Cardiac involvement in systemic disease can be broadly divided into those conditions in which the heart is involved in the disease process itself, and those in which a structural or functional cardiac abnormality is associated with other anomalies, usually in a recognisable syndrome. Many of the conditions in this latter group have received attention in the sections of this book dealing with aetiology and genetics. These will not be dealt with again, although they may be mentioned, or the discussion amplified, as necessary. A vast number of systemic diseases, nonetheless, can involve the heart during childhood. It is the cardiac aspects of these latter diseases we discuss in this chapter ( Table 57-1 ).
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METABOLIC DISORDERS: STORAGE DISEASES
We have chosen to group together here the glycogen storage diseases, the mucopolysaccharidoses, the mucolipidoses, disorders of glycoprotein degradation, acid lipase deficiency, the sphingolipidoses, and the gangliosidoses.
Glycogen Storage Diseases
Glycogen storage diseases can involve the various steps in the storage and degradation of glycogen. There may be an inability to synthesise normal glycogen. Alternatively, there may be an inability to break down glycogen. In the extreme form, abnormal glycogen is synthesised but cannot be broken down. There are eleven described types within this range of disease, and most types involve two or more subtypes. Cardiac involvement has been documented in types I to VIII.
Glycogen Storage Disease Type I (von Gierke’s Disease, Glucose-6-Phosphatase Deficiency [Type Ia], Glucose-6-Phosphatase Translocase Deficiency [Type 1b])
Clinical manifestations of type I glycogen storage disease are profound hypoglycaemia, associated with hyperlipidaemia, hyperuricaemia and lactic acidosis. It presents in childhood, primarily involving the liver, kidneys, and mucous layers of the small intestine. Pulmonary hypertension has been described in association with the type Ia variant. Postulated mechanisms include chronic stimulation of the smooth muscle of the pulmonary arterioles by the persistent hepatic metabolism of circulating catecholamines such as serotonin. Levels of serotonin have been shown to be elevated in patients with glycogen storage disease type I. Such elevation of the levels of serotonin in isolation do not appear to confer pulmonary vascular disease on these patients. Rather, it is hypothesised that other mediating factors working in concert with persistently elevated levels of serotonin increase the risk for pulmonary vascular changes. 1–3
Glycogen Storage Disease Type II (Pompe’s Disease, α-1,4-Glucosidase Deficiency)
Pompe’s disease is a generalised glycogen storage disease in which glycogen of normal structure is accumulated 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 upon age at onset of clinical symptoms. It is the form presenting in infancy that is recognised as classical Pompe’s disease, but patients can also present in childhood, adolescence (giving rise to the juvenile form), or adulthood. The age at onset correlates inversely with the measured activity of lysosomal α-1,4-glucosidase in myocytes or fibroblasts. In the infantile form, which is more severe in its cardiac involvement than those forms of later onset, there is generalised accumulation of glycogen in the heart, including 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, though cases of severe neonatal ventricular hypertrophy have been reported. 4 The median age at onset of clinical symptoms is 1.6 months. Muscular weakness and hypotonia along with loss of motor milestones are noted during the first 6 months of life, and signs of congestive cardiac failure become evident. Although there is excess glycogen in the liver, hepatomegaly is not commonly present until cardiac 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’s 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, variable murmurs being heard. Unexplained cardiomegaly and congestive cardiac failure in a generally floppy baby should suggest the diagnosis. 5
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 cardiac silhouette, but rather a generalised 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. 57-1 ). In addition, in the majority there are Q waves and inverted T waves in leads I and II and the left chest leads. 6 Electrophysiological studies have shown a short AH interval. 7 Both M-mode and cross sectional echocardiograms demonstrate gross increase in the thickness of the ventricular free walls and the ventricular septum ( Fig. 57-2 ). An impairment of ventricular filling in diastole has been noted, 8 together with reduction of the rate and extent of systolic shortening. Angiocardiography is rarely performed, as it adds little to the diagnosis or management.
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 muscular abnormalities are less evident. The presentation is then as a cardiomyopathy alone. Pompe’s 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. Recent studies using recombinant human lysosomal acid α-glucosidase show promise in improving survival. 9 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.
We include Danon disease in this section because it was previously considered to be a variant of Pompe’s disease known as glycogen storage disease type IIb with normal acid maltase. The disease is due to a deficiency of lysosome-associated protein 2, and it 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 while others are X-linked, and the degree of cardiac and skeletal involvement is variable. 10
Glycogen Storage Disease Type III (Cori’s Disease, Amylo-1,6-Glucosidase [Debrancher] Deficiency)
In Cori’s disease, an autosomal recessive condition, glycogen accumulates in skeletal muscle, in the liver, and in cardiac muscle. The disease is due to a deficiency of amylo-1,6-glucosidase, the enzyme necessary for breaking down branch points in glycogen chains. There are three subtypes dependent upon the primary site of abnormal glycogen storage. Type IIIa involves the liver and muscle, Type IIIb the liver, and Type IIIc the muscle. 4,11 A fourth subtype, IIId, involves normal debrancher enzymic activity but a deficiency of debrancher enzyme transferase activity. Patients with types IIIa and IIIc have a tendency to develop weakness of the skeletal muscles and left ventricular hypertrophy, 12 which is progressive. The clinical course appears to be less severe, with fewer symptoms as compared to hypertrophic obstructive cardiomyopathy. 13,14
Glycogen Storage Disease Type Iv (Andersen’s Disease, α-1,4-Glucan-6-Glucosyltransferase [Brancher] Deficiency)
Andersen’s disease is a rare heterogeneous glycogen storage disease characterised by deposition of glycogen of abnormal structure in the liver, leading to cirrhosis. There may also be deposition of polysaccharide in the heart. While liver dysfunction is the most common clinical manifestation, the disease can rarely present with dilated cardiomyopathy, which is typically severe. 15–17
Glycogen Storage Disease Type V (McArdle’s Disease, Muscle Phosphorylase Deficiency)
McArdle’s disease results from a deficiency of muscle phosphorylase. It is usually recognised in adolescence or adult life. Its main clinical features are muscular fatiguability, muscular cramps, and myoglobinuria. Rare lethal variants have been reported in infants, 18 but the heart is typically spared. This may be due to activity of a distinct cardiac phosphorylase isozyme, which retains activity in patients with deficiency of the skeletal isozyme. 19 No clinical cardiac manifestations have been reported, but on occasion the electrocardiogram has features similar to those seen in Pompe’s disease. 20
Glycogen Storage Disease Type VI (Hers’ Disease, Phosphorylase B Kinase Deficiency, Liver Phosphorylase Deficiency)
Hers’ disease involves both X-linked and autosomal recessive modes of inheritance. It results from deficiency of liver phosphorylase. Both types involve 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. 21
Glycogen Storage Disease Type VII (Tarui’s Disease, Muscle Phosphofructokinase I Deficiency)
Tarui’s disease is a rare form of glycogen storage disease that presents in early childhood or adult life with fatiguability, muscular weakness that can be progressive, muscular cramps, and myoglobinuria. Typically, the heart is spared. An infantile form of the disease has also 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. 22 Progressive cardiomyopathy has also been reported in an adult. 23
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 sulphate, heparan sulphate, and keratan sulphate, alone or in combination. In all forms, there is skeletal involvement. 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, producing lesions similar to atherosclerosis. 24 Deposition in cardiac valves leads to valvar stenosis or regurgitation. The various forms of these diseases are brought about by deficiencies of ten 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 the different forms of the diseases.
Mucopolysaccharidosis Type I (α- l -Iduronidase Deficiency)
The three major clinical forms of α- l -iduronidase deficiency are Hurler’s syndrome, Scheie’s syndrome, and a syndrome intermediate between the two, known unsurprisingly as 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 is thought that the clinical severity of the disease is related to the level of new enzymic activity, which in turn is due to a specific genetic defect. 25,26
Hurler’s Syndrome
The defect in Hurler’s syndrome results in a virtual absence of lysosomal α- l -iduronidase. This enzyme is responsible for 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 enzymic deficiency, both heparan and dermatan sulphates accumulate in the lysosomes of many tissues. When seen 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 pseudo-atheromatosis. There is proliferation of both elastic fibres 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. Retardation of growth then becomes evident after the age of 2 or 3 years, with subsequent development of deafness, corneal clouding, and sometimes glaucoma. 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 is an occasional symptom, 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 has been reported as the presenting feature associated with endocardial fibroelastosis. 27,28
There are typical skeletal radiological features. The clavicles have wide medial ends. The lower thoracic and upper lumbar vertebras 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. 29
Pathological 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. The mitral valve is most frequently involved, followed by the aortic and tricuspid valves. Pulmonary valvar 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 sulphate leads to impaired elastogenesis, which may lead to some of the characteristic arterial and valvar deformities. 30
Thickening of the leaflets of the mitral valve and its annulus is seen echocardiographically. Left ventricular volume load, and diastolic flutter of the mitral valve, are seen when aortic regurgitation is present. Cardiac catheterisation and angiocardiography add little to the diagnostic findings, which include systemic and mild pulmonary hypertension. When present, the haemodynamics and angiography will reflect the severity of valvar insufficiency. The disease progresses inexorably, death occurring by the age of 10 years from cardiac failure, suddenly, or from chest infection. Transplantation of haematopoeitic stem cells has been beneficial in selected patients for many aspects of the disease. 31 The valvar lesions, however, can continue to progress. Enzymic replacement therapy with human recombinant α- l -iduronidase has also been proven beneficial, but, as with transplantation of stem cells, the valvar lesions remain and may progress. 32
Scheie’s Syndrome
Patients with Scheie’s syndrome are less severely affected, having normal stature and intellect. They also have a near-normal lifespan. The most striking features are corneal clouding and stiff joints. Typical cardiac manifestations are aortic stenosis and regurgitation, or mitral regurgitation. 33,34 These should be managed in a similar fashion as for otherwise normal subjects. Scheie’s 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 are of 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 valvar involvement are the primary manifestations. Asymmetrical septal hypertrophy has also been reported. 35 The clinical course is intermediate between Hurler’s and Scheie’s syndromes, with patients living into adolescence or even to the third decade.
Mucopolysaccharidosis Type II (Hunter’s Syndrome, Iduronate Sulfatase Deficiency)
Deficiency of iduronate sulfatase results in a block of degradation of dermatan sulphate. The difference in clinical profile between this and Hurler’s and Scheie’s syndromes, for example, the absence of corneal clouding in Hunter’s 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’s syndrome both have total, or near total, deficiency of iduronate sulfatase. As with mucopolysaccharidosis type I, the clinical phenotype may be representative of the degree of residual enzymic activity specific to certain gene mutations, of which more than 300 have been found for Hunter’s syndrome. 36
The condition can occur with a wide variety in severity. Apart from the extreme rarity of corneal clouding in Hunter’s syndrome, and the presence of loss of hearing, the clinical features are those of Hurler’s syndrome, although usually less severe. A positive distinguishing physical sign, pointed out by Hunter himself in 1916, is the occurrence of pebble-like ivory-coloured dermal lesions. These are seen over the scapulas and occasionally on the pectoral regions.
Cardiac involvement produces all the manifestations so far mentioned, namely, aortic and mitral regurgitation or stenosis, ischaemic changes, and evidence of myocardial dysfunction. Echocardiography is a useful method for evaluating cardiac involvement. The clinical course is extremely varied. Severely affected individuals die before the age of 15 years. At the opposite end of the spectrum, survival beyond the sixth decade has been reported. Death in younger patients is usually associated with progressive neurological deterioration. The disease is inherited as an X-linked recessive trait, though cases in females have been reported. 37 Since the reproductive fitness of the Hunter gene is low, a large minority of cases must result from new mutations.
A new treatment for Hunter’s syndrome has recently emerged with the development of recombinant human iduronate-2-sulfatase. This was well tolerated, and demonstrated improvement in several parameters for outcome, including forced vital capacity, urinary excretion of glycosaminoglycans, the size of the liver and spleen, and 6-minute walk distance. 38,39 The effect of enzymic therapy on the cardiac lesions, however, remains to be determined.
Mucopolysaccharidosis Type III (Sanfilippo’s Syndrome)
The degradation of heparan sulphate and N-sulphated or N-acetylated α-linked glucosamine requires four enzymes: heparan N-sulphatase, N-acetyl-α- d -glucosaminidase, acetyl-CoA:α-glucosaminide N-acetyltransferase, and N-acetyl-α- d -glucosamine-6-sulphate sulphatase. Deficiency of one of the four enzymes required for this degradation results in Sanfilippo’s syndrome. Consequently, there are four biochemically distinct types of the disease, designated A through D, although they all present the same clinical features.
The onset is usually evident in the first few years of life with behavioural problems. Mental and neurological deterioration are severe and lead to death in the first two decades. Bone, joint, and cardiac involvement are generally less severe than in Hurler’s 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 an autosomal recessive fashion. A number of patients with mitral valvar involvement have been reported. 40,41 Cardiac involvement is similar to that of other mucopolysaccharidoses, with thickening of the valvar leaflets. While treatment is primarily supportive, animal studies have been undertaken to assess replacement of the enzymes in a mouse model with mucopolysaccharidosis type III-B. 42
Mucopolysaccharidosis Type IV (Morquio’s Syndrome)
Morquio’s syndrome results from defective degradation of keratan sulphate. It occurs in two biochemically distinct forms. The so-called type A is due to a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, while type B results from deficiency of β-galactosidase. The two types have similar clinical features, but type B is less severe, sometimes called the long-legged variant. Despite the generally increased severity of features in type A, more mild forms of type A can occur. Keratan sulphate is excreted in the urine in type A, but this is less evident in type B.
Keratan sulphate is found in cartilage, intervertebral discs, and the cornea. Thus, skeletal involvement with dwarfism, pectus deformities, and bow legs are the most obvious manifestations. Corneal clouding is common. In contrast to the mucopolysaccharidoses described above, the joints in patients with Morquio’s 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. The heart is clinically involved only in the severe type. Valves of the heart are primarily involved, with thickening of mitral and aortic leaflets. Concentric left ventricular hypertrophy and, rarely, asymmetrical septal hypertrophy have been described. 40,43 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 enzymic replacement therapy in animals has been undertaken and holds some promise. 44
Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome)
Deficiency of arylsulfatase B results in an inability to hydrolyse the sulfate groups in dermatan sulfate. The clinical picture is similar to that of Hurler’s syndrome, but normal intelligence is usually maintained. Although severe in its classical form, milder variations exist. Affected infants can present with an acute cardiopathy. 45 Thickened mitral and aortic valvar leaflets necessitating valvar replacement has been noted in young adults. 46 A left ventricular aneurysm has also been reported. 47 Death usually occurs in the third decade. The condition is inherited in autosomal recessive fashion, though some cases have been presumed to be X-linked. 48 Enzymic replacement therapy with human recombinant arylsulfatase B has been studied, and found to be safe and beneficial in terms of exertional tolerance and urinary excretion of glycosaminoglycan. 49
Mucopolysaccharidosis Type VII (Sly’s 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, aortic regurgitation, obstructive arterial disease, and cardiomyopathy. 50,51 Fetal hydrops has also been reported. 52 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 enzymic replacement therapy have been performed and are encouraging in terms of improving the cardiovascular changes associated with this disease. 53
Mucolipidoses
The mucolipidoses present with clinical features similar to the mucopolysaccharidoses, but are biochemically distinct. Leroy and Demars 54 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 defect in lysosomal storage 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 recognised 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, in which there is a single lysosomal enzyme defect. Mucolipidoses type II, or inclusion cell disease, and type III, or pseudo-Hurler polydystrophy, result from a deficiency of uridine diphosphate-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 levels of β-hexosaminidases, iduronate sulphatase, and arylsulphatase A in the serum are diagnostic. The characteristic enzymatic deficiencies in fibroblasts can be identified in cultured cells.
Mucolipidosis Type II (Inclusion Cell Disease, I-Cell Disease)
I-cell disease results from a severe deficiency of the phosphotransferase enzyme due to specific genetic mutations which result in a marked reduction in enzymic activity. Various defects in the gene encoding this enzyme have been discovered in patients with this disorder. 55 The patients with inclusion cell disease present with clinical features very similar to those with Hurler’s syndrome. Hepatosplenomegaly is not so obvious, while striking gingival hypertrophy is a feature not encountered in Hurler’s syndrome. Furthermore, the disease becomes evident earlier than does Hurler’s 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. Asymmetrical septal hypertrophy has been reported. 56 Treatment of the cardiac manifestations is usually supportive, though surgical management of valvar involvement has been reported. 57 Transplantation of allogeneic stem cells has stemmed the progression of disease in a small number of reported cases. 58
Mucolipidosis Type III (Pseudo-Hurler Polydystrophy)
Mucolipidosis type III is less severe, and also less common, than type II, and is due to a deficiency of the same phosphotransferase enzyme. In type III, the enzymic activity is less severely reduced, and the manifestations are less severe. There is a fair amount of variability in clinical severity. 59 This is likely due to various genetic defects leading to different levels of enzymic activity. Patients are usually spared the joint manifestations of I-cell disease early in life, 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, particularly aortic regurgitation, does occur but is usually not sufficiently severe to cause clinical problems. Patients with pseudo-Hurler polydystrophy survive into the fourth decade.
Disorders of Glycoprotein Degradation
Specific lysosomal enzymic deficiencies result in failure of degradation of glycoproteins, with consequent accumulation of glycoproteins in many tissues, especially the nervous system. They became recognised when patients with appearances similar to those with 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 results in the accumulation of oligosaccharides, as their degradation is dependent upon 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 enzymic synthesis, decreased enzymic activity within the lysosomal environment, decreased localisation of the enzyme within the lysosome, or faulty post-translational 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 shown as type I is associated with increased severity. Death occurs between 3 and 10 years of age. Late-onset, or type II, runs a more benign course. Cardiac manifestations are not frequently reported. A short PR interval has been reported in several patients, albeit that its mechanism is unknown. 60 Treatment has been attempted with transplantation of bone marrow, and current strategies under investigation include various forms of enzymic replacement therapy. 61
Fucosidosis
Deficiency of α- l -fucosidase results in the accumulation of fucosylated oligosaccharides and glycolipids. Two clinical types are recognised. The first type presents in infancy with coarse facies, growth retardation, mental retardation, and neurological deterioration. Convulsions and respiratory infections often occur. The second type has a more benign course and a later onset. Cardiomegaly, probably as a part of a generalised visceromegaly, is the most common cardiac feature. These two types probably represent both ends of a continuum which is dictated by specific enzymic activity as determined by the specific genetic defect. Transplantation of bone marrow has been performed with good results, and further experimentation with enzymic replacement therapy is under way. 62
Sialidosis
The basic defect in sialidosis is deficiency of α-neuraminidase, with accumulation of sialoglycoconjugates. There are two forms. The first is of late onset. 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. Neurological, and occasionally renal, manifestations dominate the clinical picture. The second type has an early onset, even upon occasion being obvious at birth. The patients have coarse features and enlargement of various organs, including the heart. Echocardiography has shown a thickened left ventricular wall along with thickening of the mitral valve. 63 There is great variability in the spectrum of severity, even in the group with early onset. Survival beyond 20 years is rare, while, occasionally, affected subjects are stillborn. Fetal hydrops has been reported as a presenting feature. 64 Sialidosis is inherited in autosomal recessive fashion. Enzymic replacement therapy and gene transfer are under investigation. 65
Galactosialidosis
In galactosialidosis, patients have a defect in the production of lysosomal protective protein/cathepsin A, which helps form a stable and activated complex with β-galactosidase and α-neuraminidase. 66 Thus, the symptoms are a combination of those seen in sialidosis and Morquio’s syndrome, the severity of which is likely determined by the specific genetic defect and its overall effect on production of functional levels of the protein. An infantile form has been described, 67 though there appears to be clinical variation even in those diagnosed as infants. 68 Complex congenital cardiac malformations have been reported in patients with galactosialidosis. 69 The cardiac manifestations are similar to those seen in Morquio’s syndrome and sialidosis, with aortic and mitral valvar thickening which is progressive. 70,71 Recently, the role of these enzymes and protective protein/cathepsin A in elastogenesis has begun to be unraveled, helping further to explain the phenotype associated with these genetic disorders. 72 Early work has begun on therapies involving enzymic replacement or gene transfer. 65,73
Aspartylglycosaminuria
Aspartylglycosaminuria is a lysosomal storage disease produced by defective or deficient glycosylasparaginase. This enzyme is required for complete breakdown of asparagine-linked glycoproteins within the lysosome. 74 Accumulation of these glycoprotein residues leads to severe and progressive neurologic impairment. It is associated with coarse features, joint laxity, early rapid somatic growth followed by a reduced adolescent growth spurt leading ultimately to short stature, and mental retardation. Animal models demonstrate accumulation of residues within the heart, but clinical cardiac involvement does not appear to predominate. Enzymic replacement is currently being studied in animal models. 75
Acid Lipase Deficiency (Wolman’s Disease and Cholesteryl Ester Storage Disease)
Lysosomal acid lipase is necessary for the cleavage of triglycerides and cholesteryl esters from lipoproteins delivered to the lysosome. Complete or severe deficiency of lysosomal acid lipase results in accumulation of cholesterol in most tissues of the body. The disease occurs in two forms. Wolman’s disease is a disease of infancy presenting with vomiting, diarrhoea, hepatosplenomegaly, anaemia 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, known as cholesteryl ester storage disease, though premature atherosclerosis is also seen. 76 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 an autosomal recessive fashion. Successful treatment with transplantation of both bone marrow and cord blood has been reported. 77,78
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. The primary cells affected are those of monocyte-macrophage lineage, as they are frequently employed in the metabolic turnover of these substances. At least four variants exist, but the most frequently encountered is the infantile acute neuronopathic form. Many of these patients are of Ashkenazi Jewish heritage. The disease is characterised 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. 79 Since there were no storage cells in the heart, however, this may have been a chance association. Abnormalities in the lipid profile have also been described in children with Niemann-Pick disease types A and B, possibly leading to premature atherosclerosis. 80 Low levels of high density lipid cholesterol were the most consistent finding, while elevated levels of triglyceride and low density lipid 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’s Disease)
Gaucher’s disease is the most common inherited disorder of glycolipid metabolism. In his original description, 81 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. While over 150 different mutations of the gene encoding glucocerebrosidase have been described, the disease occurs in three varieties based upon the presence or absence of, and rate of progression of, neurologic manifestations. Type I, or the chronic non-neuronopathic form, can be diagnosed at any age. It is the most common form, being characterised by hypersplenism, hepatomegaly with evidence of abnormal hepatic function, and skeletal lesions, including aseptic necrosis of the femoral head. Other long bones and vertebras may also be eroded. In patients with this type of disease, cardiac involvement may be seen with myocardial infiltration or restrictive pericardial disease. 82 The most frequently encountered cardiac problem, however, is cor pulmonale secondary to pulmonary involvement. Mitral and aortic stenosis and insufficiency can also be seen, 83 and severe valvar and aortic arch calcification has been reported. 84 The course is variable. Death may occur in early childhood or, particularly when onset is late, there may be a normal life expectancy. Further variability is apparently the consequence of the non-neuronopathic form at onset changing to one of the other forms with a poorer prognosis.
The acute neuronopathic form, or type II, is usually recognised within the second half of the first year of life. Neurological involvement is evident early, afflicting particularly the cranial nerves and extrapyramidal tracts. The mechanism of death is usually a respiratory infection, since aspiration is common owing to incoordination of the nasopharynx. The subacute neuronopathic form, or type III, falls between the acute and chronic forms. The neurological involvement renders it less benign than the chronic variant, but its course usually stretches over many years.
While describing Gaucher’s disease in terms of three distinct phenotypes is convenient, the observed characteristics of this disease are 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, while the genetic defects leading to Gaucher’s disease are being elucidated, and include over 150 specific mutations already identified, the link between genotype and phenotype is still unclear.
The diagnosis of Gaucher’s 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 an appearance of wrinkled tissue paper or crumpled silk. The nucleus is eccentric. These cells have to be differentiated from cells found in multiple myeloma, leucaemia, thalassaemia, and congenital dyserythropoietic anaemia. Demonstration of the enzymic deficiency in cultured skin fibroblasts, or in leucocytes, confirms the diagnosis. Approaches to treatment have included transplantation of organs and enzymic replacement. Improvement in the visceral involvement is common, but neurologic damage is generally not responsive to exogenous enzymic therapy. All three variants are inherited as autosomal recessive traits. Intra-uterine diagnosis is available, and heterozygotes can be identified at least for the acute and chronic types.
α-Galactosidase A Deficiency (Fabry’s Disease)
Deficiency of α-galactosidase, a lysosomal enzyme, results in 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. 85 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 start in the hands and feet. Crises occur most usually in the afternoon. Development of crises, which become less frequent and severe with time, may be followed by eruption of skin lesions, by angiokeratomas, and by 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. They do not blanch on pressure. Hyperkeratosis and hypohidrosis 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 ischaemia and infarction are common and are secondary to the vascular lesions. Mitral regurgitation and aortic stenosis are the most frequently encountered valvar lesions. 86 Infiltration of the conduction tissues occurs. This results in progressive shortening of the PR interval as in other storage diseases that affect the specialised atrioventricular conduction axis. 87 Myocardial deposition can be detected echocardiographically by demonstration of septal and left ventricular wall thickening. 88 Progressive deposition of glycosphingolipid means that the cardiac problems themselves are also progressive. Since there is concomitant renal involvement, 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 from 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 leucocytes, and by finding an abnormally high content of accumulated substrates in tears or urinary sediment. Prenatal diagnosis is available. Enzymic replacement was reported in 2002, 89 and positive effects on cardiac involvement are evident. 90
Gangliosidoses
The gangliosidoses are lysosomal storage diseases characterised by accumulation of gangliosides GM 1 or GM 2 , or their 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 enzymic 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 enzymic activity for acid β-galactosidase, leading to accumulation of GM 1 ganglioside in the brain and organs. 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.
When seen in infancy, the disease is rapidly progressive, characterised by hypotonia, poor feeding, and failure to make motor or intellectual progress. Progressive neurological deterioration results in spastic quadriplegia or decerebrate rigidity. Rarified bones and beaked vertebrae are some of the skeletal lesions encountered. As in Tay-Sachs disease, to be discussed below, 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 congestive cardiac failure with systolic dysfunction to isolated valvar thickening has been observed. 91,92 Neonatal ascites has also been reported. 93 Cardiac involvement usually includes cardiomegaly on chest radiography, left ventricular hypertrophy on the echocardiogram, and congestive cardiac failure. 94 Patients with GM 1 gangliosidosis have a defect in the same enzyme which is involved in patients with Morquio’s syndrome type B. The clinical heterogeneity among patients with this enzymatic defect is unclear, but probably is related to residual activity of the enzyme, post-processing of the enzyme, and other proteins involved, such as saposin B. 95 A novel therapeutic strategy is under investigation, and involves molecular chaperones, substances which stabilise the configuration of defective enzymes and enable them to remain enzymatically active. 96 Treatment in a mouse model demonstrated improved enzymic activity, 97 and reduced the quantity of substrate in neuronal tissues. 98
GM 2 Gangliosidoses
The GM 2 gangliosidoses 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 alpha and beta subunits, comes in two forms. Hexosaminidase A, found in the central nervous system, is composed of an alpha and beta subunit, while hexosaminidase B, found in peripheral tissues, is composed of two beta subunits. Thus, the GM 2 gangliosidoses result from a defect in either the alpha subunit, producing Tay-Sachs disease and severe deficiency of hexosaminidase A, or the beta subunit, which produces Sandhoff’s 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 A. Treatment for these disorders is still under investigation and has included gene therapy, substrate reduction, and transplantation of bone marrow. 99–101
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. Save for a prolonged QT interval and non-specific T wave changes, however, cardiac manifestations are rare. While the hallmark of the disease is accumulation of GM 2 ganglioside in the central nervous system, evidence of involvement of the peripheral and autonomic nervous system has been reported in patients with chronic disease. 102
Sandhoff’s Disease
Sandhoff’s 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. 103 Another separate report described a case of congestive cardiac failure due to aortic and mitral valvar thickening with severe mitral regurgitation. 104 The coronary arteries may also be narrowed. 105 As for GM 1 gangliosidoses, inheritance is autosomal recessive.
METABOLIC DISORDERS: INHERITED ENDOCRINE DYSFUNCTION
Diabetes Mellitus
The annual incidence of juvenile diabetes is between 8 and 10 per 100,000 of the population at risk. 106,107 New cases are half as frequent under the age of 10 years as they are between 10 and 20 years of age. Since cardiovascular complications are manifested later in the disease, they are exceedingly rare in childhood. 108 There will be problems presented to the paediatric cardiologist by diabetes because fetal mortality is high in pregnant diabetics. Furthermore, congenital cardiac anomalies occur in approximately one-sixth of offspring of diabetic women, with a wide variety of defects reported. The most frequent cardiac complication is hypertrophic cardiomyopathy, 109 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. The 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 hypoglycaemia secondary to hyperinsulinism. The organs, including the heart, are enlarged. The babies are frequently tachypnoeic, but this may not be of cardiac aetiology. Respiratory distress syndrome is quite common. Cardiac murmurs are frequent. Approximately one-third have radiological cardiomegaly. The electrocardiogram is rarely diagnostic.
Echocardiography 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, in general, most pronounced in those infants in congestive cardiac failure. 110 A spectrum of abnormality exists from that of simple hypertrophy to hypertrophic obstructive cardiomyopathy. Obstruction of the left ventricular outflow tract can occur, as has been demonstrated in the past by cardiac catheterisation. Treatment of the hypertrophic cardiomyopathy is fairly standard in that β-blockade helps in terms of diastolic dysfunction. Diuretics must be used judiciously, as the thickened myocardium requires a higher filling pressure. 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. 111
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. 112,113 The importance of late glycaemic control, and the correlation of maternal levels of haemoglobin A 1C to severity of disease, has been questioned. 114
Pituitary Gigantism and Acromegaly
Adenomas of the pituitary that secrete growth hormones cause gigantism in growing children and acromegaly in adults. Acromegalic cardiomyopathy results from elevated levels of growth hormone and the resultant elevated levels of insulin-like growth factor 1. The cardiomyopathy is characterised by biventricular and concentric involvement, which is progressive and may lead to congestive cardiac failure with myocardial fibrosis. The severity of disease relates to the age of the patient. Treatment with somatostatin analogues, which reduce growth levels, is beneficial in terms of clinical symptoms and indexes of myocardial morphology and physiology. 115
Disorders of Thyroid Function
Hypothyroidism
Congenital Hypothyroidism
Congenital hypothyroidism has many aetiologies. 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 goitre, and administration of antithyroid drugs to pregnant mothers. The cardiac features of cretinism are not dramatic. Normal to slow heart rates, and radiological cardiomegaly, are usually the only manifestations. The enlarged cardiac silhouette is usually caused by pericardial effusion, which is an extremely common feature. Cardiac performance is usually well preserved. Abnormalities of heart rate and the pericardial effusions resolve when substitution treatment of the hypothyroidism is successful. A pericardial effusion can be detected by echocardiography in approximately half of these patients. 116
Juvenile Hypothyroidism
As with congenital forms, juvenile hypothyroidism has multiple aetiologies. It is generally the result of autoimmune thyroiditis, or Hashimoto’s disease. Growth retardation is the most common form of presentation. It 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 non-specific 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 one-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 goitre, 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. Presenting symptoms include restlessness, poor performance at school, irritability, loss of weight, and occasionally diarrhoea. 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 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 non-specific systolic murmurs may be present. A high incidence of mitral valvar prolapse has been reported in adults with Graves’ disease 117,118 but has not been demonstrated in children. 119 This suggests that the appearance of the prolapse is related to the duration of the disease.
The electrocardiogram is atypical. Sinus tachycardia, first-degree atrioventricular block, and non-specific ST segment and T wave changes may be present. Signs of atrial and left ventricular enlargement are more common in children than in adults. 120 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 cardiac failure. The echocardiogram reveals hyperdynamic contractions of the ventricular septum and the left ventricular posterior wall.
Evaluation of cardiac function by radionuclide angiography in the presence of hyperthyroidism has shown a fall in left ventricular ejection fraction with exercise. Upon restoration of a normal thyroid state, the ejection fraction shows its normal exercise-induced increase. 121 In general, the cardiovascular system in childhood tolerates well the effects of hyperthyroidism. In the presence of cardiac failure, however, concomitant cardiovascular lesions must be excluded. Cardiovascular manifestations of hyperthyroidism are reversible with treatment but, if long-standing or poorly treated, the disease may predispose to irreversible cardiac dysfunction. 122
Addison’s 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, presumably due to disuse atrophy. 123 The electrocardiogram 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 congestive cardiac failure can ensue. This is presumably due to the acute load of salt and water that is thrust upon the previously unloaded myocardium. This complication is readily treatable and is generally transient. 124
DISORDERS OF ENERGY METABOLISM
Mitochondrial Myopathies
The mitochondrial myopathies are muscle and systemic disorders characterised by the presence of mitochondria with abnormal structure, number and/or function. They are typically caused by deletions in mitochondrial deoxyribonucleic acid, though some are caused by defects in nuclear deoxyribonucleic acid. These disorders involve complexes of the respiratory chain, and thus affect oxidative phosphorylation.
Chronic progressive ophthalmoplegia, or Kearns-Sayre syndome, 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 endocrinal anomalies. The disease appears in childhood and has a progressive course. The most frequently reported cardiac anomaly is progressive heart block. Electrocardiograms should be performed frequently for early recognition and appropriate implantation of a pacemaker (see Chapter 19 ). 125 Cardiomyopathy, prolonged QT interval, torsades de pointes, atrial arrhythmias, and mitral valvar prolapse have also been described. 126–130
Myoclonic epilepsy with ragged red fibers (MERRF) and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) can present with a dilated cardiomyopathy. 131 Patients with Leigh syndrome, or subacute necrotizing encephalomyelopathy, can develop hypertrophic cardiomyopathy and conduction system defects. 132 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 tafazzin gene, which produces a deficiency of cardiolipin. While the precise pathogenetic mechanism linking this deficiency to the clinical features of Barth syndrome remains to be elucidated, it is known that cardiolipin plays an important role in the processes of mitochondrial energy metabolism. 133 The disease is characterised by a dilated cardiomyopathy, skeletal myopathy, cyclic neutropenia, and retardation of growth. The heart typically displays poor contractility, and is often hypertrabeculated, showing features of ventricular non-compaction. Hypertrophy has also been noted. Cardiac involvement usually becomes manifest in the first decade of life. 134 Sudden death has been reported, and may be due to the increased risk of ventricular arrhythmias, which may require implantation of a defibrillator. 135 Treatment of the cardiomyopathy rests with traditional medical therapy, but cardiac transplantation has been successfully performed. 136 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. 137 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 in clinical presentation, from severe early onset of the disease in the first days of life to relatively mild forms presenting in adulthood. Patients develop hypoglycinaemia, hyperammonaemia, hypoglycaemia, 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. 138 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. 139 Because of this, regular electrocardiographic screening is necessary. When involved, the heart is typically dilated with depressed function, though hypertrophy is also seen. 140 Poor ventricular contractility can complicate acute metabolic crises, and patients presenting with encephalopathy should be assessed for left ventricular systolic dysfunction. The precise aetiology 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 proteins and supplemental oral carnitine.
Methylmalonic Aciduria
Methylmalonic aciduria is clinically similar to propionic acidaemia and is due to a deficiency of methylmalonyl-CoA mutase. It can also be due to defects in its cofactor, adenosylcobalamin. 141 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 cardiomyopathy. 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. Recently, hepatocyte-directed gene delivery has been shown to correct the enzymic activity, and may hold promise as a future corrective therapy. 142
Disorders of Fatty Acid Metabolism
The heart utilises 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 the mitochondria. Deficiency often results in early death due to severe metabolic collapse with encephalopathy and hypertrophic cardiomyopathy, though 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. 143
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 hypoglycaemia 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. 144
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 generalised myopathy along with nonketotic hypoglycemia and cardiomyopathy. 91
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. The skin, apart from the palms and soles, 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 Metenier’s sign, blue scleras, and a dislocated lens. A variety of congenital cardiac malformations have been reported, 145–147 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 showed an incidence similar to that of the general population. 148
More than 10 subtypes of Ehlers-Danlos syndrome have been described, but six major subtypes are recognised and encompass 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, while not characteristically demonstrating vascular changes, have been shown to be associated with dilation of the aortic root and valvar dysfunction. 149 The vascular type, also known as Ehlers-Danlos syndrome type IV, results from mutations in the gene encoding type III procollagen. These patients are at risk for arterial rupture, which typically occurs after the onset of the third decade of life. 150 A more severe recessive form has been reported, and includes both the cutaneous findings of the classic form coupled with cardiac valvar involvement. 151
Cutis Laxa
Cutis laxa is, again, a genetically heterogeneous group of conditions characterised in the phenotype by the skin being so loose that it appears too large for the body. Unlike the 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 152 and aortic dilation have been reported. 153 These findings, coupled with reports of supravalvar aortic stenosis, 154 have helped lead to the discovery that defects in the elastin gene are one cause of this disorder. 155 Defects in other genes, including fibulin-4 and fibulin-5, have also been implicated in some forms. 156,157 Another major complication is cor pulmonale, since emphysema is frequently progressive and severe. 158 Patients with the neonatal variant of cutis laxa can have severe mitral regurgitation with dysplastic valvar leaflets. 159
Osteogenesis Imperfecta
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 vertebras are biconcave, with the disc sometimes perforating the vertebral body to give the appearance known as Schmorl’s 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. 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. 160 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. 161 Aortic stenosis, defects of the oval fossa, and tetralogy of Fallot have also been reported. 162
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 500 mutations in the gene have been identified, and approximately one-quarter to three-tenths of cases represent new mutations. While the 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. 163 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. 164 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. 57-3 A). They have long, thin fingers ( Fig. 57-3 B), 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 multi-disciplinary group of experts produced diagnostic criterions known as the Ghent nosology. 165 These criterions included skeletal findings as a major criterion, and also introduced molecular diagnostic tools into the clinical diagnosis of this disease ( Table 57-2 ). Patients with a positive family history must meet the major criterions for at least one category, not including the genetic category, plus the criterions for involvement in a second category. Patients with no family history must meet the major criterions for two categories, plus the criterion for involvement in a third category.
| Category | Major Criterions | Minor Criterions |
|---|---|---|
| Family history/genetics |
| None |
| Cardiac |
|
|
| Pulmonary | None |
|
| Skin and integument | None |
|
| Dura | Lumbosacral dural ectasia | None |
Cardiac manifestations in childhood are usually less severe than in adults. Mitral valvar disease in the form of prolapse and incompetence are the most frequent abnormalities. They are present in approximately three-quarters of the patients. 166 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. Histopathological examination of the ascending aorta reveals degeneration of the elastic fibres, 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 aneurysmal formation have also been reported. 167 The electrocardiogram 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 valvar prolapse and prolonged ventricular repolarisation. 168 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. Echocardiographic evaluation is essential. Mitral valvar 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 catheterisation is useful for further assessment of these lesions. Aortic angiography will reveal the dilation of the aortic root. Evaluation with magnetic resonance imaging has demonstrated decreased aortic distensibility and increased stiffness in children with Marfan syndrome. 169
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. 170 Additionally, defective microfibrils result in excessive activity of transforming growth factor–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. 171 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. 172 The complex interplay between fibrillin, microfibrils, LTBPs (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. 173 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 benefits in children of prophylactic propranolol to delay the dilation of the aorta through its negative inotropic effects has been the subject of some debate. Arguments for 174 and against 175 a beneficial effect have been published. Additionally, with the discovery of a role for angiotensin II and TGF-β in the pathogenesis of aortic aneurysmal formation, investigations into inhibition of angiotensin converting enzyme and blockade of angiotensin receptors have begun. 176,177
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. 178 On the other hand, replacing the aortic root emergently due to acute dissection carries a much higher risk of short- and long-term mortality. 179 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. 180 Thus, recent recommendations concluded that replacement should occur electively before the root reaches a diameter of 55 mm. 181 Additionally, it is difficult to determine which patients might have an increased risk for dissection at a relatively smaller size of the root. Certainly, for patients with a family history of aortic dissection, or for those in whom pregnancy is likely, intervention is encouraged at a relatively smaller size. Also, women appear to be at risk for dissection at a smaller size. 182 Thus, some are now advocating elective replacement of the aortic root at sizes less than 50 mm. 183 In addition, procedures which allow for replacement while maintaining the native aortic valve have been evaluated and appear to be satisfactory, potentially eliminating the need for chronic anticoagulation. 184,185
Our group emphasises the importance of early diagnosis and follow-up, with serial measurement of the aortic root, and indexing this to document rates of relative growth, with respect to somatic growth. We institute β-blockade therapy early, and add inhibition of the angiotensin converting enzyme at the first sign of an increased rate of aortic dilation, and in patients with other risk factors such as a family history of aortic dissection. We review each patient carefully when the aortic root measures 45 mm to assess the need for surgical intervention, taking into consideration the specifics of each patient before deciding on the timing of elective repair.
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. 186 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. 187 Additionally, patients with the infantile syndrome frequently exhibit pulmonary emphysematous changes. Because the infantile syndrome carries a poor prognosis, it is important to differentiate it from the classic syndrome, which can occasionally be evident in a neonate. Neonates with the infantile syndrome present in congestive cardiac failure that responds poorly to conventional therapy. Death often occurs within the first 2 years of life, though surgical repair of mitral valvar 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. 188 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. It is characterised by hypertelorism, bifid uvula and/or cleft palate, and generalised arterial tortuosity with ascending aortic aneurysmal formation and dissection. 189 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 other 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, replacement is recommended at diameters of 40 mm in adults and at even smaller diameters in children. 190
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 bodily habitus similar to those with Marfan syndrome, albeit that 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. 191 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’s Muscular Dystrophy
Duchenne’s muscular dystrophy is an X-linked recessive disease. Because of this, it almost always afflicts males. Its incidence in male children is calculated at between 13 and 33 cases for each 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 which stabilises the sarcolemmal membrane during contraction. While 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. 192
The earliest symptoms are clumsiness in walking, a tendency to fall, and an inability to run. Those with the disease also have difficulty in climbing stairs and getting up from the floor. Clinical onset is usually manifested 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 owing to improved medical therapies, including nocturnal ventilation, early and aggressive management of cardiomyopathy, and perhaps the use of corticosteroids. 193 Muscular weakness and atrophy initially affect the proximal muscle groups of the upper limbs. Involvement of the legs 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 the 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 flexor muscles of the hip 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. Generalised decalcification of the bones leads to frequent pathological fractures.
Myocardial involvement is 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, and in ambulatory patients, subclinical disease may become symptomatic with exercise. In non-ambulatory patients, a resting tachycardia, 194 decreased heart rate variability, 195 echocardiographic evidence of diastolic dysfunction, 196 and myocardial strain changes on magnetic resonance imaging 197 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. 198 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, 199,200 but others have shown a benefit only when afterload reduction is combined with β-blockade. 201
There is a distinctive electrocardiographic pattern in from half to nine-tenths 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 the abnormal electrocardiogram. 202 These findings correspond to pathological 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. Histological studies of the conduction system show multifocal areas of fibrosis, vacuolisation and fatty infiltration. 203 The echocardiogram reveals impairment of both systolic and diastolic function. The 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 activity of creatine kinase, and biopsy of the skeletal muscles. Creatine kinase activity is from 100 to 300 times the normal when the patients are aged from 1 to 5 years. Other muscle enzymes, like aldolase, glutamic oxalic transaminase, lactic dehydrogenase, and pyruvate kinase are also grossly elevated. The levels of creatine kinase diminish later in the disease, but still remain well above normal limits. Muscle biopsy shows scattered hyaline fibres with active muscular necrosis and regeneration. There is splitting of the muscle fibres, with fatty replacement. The nucleuses are of varied size. 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 bedrest is harmful, regular physical activity and exercise are to be encouraged. Avoidance of obesity is an important general measure, along with prevention of muscular contractures by passive stretching. Because of the risks of anaesthesia and immobilisation, the benefit from major orthopaedic 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, and cardiac failure or arrhythmias. Detection of carriers is important for appropriate genetic counselling. More than half the carriers can be identified by their elevated levels of creatine kinase, by electromyography and by muscle biopsy. The analysis of the pedigree is particularly useful. Novel treatments for this myopathy are actively being investigated. They include gene therapy, 204 use of inhibitors of proteases, 205 membrane stabilisers, 206 and transplantation of the muscle precursor cells. 207
Childhood Limb-girdle Muscular Dystrophy
The childhood limb-girdle muscular dystrophies 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, with 7 genetic defects now identified in the dominant forms, and 11 in the recessive forms. 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, the patients often becoming unable to walk by their twenties. The disease is first suspected when weakness of the limb girdles becomes apparent, although Duchenne’s and Becker’s muscular dystrophy must be ruled out. An elevated level of creatine kinase will not differentiate between this entity and the dystrophinopathies. This can be done through analysis of the dystrophin gene, and by examination of a muscle biopsy. Various forms of the disease affect the heart. Those with the so-called 1B variant, produced by a mutation in the lamin A/C gene, frequently develop arrhythmias which can be lethal and which may require placement of an implantable defibrillator. Atrioventricular block can also occur, necessitating placement of a pacemaker. 208 This disorder can also result in a dilated cardiomyopathy.
Those with the 2I variant, caused by a defect in the gene encoding the fukutin-related protein, may develop a dilated cardiomyopathy by the third decade. Evidence of arrhythmias is not seen. 209 The precise role of the fukutin-related protein is unknown, but it may play a role in the glycosylation of muscle membrane proteins.
Myotonic Muscular Dystrophy (Steinert Disease)
The involvement of systemic tissues, together with the presence of myotonia and muscular atrophy, separates myotonic muscular dystrophy from the other muscular dystrophies. It 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. It is due to an expansion of a CTG trinucleotide repeat on the q arm of chromosome 19. 210 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 it extends to neighbouring muscle groups. The typical facies are characterised 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 generalised. 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 oesophagus are thought to be the cause of dysphagia and pulmonary aspiration. Testicular atrophy, diabetes mellitus, increased metabolism of immunoglobulin G with low levels in the serum, 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 implantation of a pacemaker. 211 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 elevated hemidiaphragms. 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 electrocardiogram 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. 212 Rhythm disturbances include sinus brachycardia, premature atrial beats, atrial fibrillation, atrial flutter, ventricular premature beats and ventricular tachycardia. Four-fifths of the patients have electrophysiological evidence of disease of the atrioventricular conduction axis. A further one-fifth have evidence of intra-atrial conduction disturbances. 213 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 electrocardiographic and electrophysiological evaluation performed during life. 186
Mitral valvar 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 valvar prolapse and the arrhythmias. Systolic and diastolic function are normal. Normal ejection fractions at rest are recorded with radionuclide angiography. Some patients fail to show an increase 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 examination for cataracts using a slit lamp. Cardiological evaluation is required in all patients because of the frequent association of cardiac disease. The disease shows progressive deterioration, with physical incapacity usually occurring 15 to 20 years after the onset of muscular symptoms. Death is usually from respiratory infections, aspiration, cardiac arrhythmias, or anaesthetic complications. There is no specific treatment for the condition. Active exercise and control of weight are important general therapeutic measures. Systemic complications are treated as they arise. Myotonia is relieved by the use of procainamide or phenytoin. Caution must be exerted, however, since procainamide exacerbates pre-existing disturbances of conduction. Electrophysiological 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. In the fullness of time, they come to resemble the adult form.
The congenital form is characterised 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 are 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. Non-specific 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. Her clinical involvement has often failed previously to be noted.
Autosomal Dominant Scapuloperoneal Myopathy
Scapuloperoneal myopathy is a very rare form of muscular dystrophy. It is possible to recognise two distinct groups according to the age of onset. They share an autosomal dominant form of inheritance, and involve the same muscle groups. Weakness and atrophy affect 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. Levels of creatine kinase are slightly elevated in the serum. Electromyography and muscle biopsy show the changes common to muscular dystrophies.
The group of patients with early onset generally present under the age of 10 years. 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 congestive cardiac failure. 214 Those patients having a late onset present over the age of 40 years, and their clinical course is slow. They seldom develop contractures. Cardiac involvement, usually late, could well be a result of ischaemic heart disease. 215
Becker’s Muscular Dystrophy
Becker’s muscular dystrophy is one of the most frequent types of muscular dystrophy. It 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’s muscular dystrophy. The peroneal and anterior tibial muscles are also affected in the Becker variant. 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. Activity of creatine kinase in the serum is 25 to 200 times the 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. 216 Electrocardiographic 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. 217 Heart rate variability is also decreased and may indicate a risk for sudden death. 218 Dilated cardiomyopathy is seen, and the risk of ventricular dysfunction increases with age, though many patients are asymptomatic from a cardiac standpoint, exhibiting abnormalities only on the electrocardiogram or echocardiogram. 219 Transplantation of the heart for severe left ventricular systolic dysfunction is a well-established palliative option. 220
Facioscapulohumeral Muscular Dystrophy (Landouzy-Dejerine Syndrome)
Fascioscapulohumeral 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 later stages, the quadriceps and sartorius in the lower limbs are also affected. Retinal vasculopathy is also seen frequently. The levels of creatine kinase in the serum are normal or else 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 within this region, and so various hypotheses have been presented to explain the mechanism whereby this deletion induces clinical disease. 221
Ventricular function is not affected. Supraventricular tachycardia has been reported with a frequency higher than that of the general population. 222 Sinus nodal dysfunction, abnormal atrioventricular nodal or infranodal conduction, and easily inducible atrial fibrillation or flutter have also been reported in around one-quarter of patients studied. 223
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 autosomal dominant or autosomal recessive forms. 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 Achilles tendon. Pseudohypertrophy is absent. Levels of creatine kinase are from 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 which plays a role in the regulation of many cellular and nucleolar processes. Its role in the pathogenesis of muscle damage remains to be elucidated. The autosomal dominant form is due to defects in the lamin A/C gene, similar to variant 1B of limb-girdle muscular dystrophy. 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. 224 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 manifested 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 require implantation of a pacemaker because of the increased risk of sudden death. 225 Atrial paralysis, with the absence of P waves and an inability to electrically pace the atrium, is seen. Ventricular function is often normal, but progressive left ventricular dysfunction occurs due to fibrous infiltration of the myocardium. 226 Cardiac transplantation has been employed for end-stage disease. 227 Those with bradycardia may have hypertrophied and dilated left ventricles, probably as a compensatory physiological response. Electrophysiological studies show prolonged HV 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 characterised by ptosis, strabismus, generalised muscle wasting, and weakness, together with absent or reduced deep tendon reflexes. Developmental delay and dysarthria are common. A dilated cardiomyopathy has been occasionally observed, and cardiac transplantation has been performed. 228 Patients have a prolonged PR interval and a superior axis on the electrocardiogram. The diagnosis is based on clinical findings, raised levels of creatine kinase in blood, evidence of a myopathy on electromyography, and a typical histological picture. This consists of central location of the nucleus, with variation in the diameter of the muscle fibres and a tendency for predominance of type 1 fibres. Inheritance is variable. The X-linked form is usually the most severe and involves the gene encoding myotubularin. An autosomal recessive form seems to have a milder course, though patients still present in childhood. 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. While 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. 229 Patients can have a very mild course of skeletal muscle weakness or severe neonatal disease leading to respiratory failure. Hypertrophic cardiomyopathy is more commonly seen, 230 but dilated forms of cardiomyopathy have also been reported. 231
Friedreich’s Ataxia
Friedreich’s ataxia is a rare spinocerebellar neuromyelopathy occurring in approximately 1 to 2 per 40,000 persons. The disease is inherited in an autosomal recessive fashion, and most cases are due to homozygosity for an expanded GAA triplet on chromosome 9q13. 232 This gene encodes frataxin, a precursor protein which may be involved in the maturation and assembly of iron and sulphur proteins of the mitochondria and cytosol. 233 Children present around the age of 6 years. The most frequent early symptom is an abnormal gait. Neurological signs include the ataxic gait, absent tendon reflexes, incoordination, and a positive Romberg test. 234 Weakness and muscular atrophy of the legs 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’s 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, electrocardiographic, and radiographic examination of the heart are non-specific for the evaluation of cardiac involvement, an echocardiogram is necessary in every patient.
The heart is involved in a very high percentage, and cardiac symptoms are an integral part of the clinical spectrum of the disease. Most usually, the heart exhibits a symmetrical, concentric, and slowly progressive hypertrophic cardiomyopathy. Cardiac involvement may occasionally precede the onset of neurological manifestations. 235 Cardiac symptoms are present in approximately one-third of the patients, and consist mainly of exertional dyspnoea, 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 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. 236
Pathological 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 hypothesised that iron-catalysed mitochondrial damage may lead to the pathologic findings in the myocardium. 237 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 non-specific and are presumably caused by repolarisation 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. 238
The presence of scoliosis makes radiographic evaluation of the heart difficult, albeit that its size is usually normal. Most patients have an abnormal echocardiogram. The most common anomalies reflect the presence of symmetrical concentric hypertrophic cardiomyopathy. There is an increase in left ventricular mural and septal thickness. Asymmetrical septal hypertrophy is seen on occasion. 239 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. A constant feature is the delay in mitral valvar 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 pre-terminal event. Most patients die from cardiac causes. Cardiac failure accounts for half of the deaths. Cardiac arrhythmias and respiratory complications are the other major causes of death. While conventional methods for treating hypertrophic and dilated cardiomyopathy are frequently employed, newer therapeutic options for patients with Friedreich’s 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. 240 Though 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. 241,242
Arthrogryposis Multiplex Congenita
Arthrogryposis multiplex congenita 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, though 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 cardiac disease in one-quarter. 243 These cases resulted from consanguineous matings, and 5 of 6 with congenital cardiac malformations resulted from one pairing. 244 Patency of the arterial duct, congenital aortic stenosis, and mitral stenosis have been reported. 221,245
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. 246 They are predominantly a motor neuropathy producing atrophy and weakness of the distal muscles. This determines the typical likeness of the legs to an inverted bottle. 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. 247,248 It has been postulated that there is a primary degeneration of the conduction system rather than changes secondary to a cardiomyopathy. 249 In addition to arrhythmias, left ventricular hypertrabeculation or non-compaction has been reported in a patient with the type 1A variant of Charcot-Marie-Tooth disease, and a duplication defect on chromosome 17 involving the peripheral myelin protein 22. 250 The Roussy-Lévy syndrome is a phenotypic variant of the type 1A, and shares many features with this disease. 251 Dilated cardiomyopathy has been reported. 252
Spinal Muscular Atrophy Type III (Juvenile Spinal Muscular Atrophy, Kugelberg-Welander Syndrome)
Juvenile spinal muscular atrophy appears in childhood or adolescence. Initially it is manifested 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 those affected. The clinical course is slowly progressive. There is evidence from electromyography and muscle biopsy to indicate disease of the lower motor neurons. Some patients have an associated dilated cardiomyopathy, though this may be secondary to associated respiratory disturbances. 253 Disturbances of rhythm 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. 254 The electrocardiogram frequently shows a fine tremor on the isoelectric line, which represents fasciculations characteristic of this disease. 255 The syndrome is transmitted in autosomal recessive fashion and is due to defects in the survival motor neuron 1 gene. 256 The infantile form of spinal muscular atrophy, or Werdnig-Hoffman disease, is a lethal variant presenting with severe hypotonia and respiratory failure. Various congenital cardiac malformations have been reported in patients with this disease, but these are likely chance associations. 257,258
Refsum Disease
Refsum disease is a rare neurological disorder due to the accumulation of phytanic acid in peroxisomes. Phytanic acid is a branched-chain fatty acid which is partially broken down by phytanoyl-CoA 2-hydroxylase. Many cases of the disease are due to defects in the gene encoding this enzyme. 259 This leads to accumulation of phytanic acid in blood and tissues. Symptoms appear in the first and second decade of life, the initial presentation being weakness, unsteady gait and night blindness. These patients have a diagnostic tetrad made up of retinitis pigmentosa, peripheral polyneuropathy with diminished or absent deep tendon reflexes, cerebellar ataxia, and high levels of protein in cerebrospinal fluid without pleocytosis. Other frequent signs are neural 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. 260 Diets low in phytanic acid produce clinical improvement. Complete recovery is rarely obtained, but treatment will slow the progression of the disease. The addition of plasmapheresis to the diet reduces the levels of phytanic acid more rapidly. 261
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