is an autosomal recessive disorder usually due to deficiency of cystathionine synthase, an enzyme needed for the metabolism of methionine. Affected patients have a body habitus similar to that of patients with Marfan syndrome, albeit their joints usually demonstrate restricted mobility. Cognitive deficits are also common. The primary cardiac complication is that of atherosclerotic disease, which often occurs by adolescence. Endothelial dysfunction contributes to the arterial complications and produces an increased risk for myocardial infarction. Vitamin B 6 helps to reduce levels of homocysteine in approximately half of patients, and this, along with supplementation of vitamin B 12 and folic acid, forms the mainstay of therapy.




Neuromuscular Diseases


Muscular Dystrophies


Duchenne Muscular Dystrophy


Duchenne muscular dystrophy is an X-linked recessive disease. Because of this, it almost always afflicts males. Its incidence in male children is calculated at 13 to 33 per 100,000 live births. Since females with Turner syndrome have only one X chromosome, they too can inherit the disease, and it is seen rarely in this setting. The disease is due to a defect in the gene encoding dystrophin. Dystrophin helps to form a complex that stabilizes the sarcolemmal membrane during contraction. Although the exact mechanism for muscle degeneration has not been elucidated, abnormal nitric oxide regulation, abnormal sarcolemmal fragility, and increased susceptibility to oxidative stress are felt to play important roles.


The earliest symptoms are clumsiness in walking, a tendency to fall, and the inability to run. Those with the disease also have difficulty in climbing stairs and getting up from the floor. Clinical onset is usually manifest before 4 years of age, and the diagnosis is usually made around 6 years of age. Deterioration is continuous. Most are unable to walk by the age of 10 years. Life expectancy is increasing due to improved medical therapies, including nocturnal ventilation, early and aggressive management of cardiomyopathy, and perhaps also the use of steroids. Muscular weakness and atrophy initially affect the proximal muscle groups of the upper limbs. Leg involvement extends from the quadriceps and gluteal muscles to the anterior tibial muscles. Weakness later affects other muscle groups. More power is generally retained in the distal muscles. Slight facial weakness occurs in the late stages. Scapular “winging” is also a later phenomenon. Muscular hypertrophy of calves, masticatory muscles, and deltoids is followed by a pseudohypertrophic phase of fatty replacement. Tendon reflexes are lost in the weak muscles. Contractures of the calves and hip flexor muscles develop around the age of 8 years. Contractures appear in the hips, knees, elbows, and wrist, when the patients are confined to wheelchairs. Severe spinal and thoracic deformities are seen late in the disease. Kyphoscoliosis is common. These result from disuse and abnormal posture. Generalized decalcification of the bones leads to frequent pathologic fractures.


Myocardial involvement is very common. It is uncertain at what stage it begins, since the physical incapacity limits its manifestation. The heart can be involved from an early age, though, and in ambulatory patients, subclinical disease may become symptomatic with exercise. In nonambulatory patients, a resting tachycardia, decreased heart rate variability, echocardiographic evidence of systolic and diastolic dysfunction, and abnormal myocardial strain changes on magnetic resonance imaging may help to alert the clinician to subclinical myocardial involvement so that medical therapy can be initiated. The roles of cardiac troponins and brain natriuretic peptide are also being evaluated in the assessment of these patients. The cardiac dysfunction is progressive, ultimately resulting in a dilated cardiomyopathy, and the benefits of early medical therapy are controversial. Some advocate early use of afterload reduction therapy, but others have only shown a benefit when afterload reduction is combined with β blockade.


There is a distinctive ECG pattern in 50% to 90% of patients. This includes tall R waves over the right precordial leads with increased R:S amplitude ratios, together with narrow and deep Q waves in the limb and left precordial leads. Female carriers may also have an abnormal ECG. These findings correspond to pathologic observations. There is fatty and fibrous tissue replacement of the myocardium with selective scarring of the posterolateral wall of the left ventricle and, sometimes, involvement of the posterolateral papillary muscle. Conduction abnormalities are also frequently seen. Among these are prolonged intra-atrial conduction, right bundle branch block, a superior QRS axis, and a short PR interval. Histologic studies of the conduction system show areas of fibrosis, vacuolization, and fatty infiltration. The echocardiogram reveals impairment of both systolic and diastolic function. Thickness of the left ventricular wall is decreased, and this is not related to physical inactivity. The end-diastolic and end-systolic dimensions of the left ventricle increase as systolic function deteriorates.


The diagnosis is made from the clinical characteristics, the high levels of creatine kinase activity, and biopsy of the skeletal muscles. Creatine kinase activity is 100 to 300 times normal at 1 to 5 years of age. Other muscle enzymes—such as aldolase, glutamic oxalic transaminase, lactic dehydrogenase, and pyruvate kinase—are also grossly elevated. Creatine kinase levels diminish later in the disease but still remain well above normal limits. Muscle biopsy shows scattered hyaline fibers with active muscle necrosis and regeneration. There is splitting of the muscle fibers with fatty replacement. The muscle fascicles also become surrounded by perimysial and endomysial connective tissue. Electromyography reveals a decrease in the mean action potential voltage and its duration. An increase in the number of polyphasic potentials is also seen.


Careful general medical management is critical. Since bed rest is harmful, regular physical activity and exercise are to be encouraged. Avoidance of obesity is an important general measure, along with the prevention of muscle contractures by passive stretching. Because of the risks of anesthesia and immobilization, the benefit from major orthopedic procedures must be carefully considered. Prevention of scoliosis and thoracic deformities in the wheelchair phase help to avoid respiratory impairment and slow the deterioration of respiratory function. Death is usually from respiratory infections and insufficiency, heart failure, or cardiac arrhythmias. Detection of carriers is important for appropriate genetic counseling. Over half the carriers can be identified by their elevated creatine kinase levels, electromyography, and muscle biopsy. The analysis of the pedigree is particularly useful.


Novel treatments for this myopathy are actively being investigated and include gene therapy, protease inhibitors, membrane stabilizers, and muscle precursor cell transplantation.


Childhood Limb-Girdle Muscular Dystrophy


The childhood limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of genetic muscular disorders. At least 17 different types have been described. They can be inherited in either an autosomal dominant or recessive fashion. Seven genetic defects have been identified in the dominant forms (LGMD 1) and 11 in the recessive forms (LGMD 2). The age at onset is variable, but symptoms generally appear between 5 and 10 years of age. Weakness of the pelvic and shoulder muscles predominates. The disease is slowly progressive, and the patients often become unable to walk by their twenties.


The disease is first suspected when limb-girdle weakness occurs, although Duchenne or Becker muscular dystrophy must be ruled out. An elevated creatine kinase will not differentiate between LGMD and the dystrophinopathies. This can be done through analysis of the dystrophin gene and by examination of a muscle biopsy.


Various forms of LGMD affect the heart. Patients with LGMD 1b, due to a mutation in the lamin A/C gene, frequently develop arrhythmias that can be lethal and may require placement of an implantable defibrillator. Atrioventricular block can also occur, necessitating placement of a pacemaker. This disorder can also result in a dilated cardiomyopathy.


Patients with LGMD 2I, caused by a defect in the gene encoding the fukutin-related protein ( FKRP ), may develop a dilated cardiomyopathy by the third decade. Evidence of dysrhythmias is not seen.


Myotonic Muscular Dystrophy (Steinert Disease)


The involvement of systemic tissues together with the presence of myotonia and muscular atrophy separate myotonic muscular dystrophy from the other muscular dystrophies. Myotonic muscular dystrophy has a high incidence, calculated at 13.5 per 100,000 live births. Onset is usually between 20 and 50 years of age, but many cases are clinically apparent during childhood. This disease is due to an expansion of a CTG trinucleotide repeat on the q arm of chromosome 19. It is transmitted in an autosomal dominant fashion and demonstrates genetic anticipation.


Myotonia is the presenting clinical feature in one-third of cases. Others present with weakness of the hands, foot drop, or a tendency to fall. The heart may occasionally become involved prior to diagnosis of the neuromuscular disorder. The facial, masticatory, sternomastoid, forearm, anterior tibial, and peroneal muscles are those first affected by weakness. Later weakness extends to neighboring muscle groups. The typical facies are characterized by lack of facial expression and difficulty in closing the eyes and moving the mouth. Ptosis and dysarthria are frequent. Myotonia is often limited to the tongue, forearms, and hands, but it may be generalized. The tendon reflexes in the affected muscle groups are reduced.


Cataracts are present in almost all those affected. Impaired pulmonary vital capacity and maximum breathing capacity are common. Abnormal contractions of the esophagus are thought to be the cause of dysphagia and pulmonary aspiration. Testicular atrophy, DM, increased metabolism of immunoglobin G with low serum levels, progressive dementia, and subnormal intelligence are frequent associations. Cardiac involvement is common and manifests with conduction defects and arrhythmias. First-degree atrioventricular block is commonly seen, and this may progress to complete heart block requiring pacemaker implantation. No relationship exists between the degree of involvement of the cardiac and the skeletal muscles. Chest radiography will show the associated deformities of the bony thorax together with an elevated hemidiaphragm. The cardiac silhouette is normal. Death from cardiac involvement is almost always caused by complete atrioventricular block or ventricular tachycardia. It is very rarely caused by myocardial failure.


The most common abnormalities in the ECG are low amplitudes of the P wave, atrioventricular block of any degree, right and left bundle branch block, abnormal Q waves, and changes in the ST segment and T wave. It is believed that regional myocardial dystrophy is responsible for the abnormal Q waves. Rhythm disturbances include sinus bradycardia, premature atrial beats, atrial fibrillation, atrial flutter, ventricular premature beats, and ventricular tachycardia. Four-fifths of the patients have electrophysiologic evidence of disease of the atrioventricular conduction axis. A further one-fifth have evidence of intra-atrial conduction disturbances. Disease of the atrioventricular conduction axis progresses with time. A correlative study revealed fibrosis of the right and left bundle branches and fatty infiltration and degeneration around the atrioventricular node, which corresponded accurately with the ECG and electrophysiologic evaluation performed during life.


Mitral valve prolapse is frequently associated with myotonic muscular dystrophy and is diagnosed echocardiographically. It is present in approximately one-third of patients. There is no relationship, however, between mitral valve prolapse and the arrhythmias. Systolic and diastolic function is normal, although some patients fail to show an increase in ejection fraction with exercise. Apical hypokinesia may be present but is of doubtful significance.


Careful clinical examination and a high degree of suspicion are required for an early diagnosis. Electromyography and muscle biopsy are useful techniques, as is slit-lamp examination for cataracts. Regular cardiac evaluation is required in all patients because of the frequent association of heart disease. The diseases show progressive deterioration, with physical incapacity 15 to 20 years after the onset of muscular symptoms. Death is usually from respiratory infections, aspiration, cardiac arrhythmias, or anesthetic complications.


There is no specific treatment for the condition. Active exercise and weight control are important general therapeutic measures. Systemic complications are treated as they arise. Myotonia is relieved by the use of procainamide or phenytoin (diphenylhydantoin). Caution must be exercised, however, since procainamide exacerbates preexisting conduction disturbances. Electrophysiologic studies are warranted in symptomatic patients presenting with syncope or presyncope. A ventricular pacemaker is needed when there are significant abnormalities in the formation or conduction of the cardiac impulse.


Myotonic muscular dystrophy appears and progresses during early adult life in the majority of those affected. In a proportion, however, the disease is present at birth. Such congenital cases are often treated as a separate entity. Indeed, as will be seen, they have a totally different presentation and clinical picture. Nonetheless, in the fullness of time they come to resemble the adult form. The congenital form is characterized by bilateral facial weakness, hypotonia, and mental retardation with delayed motor and speech development. Neonatal respiratory distress is very frequent. Such infants have a high incidence of feeding difficulties owing to muscle weakness. Talipes is a common association. Clinical myotonia is absent but can be demonstrated electromyographically. The adult features of the disease appear during late childhood and adolescence. Cardiac involvement takes the form of a dilated cardiomyopathy. Nonspecific electrocardiographic abnormalities appear with progression of the disease. Mortality occurs in the neonatal period as a result of respiratory distress. Beyond this time, there is a tendency to improve, only for the patients to deteriorate as the adult characteristics of the disease appear. The condition is transmitted by the mother. Previously her clinical involvement has often been missed.


Autosomal Dominant Scapuloperoneal Myopathy


Scapuloperoneal myopathy is a very rare form of muscular dystrophy. Two distinct groups are recognized according to the age of onset. They share an autosomal dominant form of inheritance and involve the same muscle groups. Weakness and atrophy affects the neck, shoulder girdle, and upper arm muscles together with the tibial and peroneal muscles in the legs. Foot drop and an awkward gait are frequent early symptoms. Deep tendon reflexes are commonly absent. Serum levels of creatine kinase are slightly elevated. Electromyography and muscle biopsy show the changes common to muscular dystrophies.


Patients with early onset generally present under the age of 10 years, and in these the disease takes a rapid course. Patients develop early contractures and are severely incapacitated by their late teens. They frequently have clinical and electrocardiographic signs of a dilated cardiomyopathy with CHF. Those having a late onset present over the age of 40 years and the clinical course is slow. They seldom develop contractures. Cardiac involvement, usually late, could well be a result of ischemic heart disease.


Becker Muscular Dystrophy


Becker muscular dystrophy is one of the most frequent types of muscular dystrophy and is inherited in X-linked recessive fashion. The incidence is of the order of 3 to 6 per 100,000 male births. The muscular groups involved are very similar to those in Duchenne muscular dystrophy. The peroneal and anterior tibial muscles are also affected in the Becker form of dystrophy. The facial muscles are not involved. Calf hypertrophy and muscle cramps are frequent early symptoms. Club feet are often seen. Contractures appear in the final stages and scoliosis is rare. Developmental delay is uncommon. The onset of the symptoms is between 5 and 15 years of age, with inability to walk being present by the third decade and death occurring in the fifth. The individual range, however, is very wide. The diagnosis is primarily clinical. Serum creatine kinase activity is 25 to 200 times normal. The electromyogram and the muscle biopsy are nonspecific but help to rule out other conditions.


Cardiac abnormalities are infrequent in childhood but are almost always present in some form by the onset of the fourth decade. ECG abnormalities are common and include resting tachycardia, interventricular conduction delay, and Q waves in leads II, III, and AVF, suggesting damage to the lateral wall of the left ventricle. Heart rate variability is also decreased and may indicate risk for sudden death. Dilated cardiomyopathy associated with Becker muscular dystrophy is also seen. The risk of ventricular dysfunction increases with age, although many patients are asymptomatic from a cardiac standpoint and exhibit abnormalities only on the ECG or echocardiogram. Heart transplantation for severe left ventricular systolic dysfunction is a well-established palliative option.


Facioscapulohumeral Muscular Dystrophy (Landouzy-Déjérine Syndrome)


Facioscapulohumeral muscular dystrophy is inherited in an autosomal dominant fashion. It has an incidence of approximately 5 per 100,000 live births. Facial and shoulder weakness generally develop in the second or third decade and progress very slowly. Patients with severe forms of this disease will occasionally present early in life, and progression is then rapid. Characteristically there are no facial lines and the eyelids are very weak. Winging of the scapulas is seen when the arms are abducted and there is a marked thoracolumbar lordosis. Affected muscles include the neck flexors, the serrate and pectoral muscles, biceps and triceps in the upper limbs, the hip flexors, and the anterior tibial muscles; in the late stages, the quadriceps and sartorius in the lower limbs are also affected. Retinal vasculopathy is also frequently seen. The serum levels of creatine kinase are normal or only mildly elevated. The precise molecular mechanism for expression has not been elucidated, but patients are known to have a large deletion involving the q arm of chromosome 4. No gene has been identified in this region; therefore various hypotheses have been presented to explain the mechanism whereby this deletion induces clinical disease.


Ventricular function is not affected. However, supraventricular tachycardia has been reported with a frequency higher than that of the general population. Sinus node dysfunction, abnormal AV node or infranodal conduction, and easily inducible atrial fibrillation/flutter have also been reported with an incidence of 27% of the patient population studied.


Emery-Dreifuss Muscular Dystrophy


Emery-Dreifuss muscular dystrophy typically presents between 5 and 15 years of age. It can be inherited in an X-linked recessive fashion or in an autosomal dominant or autosomal recessive form. The biceps and triceps are more severely affected than the deltoid muscle. The peroneals are more involved than the proximal musculature of the legs. Contractures generally develop at the elbows, posterior cervical muscles, and the Achilles tendon. Pseudohypertrophy is absent. Creatine kinase levels are 3 to 10 times above normal. Progression is very slow, and the physical limitations are minimal. There is normal intellectual function.


The X-linked form is due to a defect in the gene encoding emerin, a nuclear envelope protein that plays a role in the regulation of many cellular and nucleolar processes. However, its role in the pathogenesis of muscle damage has not be elucidated. The autosomal dominant form is due to defects in the lamin A/C gene, similar to limb-girdle muscular dystrophy type Ib. Again, the role of lamin A/C mutations in the development of the myopathy is not clear. The recessive form is also due to defects in the gene encoding lamins A and C. How and why defects in the same gene can cause dominant and recessive forms of the disease remains to be discerned.


Cardiac involvement is often manifest by atrial arrhythmias and atrioventricular block. Any degree of atrioventricular block can be present, and a slow junctional escape rhythm is common. Severe sinus bradycardia or sinus arrest is seen and may also require pacemaker implantation due to the increased risk of sudden death. “Atrial paralysis,” with the absence of P waves and an inability to electrically pace the atrium, is seen. Ventricular function is usually normal, but progressive left ventricular dysfunction with fibrous infiltration of the myocardium can be seen, and cardiac transplantation has been employed for end-stage disease. Patients with bradycardia may have a hypertrophied and dilated left ventricle, probably as a compensatory physiologic response. Electrophysiologic studies show prolonged H-V intervals and, on some occasions, a complete absence of the His potential. This finding, together with the very slow junctional escape rhythms, suggests that the myopathic process extends into the atrioventricular conduction axis. The high risk of sudden death in this variety of muscular dystrophy makes early recognition important, since insertion of a ventricular pacemaker in patients with bradycardia will improve survival.


Centronuclear Myopathy


This uncommon muscular disorder is characterized by ptosis, strabismus, generalized muscle wasting and weakness, and absent or reduced deep tendon reflexes. Developmental delay and dysarthria are common. A dilated cardiomyopathy has occasionally been observed, and cardiac transplantation has been performed. Patients have a prolonged PR interval and a superior axis on the ECG. The diagnosis is based on clinical findings, raised levels of creatine-kinase in blood, evidence of a myopathy on electromyography, and a typical histologic picture. This consists of central location of the nucleus, with variation of muscle fiber diameter and a tendency for predominance of type 1 fibers. Inheritance is variable. The X-linked form is usually the most severe form and involves the gene encoding myotubularin. An autosomal recessive form seems to have a milder course, although patients still present in childhood. Finally, the autosomal dominant form is milder, with patients reaching adulthood before the onset of symptoms.


Nemaline Myopathy


The nemaline myopathies are so named because muscle specimens demonstrate rods within the myocytes. This group of clinically heterogeneous disorders can result from defects involving actin, troponin, myosin, or tropomyosin. Although the skeletal muscles are predominantly involved, cases of hypertrophic and dilated cardiomyopathy are becoming increasingly evident. The main focus is on the α-actin gene, ACTA1 , in which numerous defects have been described. Patients can have a very mild course of skeletal muscle weakness or severe, lethal neonatal disease leading to respiratory failure. Hypertrophic cardiomyopathy is more commonly seen, but dilated forms of cardiomyopathy have also been reported.


Friedreich Ataxia


Friedreich ataxia is a rare spinocerebellar neuromyelopathy occurring in approximately 1 to 2 per 40,000. The disease is inherited in an autosomal recessive fashion, and most cases are due to homozygosity for an expanded GAA triplet on chromosome 9q13. This gene encodes frataxin, a precursor protein that may be involved in the maturation and assembly of iron and sulfur proteins of the mitochondria and cytosol. Children present around the age of 6 years. The most frequent early symptom is an abnormal gait. Neurologic signs include the ataxic gait, absent tendon reflexes, incoordination, and a positive Romberg test. Lower limb weakness and muscular atrophy are common, as are dysarthria and loss of vibration and positional sense and extensor plantar responses. Some patients have nystagmus. The presence of brisk tendon reflexes makes the diagnosis of Friedreich ataxia very unlikely. Skeletal involvement is common, with club feet and scoliosis among the most frequent manifestations. Apart from the clinical aspects of the disease, nerve conduction studies are essential to support the diagnosis. Motor conduction velocity is normal and sensory conduction is absent or markedly reduced. Since clinical, ECG, and radiographic examinations of the heart are nonspecific for the evaluation of cardiac involvement in Friedreich ataxia, an echocardiogram is necessary in every patient.


The heart is involved in a very high percentage of patients, and cardiac symptoms are an integral part of the clinical spectrum of the disease. Most usually, the heart exhibits a symmetric, concentric, and slowly progressive hypertrophic cardiomyopathy. Cardiac involvement may occasionally precede the onset of neurologic manifestations. Cardiac symptoms are present in approximately one-third of the patients and consist mainly of exertional dyspnea, palpitations, and angina. Clinical findings of cardiac disease are not present in every case. When they are, they include systolic murmurs at the left sternal border and apex, together with third and fourth heart sounds. The pulse may have a rapid upstroke. Evaluation of the severity of heart disease by physical examination is often difficult because of the presence of scoliosis and the lack of consistent cardiovascular signs. Interestingly, the degree of cardiac involvement appears to correlate with the size of the GAA repeat of the smaller allele or with the mean size of the repeats in both alleles.


Pathologic studies reveal cardiac dilation with ventricular hypertrophy. Histologically there is a degeneration of myocardial cells with myocardial fibrosis. Intracellular granular deposits of calcium and iron are seen. It is hypothesized that iron-catalyzed mitochondrial damage may lead to the pathologic findings in the myocardium. Electrocardiographic changes are present in over two-thirds of patients, and they progress in relation to the duration of the disease. The most frequent changes involve the ST segments and T waves. These are nonspecific and are presumably caused by repolarization disturbances from the underlying myocardial fibrosis. Signs of ventricular hypertrophy are also frequent, and right- or left-axis deviation is common. Arrhythmias are not frequent. When present, they include supraventricular and ventricular premature beats, supraventricular tachycardia, atrial flutter, and atrial fibrillation.


The presence of scoliosis makes radiographic evaluation of the heart difficult. Heart size is usually normal. Most patients have an abnormal echocardiogram. The most common anomalies reflect the presence of a symmetric concentric hypertrophic cardiomyopathy. There is an increase in left ventricular wall and septal thickness. Asymmetric septal hypertrophy is seen on occasion. Impaired left ventricular function has also been shown echocardiographically and may be the end stage of the cardiomyopathic process, as reduced fractional shortening of the left ventricle is common. The systolic function of the posterior wall is more severely affected than that of the septum. Abnormal diastolic function may antedate systolic abnormalities. Interestingly, a constant feature is delay in mitral valve opening.


The clinical course is marked by steadily progressive deterioration. Cardiac failure, which appears late in the course of the disease, has a poor prognosis and is often a preterminal event. Most patients with Friedreich ataxia die from cardiac causes. Heart failure accounts for half of the deaths. Cardiac arrhythmias and respiratory complications are the other major causes of death.


Although conventional methods for treating hypertrophic and dilated cardiomyopathy are frequently employed, newer therapeutic options for patients with Friedreich ataxia have come to light in recent years. Idebenone, a free-radical scavenger, was tested under the hypothesis that iron overload leads to damage of iron-sulfur cluster–containing enzymes, which may lead to the damage seen in the myocardium. Although the treatment remains somewhat controversial and is not universally accepted, several small trials show a consistent benefit in terms of reduction of cardiac mass and improvement in function.


Arthrogryposis Multiplex Congenita


This condition presents with joint contractures at birth in at least two different areas of the body. A typical presentation includes equinovarus deformities of the feet, abducted hips, incompletely extended knees and elbows, pronated forearms, and claw hands. The majority of those affected have a neurogenic cause with patchy loss of anterior horn cells, although some cases are caused by primary myopathic disorders. They may result from environmental factors or may demonstrate a familial propensity.


The heart is rarely involved. A report of the myopathic form of arthrogryposis multiplex congenita revealed congenital heart disease in one-quarter of the patients. These cases resulted from consanguineous parents, and five of six with congenital heart disease resulted from one pairing. Patency of the arterial duct, congenital aortic stenosis, and mitral stenosis have been reported.


Hereditary Motor and Sensory Neuropathy (Peroneal Muscular Atrophy, Charcot-Marie-Tooth Disease)


The hereditary motor and sensory neuropathies are a diverse group of disorders typically inherited in an autosomal or X-linked dominant fashion. Links to defects in connexins and other Schwann cell proteins are well described. They are predominantly a motor neuropathy producing atrophy and weakness of the distal muscles. This determines the typical “inverted bottle” appearance of the legs. Bilateral club foot is a frequent association. The hand and forearm muscles may also be involved. There is a decrease or loss of the deep tendon reflexes. Electromyographic studies show slowing of nerve conduction velocity or signs of denervation.


The cardiac involvement has classically been related to supraventricular arrhythmias and conduction system abnormalities. Sick sinus syndrome, right bundle branch block, complete heart block, Wolff-Parkinson-White syndrome, atrial fibrillation, and atrial flutter have been described. It has been postulated that there is a primary degeneration of the conduction system rather than changes secondary to a cardiomyopathy. In addition to dysrhythmias, left ventricular hypertrabeculation/noncompaction has been reported in a patient with Charcot-Marie-Tooth disease type IA and a duplication defect on chromosome 17 involving the peripheral myelin protein 22. The Roussy-Lévy syndrome is a phenotypic variant of Charcot-Marie-Tooth type IA and shares many features with this disease. Dilated cardiomyopathy has also been reported.


Spinal Muscular Atrophy Type III (Juvenile Spinal Muscular Atrophy, Kugelberg-Welander Syndrome)


Juvenile spinal muscular atrophy appears in childhood or adolescence. Initially it is manifest by weakness and atrophy of the proximal limb muscles, which is later followed by distal disease. The usual presentation is with difficulty in walking, climbing stairs and lifting the arms. Fasciculation is seen in half of those affected. The clinical course is slowly progressive. There is evidence from electromyography and muscle biopsy to indicate lower motor neuron disease. Some patients have an associated dilated cardiomyopathy, although this may be secondary to associated respiratory disturbances. Rhythm disturbances are very frequent and include atrial premature beats, atrial fibrillation, atrial flutter, and advanced degrees of atrioventricular block. Some patients require the implantation of a pacemaker. The ECG frequently shows a fine tremor on the isoelectric line, which represents fasciculations characteristic of this disease. The syndrome is transmitted in autosomal recessive fashion and is due to defects in the survival motor neuron 1 ( SMN1 ) gene. The infantile form of spinal muscular atrophy (spinal muscular atrophy type 1, Werdnig-Hoffman disease) is a lethal variant presenting with severe hypotonia and respiratory failure. Various congenital heart defects have been reported in patients with this disease, but these are likely chance associations.


Refsum Disease


Refsum disease is a rare neurologic disorder due to the accumulation of phytanic acid in peroxisomes. Phytanic acid is a branched-chain fatty acid that is partially broken down by phytanoyl-CoA2-hydroxylase, and many cases of the disease are due to defects in the gene encoding this enzyme. This leads to the accumulation of phytanic acid in blood and tissues. Symptoms appear in the first and second decades of life, and the initial presentation is with weakness, unsteady gait, and night blindness. These patients have a diagnostic tetrad: retinitis pigmentosa, peripheral polyneuropathy with diminished or absent deep tendon reflexes, cerebellar ataxia, and high protein levels in cerebrospinal fluid without pleocytosis. Other frequent signs are nerve deafness, anosmia, nystagmus, and abnormalities of the pupils. The heart is rarely affected. Conduction abnormalities, especially advanced degrees of atrioventricular block requiring pacemaker therapy, are well known. Cardiomyopathy is a rare association.


Diets low in phytanic acid produce clinical improvement. Complete recovery is rarely obtained, but treatment will slow progression of the disease. The association of plasmapheresis with the diet reduces the levels of phytanic acid more rapidly.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Jan 19, 2020 | Posted by in CARDIOLOGY | Comments Off on Cardiologic Aspects of Systemic Disease

Full access? Get Clinical Tree

Get Clinical Tree app for offline access