Chapter 10 – Metabolic and Storage Disease


This chapter deals with the inherited metabolic diseases affecting the heart in which there are morphological changes sufficient to permit a tentative diagnosis to be offered by a pathologist. A large first section deals with glycogen storage disorders and is well illustrated. This is followed by discussion of lysosomal storage disorders, including Niemann–Pick disease, sections on mucopolysaccharidosis and of the commoner disorders of lipid oxidation. Disorders of iron metabolism and amino acidurias close the chapter.

Chapter 10 Metabolic and Storage Disease

10.1 Introduction

Inborn errors of metabolism are uncommon. Even so, they account for up to 5% of all cases of cardiomyopathy in the Pediatric Cardiomyopathy Register in the United States and Canada [1]. More than 40 inborn errors of metabolism are documented to cause myocardial disease [2]. The more common ones are listed in Table 10.1. Cardiac involvement in metabolic disease may be minor in comparison to the other manifestations of the disease, but heart involvement may dominate the clinical picture. Affected individuals may present with cardiomyopathy (dilated, hypertrophic or restrictive), rhythm disturbance, valvar disease or even sudden death. Inheritance is typically autosomal recessive, but X-linked diseases do occur, for example Anderson–Fabry disease, Barth syndrome and Danon disease. Increasingly, there are targeted treatments for these disorders. The pathologist is likely to come across inherited metabolic disease in endomyocardial biopsy, in explanted hearts or at autopsy. Not infrequently the condition is unexpected, and one should always be open to the possibility.

Table 10.1 Metabolic diseases affecting the heart

Disorders of glycogen metabolism
GSD II (Pompe disease, acid alpha glucosidase deficiency)
GSD IIb (Danon disease, LAMP2 deficiency)
GSD III (Cori disease, debranching enzyme)
GSD IV (Andersen disease, branching enzyme)
GSD IX (cardiac phosphorylase b kinase)
GSD XV (Glycogenin1)
GSD O (glycogen synthase deficiency)
PRKAG2 deficiency
Phosphorylase B kinase deficiency
Lysosomal storage diseases
Disorders of metabolism of glycosphingolipid, ganglioside, mucopolysaccharide and oligosaccharide (sphingolipidoses)
Anderson–Fabry disease (alpha-galactosidase deficiency)
Gaucher disease (glucocerebrosidase deficiency)
Niemann–Pick disease
GM1 gangliosidosis (beta-galactosidase deficiency)
GM2 gangliosidosis (Tay–Sachs and Sandhoff disease)
Metachromatic leukodystrophy
Krabbe disease
Disorders of mucopolysaccharide (glycosaminoglycan) metabolism
MPS I (Hurler’s syndrome)
MPS II (Hunter’s syndrome)
MPS III (Sanfilippo’s syndrome)
MPS IV (Morquio’s syndrome)
MPS VI (Maroteux–Lamy syndrome)
MPS VII (Sly’s syndrome)
Mucolipodosis type II (I-cell disease)
Mucolipodosis type III (pseudo-Hurler polydystrophy)
Mucolipodosis type II/III
Disorders of glycoprotein and glycosylation metabolism
Congenital disorders of glycosylation
Schindler disease
Sialidosis (infantile sialic acid storage disease)
Disorders of amino acid and organic acid metabolism
Propionic acidaemia (propionyl-CoA carboxylase deficiency)
Barth syndrome (3-methylglutaconic aciduria type II)
Sengers syndrome
Methylmalonic aciduria
Beta-ketothiolase deficiency
Mevalonic aciduria
Alkaptonuria (homogentisate 1,2- dioxygenase deficiency”? deficiency)
Homocystinuria (csytathionine beta-synthase deficiency)
Mitochondrial disorders
Pyruvate dehydrogenase deficiency (Leigh disease)
Complex I deficiency
Complex II deficiency
Complex III deficiency
Complex IV deficiency
Complex V deficiency
Cytochrome–c reductase coenzyme deficiency
Cytochrome–c oxidase deficiency
Kearns–Sayre syndrome (mitochondrial DNA depletions/duplications)
MELAS (mitochondrial transfer RNA mutation)
MERRF (mitochondrial transfer RNA mutation)
Peroxisomal disorders
Refsum disease (phytanic acid oxidase deficiency)
Disorders of fatty acid metabolism
Carnitine transporter defects
Systemic primary carnitine deficiency
Muscle carnitine deficiency
Carnitine palmitoyl transferase deficiency type I
Carnitine palmitoyl transferase deficiency type II
Carnitine-acylcarnitine translocase deficiency
Carnitine transporter defect
Fatty acid oxidation defects
Very-long-chain acyl-CoA dehydrogenase deficiency
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Long-chain 3-ketoacyl-CoA thiolase deficiency
Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
Multiple acyl-CoA dehydrogenase deficiency
Mitochondrial trifunctional protein deficiency
Cholesterol biosynthesis defects
Smith–Lemli–Opitz syndrome (3-beta hydroxysterol-delta7-reductase deficiency)
Mevalonate kinase deficiency
CHILD syndrome
Desmosterolosis (3-beta hydroxysterol-delta24-reductase deficiency)
X-linked dominant chondrodysplasia punctate
Iron metabolism disorders
Hereditary haemochromatosis
Neonatal haemochromatosis/GALD

Adapted from Wicks and Elliott [2].

10.2 Glycogen Storage Disorders

These are among the commonest inborn errors of metabolism to affect the heart that are encountered by the pathologist. In order to understand them better and how they arise it is necessary to know something of glycogen metabolism [3].

10.2.1 Brief Overview of Glycogen Metabolism (Figure 10.1)

Glycogen is an intracellular polymer of glucose. It is a means to store large amounts of glucose in the cell without osmotic effects. The polymer consists of chains of glucose linked by α-1:4 glycosidic linkages with multiple side chains added by α-1:6 glycosidic linkage. Glycogen is synthesised in the cell cytoplasm by first converting glucose to glucose-6-phosphate. In the liver this reaction is catalysed by the enzyme glucokinase and in the peripheral tissues, including heart, by the enzyme hexokinase. Glucose-6-phosphate is then converted to glucose-1-phosphate by the enzyme phosphoglucomutase. Glucose-1-phosphate is then “activated” by linking to uridyl diphosphate (UDP), and in this state the glucosyl moiety is added to the glycogen molecule. There are three main enzymes involved in glycogen synthesis: Glycogenin 1 (GYG1), glycogen synthase (GYS1) and glycogen branching enzyme (GBE1). Glycogenin-1 is a glycosyltransferase that forms a short glucose polymer of approximately 10 glucose residues by autoglucosylation. It acts as a primer for glycogen synthase. Glycogen synthase and branching enzyme allow further elongation and branching of the glucose polymer primer. Glycogen is primarily stored in liver, skeletal muscle and heart.

Figure 10.1 Overview of cellular glycogen metabolism.

Glycogen is catabolised largely by the enzymes in the cytoplasm. The enzyme glycogen phosphorylase removes glucose molecules from glycogen as glucose-1-phosphate. The enzyme is activated by another enzyme, phosphorylase b kinase. Phosphorylase can only catabolise up to the branching points, leaving a molecule termed “phosphorylase limit dextrin”. For further catabolism debranching enzyme is required, which removes the molecules at the branch points and permits phosphorylase to remove glucosyl moieties up to the next branch point. A second, quantitatively lesser, method of catabolism occurs within lysosomes via the enzyme acid maltase (glucosidase).

10.2.2 Pompe Disease (Glycogen Storage Disease (GSD) II)

Pompe disease (GSD type II) is caused by mutations in the gene for the lysosomal enzyme acid α-1:4 glucosidase (acid maltase) on chromosome 17q25.2-q25.3 [4]. It is rare, with an estimated frequency in the Netherlands of 1:40 000 [5]. It leads to accumulation of glycogen in lysosomes in multiple tissues, including the heart. Depending on the severity of the enzyme deficiency and the age of clinical presentation, three types are identified: a classical infantile form with presentation in the first year of life with severe cardiomyopathy and hypotonia; a childhood form presenting at any time between birth and adolescence without hypertrophic cardiomyopathy; and an adult onset form with presentation from adolescence onwards [6]. Severe cardiac involvement occurs predominantly in the infantile form but may be present in the late-onset form. Generally the late-onset form shows vacuolar change in skeletal and smooth muscle but not cardiac muscle [7], and cardiac imaging is normal [8]. The cardiac involvement in the infantile form takes the form of hypertrophic cardiomyopathy. The cardiomyopathy associated with glycogen storage tends to be associated with abnormal electrophysiology. The heart is globular and there is marked thickening of both ventricular walls sometimes with subaortic obstruction. The myocardium is firm and pale pink. The valves are normal but there is endocardial fibroelastosis. Histologically, there is very marked vacuolar change in the myocytes with accumulation of glycogen (Figure 10.2). Myocyte disarray and myocardial fibrosis are not found. Glycogen can also be demonstrated in the smooth muscle in the walls of the coronary arteries. Ultrastructure of the myocytes shows glycogen displacing the cell organelles. The glycogen is typically present within lysosomes, but also free within the cytoplasm. In the past, the infantile form was fatal in the first year of life. However, treatment with enzyme replacement therapy has dramatically improved the cardiac effects of the disease but has had only limited effects on the skeletal muscle pathology [9, 10]. This has led to the conclusion that there are other pathogenic mechanisms at work in the muscle including disordered autophagy [11].

(A) Post-mortem frozen section of myocardium showing marked vacuolation of myocytes.

(B) The PAS preparation shows intense granular cytoplasmic staining for glycogen.

Figure 10.2 Infantile Pompe disease.

Pompe disease may be suspected by the finding of vacuolated lymphocytes in blood film [12] that are strongly PAS-positive (Figure 10.3).

Figure 10.3 Vacuolated lymphocytes in infantile Pompe disease. A blood film stained with PAS shows small cytoplasmic PAS-positive granules.

10.2.3 Danon Disease

Danon disease is a systemic disorder caused by mutations in the lysosomal-associated membrane protein 2 (LAMP2) gene on chromosome Xp24 that can give rise to hypertrophic cardiomyopathy with glycogen accumulation [13]. More than 60 mutations in the LAMP2 gene have been reported. Usually there are other systemic manifestations (skeletal myopathy, mental retardation, ophthalmic abnormalities), but these may be subclinical, and hypertrophic cardiomyopathy may be the presenting feature. LAMP2 deficiency accounts for approximately 4% of cases of unselected hypertrophic cardiomyopathy in children [14]. The disorder is described in (usually male) children as young as 8 years and carries a poor prognosis with progressive heart failure and death (15). Male patients are usually diagnosed in the teenage years; diagnosis in female carriers tends to be a decade or so later [16]. The disease may present as sudden cardiac death. Clinically, there is concentric left ventricular hypertrophy, which may be severe. Right ventricular involvement is common. Ventricular pre-excitation is usual. Wolff–Parkinson–White syndrome and hypertrophic cardiomyopathy are more common in male patients. The diagnosis is confirmed by sequencing of the LAMP2 gene.

Histologically, there is prominent myocardial hypertrophy with vacuolation of myocytes. The vacuoles contain glycogen and confer a spider’s web appearance on the myocyte cytoplasm [15]. There may be myocyte disarray. Ultrastructurally the glycogen is membrane bound. Intracytoplasmic vacuoles contain autophagic material and glycogen in skeletal and cardiac muscle cells [14].

There appears to be a distinct third type of lysosomal cardiac and skeletal muscle GSD, with normal α-1,4-glucosidase and LAMP-2, an infantile-fatal course and an unidentified gene defect [17].

10.2.4 GSD III (Cori Disease, Debranching Enzyme)

GSD III is caused by deficiency of glycogen debranching enzyme due to mutation in the gene AGL. The responsible gene is located on chromosome 1p21. It manifests as variable muscle, cardiac and liver involvement with onset in infancy or childhood. There are two clinical subtypes, one myopathic with cardiomyopathy (type a) [4] and the other predominantly hepatic (type b). Myopathy tends to occur in older children [18]. The cardiac involvement is usually left ventricular hypertrophy that may progress to hypertrophic cardiomyopathy. Pathologically, the cardiac myocytes are vacuolated and contain an excess of glycogen [19]. This would appear to be particularly the case for the cells of the conduction system. Smooth muscle of the coronary arteries may also focally contain excess glycogen [20].

Very rarely GSD type III may present in infancy with myocardial hypertrophy [16].

10.2.5 GSD IV (Andersen Disease, Branching Enzyme)

GSD IV is rare and has a variable presentation, albeit almost always in childhood. The classical form presents with liver disease progressing to cirrhosis. It typically presents in early infancy with hepatosplenomegaly and growth failure. The disorder is rapidly progressive, leading to liver failure without transplantation [21]. The neuromuscular form of disease may present in utero with fetal akinesia sequence and polyhydramnios and death shortly after birth from respiratory failure [22]. It may present after birth with hypotonia and death in early childhood [23], in later childhood with skeletal myopathy or cardiomyopathy [24] or in adulthood with myopathy or adult polyglucosan inclusion disease. Mutations in GBE1 cause Andersen disease (GSD IV). There is accumulation of polyglucosan, a substance resembling amylopectin – long straight polymers of glucose – in liver, muscle or heart. Dilated cardiomyopathy is the usual form of heart involvement (Figure 10.4), but hypertrophic cardiomyopathy has been reported [25]. The affected myocytes contain polyglucosan inclusions that are PAS positive and diastase resistant (Figure 10.5).

Figure 10.4 GSD IV. One-week-old male infant born at term by caesarean section for fetal bradycardia. Poor condition at birth and floppy. Myocardial hypertrophy noted. Suffered cardiac arrest. The left ventricle is opened to show the marked myocardial hypertrophy.

(A) in myocytes that are intensely PAS-positive

(B). Under polarised light a few inclusions exhibited a Maltese-Cross pattern. No inclusions were seen in endothelium or smooth muscle cells.

Figure 10.5 GSD IV. Histology of the myocardium of the same case as Figure 10.4 shows large glassy cytoplasmic inclusions

10.2.6 GSD IX (Phosphorylase b Kinase Deficiency)

GSD IX is caused by mutations in the genes encoding for the subunits of Phosphorylase b kinase, the enzyme that activates glycogen phosphorylase and commences breakdown of glycogen to glucose-1-phosphate [26].

Phosphorylase b kinase contains four subunits – α, β, γ and δ. The α, β and γ subunits are encoded by the genes PHKA1 or PHKA2, PHKB and PHKG2, respectively. Mutations in the δ subunit have not to date been described.

Four forms of the disease are recognised: GSD IX a, b, c and d. GSD IXa is the most common form, accounting for about 75% of all GSD IX cases, and GSD IXc is said to be the most clinically severe. The presenting features are liver enlargement and slow growth, with affected children showing a height that is usually below average for age. During prolonged fasting, hypoglycaemia or elevated blood ketones are present. Some have mild muscle weakness. These signs and symptoms usually improve with age. However, some patients may develop fibrosis of the liver tissue that may progress to cirrhosis.

The enzyme deficiency can be in either liver or muscle:

  • PHKA1 located on chromosome Xq13.1 encodes the muscle form of the α subunit, and mutations in it result in X-linked GSD IXd

  • PHKA2 located on Xp22.1 encodes the hepatic form with mutations causing X-linked GSD IXa

  • PHKB located on 16q12.1 encodes the hepatic and muscle forms, and mutations cause recessively inherited GSD IXb

  • PHKG located on 16p11.2 encodes the hepatic form, mutations leading to recessive GSD IXc

Mild cardiomyopathy has been reported in GSD IXb [27].

There are cases reports in the older literature of hypertrophic cardiomyopathy with cardiac-specific phosphorylase b kinase deficiency [2830]. However, it has recently been questioned whether these cases actually represent GSD IX and are in fact PRKAG2 disease [31].

10.2.7 GSD XV (Glycogenin Deficiency)

An autosomal recessive condition due to homozygous or compound heterozygous mutations of GYG1 on chromosome 3q24. There is one case report of skeletal myopathy with glycogen depletion and cardiac arrhythmias with accumulation of storage material in myocytes (32). The condition presented in childhood. Other patients have been reported with mutations in GYG1 in whom there is muscle weakness and polyglucosan accumulation on skeletal muscle biopsy but no cardiomyopathy [33,34]. Although there is only one case report in the literature [35], the disease is probably commoner than this would imply. I have seen two further enzymatically and genetically proven cases with polyglucosan accumulation in cardiac muscle (Figire 10.6).

(A) Hypertrophic cardiomyopathy with left ventricular impairment. LV biopsy shows vacuolation of myocytes with inclusions.

(B) The inclusions are PAS-positive and are partly resistant to diastase digestion.

(C) Electron microscopy shows large intracellular, non-lysosomal collections of glycogen. Next-generation sequencing showed a homozygous mutation in the GYG1 gene in keeping with GSD XV.

Figure 10.6 GSD XV.

10.2.8 GSD 0 (Glycogen Synthase Deficiency)

GSD 0 is an autosomal recessive disorder of glycogen metabolism caused by mutations in the enzyme glycogen synthase. Separate muscle, including cardiac muscle (GYS1), and liver isoforms (GYS2) of the enzyme occur and mutation in either cause GSD 0 but have different clinical effects. With mutation of the liver-specific isoform of glycogen synthase on chromosome 12p12.2, affected children usually present after infancy when ketotic hypoglycaemia is found during investigation of lethargy following episodes of illness, short stature or failure to thrive. In contrast to all other forms of GSD they do not show hepatomegaly or hepatic accumulation of glycogen. Indeed, the original diagnostic feature was the absence of glycogen on liver biopsy. The clinical course is usually benign with treatment.

Mutation of GYS1 on chromosome 19q13.3 causes depletion of muscle glycogen and increased numbers of mitochondria, and can result in syncope, myalgia, muscle weakness, hypertrophic cardiomyopathy and cardiac arrest and sudden death [36,37].

10.2.9 PRKAG2 Deficiency

A similar histological appearance to Danon disease may be seen with mutations in the PRKAG2 gene (on chromosome 7q36.1) encoding the γ-subunit of AMP-activated protein kinase [16]. This produces a hypertrophic phenotype with ventricular pre-excitation and progressive conduction system dysfunction; there is no myocyte disarray or fibrosis, but there is myocyte vacuolation and glycogen accumulation (Figure 10.7) The glycogen accumulation, in contrast to Pompe disease and Danon disease, is not membrane-bound, but is present throughout the myocyte (Figure 10.8) [20]. By contrast with the other glycogen storage cardiomyopathies, there are no extracardiac manifestations. The disorder was initially described in adults, but infantile forms with hypertrophic cardiomyopathy are now recognised [38].

(A) A 20-year-old with impaired left ventricular function. Biopsy of the left ventricular myocardium shows irregular vacuolation of the myocyte cytoplasm.

(B) PAS stain shows that most of the vacuoles are empty, but some contain granular glucogen.

(C) Electron microscopy shows an increase in non-lysosomal glycogen.

Figure 10.7 PRKAG2.

(A) The explanted heart shows vacuolation of the cardiac myocytes with cytoplasmic inclusions.

(B) The inclusions are PAS-positive and diastase resistant.

(C) Similar inclusions are also present in the smooth muscle cells.

Figure 10.8 Polyglucosan body disease. Teenaged girl, one of siblings with dilated cardiomyopathy, who underwent heart transplant.

10.2.10 Polyglucosan Storage Disease

Polyglucosan storage disease is a descriptive term that encompasses several different conditions all linked by the presence of polyglucosan inclusion in myocytes, whether skeletal, smooth muscle or cardiac. These include:

  • Infantile GSD IV

  • Adult polyglucosan disease

  • GSD VII (some cases)

  • Lafora disease

  • Polyglucosan body myopathy due to GYG1 mutation

  • Polyglucosan myopathy with cardiomyopathy due to mutations in RBCK1

Polyglucosan inclusions are strongly PAS-positive and variably resistant to digestion by alpha-amylase, and contain abnormally long and poorly branched glucosyl chains (Figure 10.8).

10.3 Lysosomal Storage Disorders

Pompe disease, although usually described under the category of glycogen storage disorders, is also a lysosomal storage disorder, with accumulation of abnormal material in the lysosomes. Other lysosomal storage disorders that may affect the heart include Anderson–Fabry disease, Gaucher disease, Nieman–Pick disease, GM1 and GM2 gangliosidoses, Krabbe disease and metachromatic leukodystrophy. All share abnormal accumulation of substrate in the lysosomes.

10.3.1 Anderson–Fabry Disease

Anderson–Fabry disease is caused by deficiency of alpha-galactosidase A, leading to the accumulation of globotriaosylceramide (Gb3) in vascular endothelial and other cells, resulting in progressive organ damage, particularly in heart, brain and kidney. Up to 60% of males with classic Fabry disease have cardiac abnormalities, including left ventricular hypertrophy, valvar dysfunction and conduction abnormalities [39]. The usual manifestations in childhood are angiokeratoma, paraesthesia and abdominal pain [40]. Symptoms may even be present in the first half-decade of life [41]. Although unusual, cardiac manifestations such as left ventricular hypertrophy and arrhythmia may occur in 1–3% of affected children [42]. The diagnosis is made by demonstrating low plasma alpha-galactosidase activity and by mutational analysis of the GLA gene.

Cardiac disease is associated with Gb3 accumulation in all cellular components of the heart, including myocytes, conduction system cells, valvar fibroblasts, endothelial cells and vascular smooth muscle cells (Figure 10.9) [43]. The cardiac myocytes are vacuolated and hypertrophied, but myocyte disarray is not prominent. By electron microscopy, lysosomal inclusions resembling myelin are present within myocytes and vascular smooth muscle cells (Figure 10.10). Fibrosis is evident within the mid‐myocardial layers and the posterolateral segments of the left ventricle. With disease progression, patients develop bundle branch block, atrioventricular conduction delay and progressive sinus node dysfunction. Valvar disease is caused by infiltration of valvar fibroblasts, most frequently in the left-sided valves, possibly because of higher haemodynamic stress (Figure 10.11). Macroscopically, the valves are thickened and distorted, resulting in mild‐to‐moderate regurgitation; severe valve disease requiring surgical correction is infrequent. Aortic root dilatation is a feature in some.

Figure 10.9 Anderson–Fabry disease. Myocardium from a case of Anderson–Fabry disease. There is irregular ragged vacuolation of myocytes.

Figure 10.10 Anderson–Fabry disease. Electron microscopy shows typical, regular, laminated, lipid inclusions in lysosomes within the cytoplasm.

Figure 10.11 Anderson–Fabry disease valve. Section of aortic valve leaflet removed during surgery for severe aortic stenosis in a patient with Anderson–Fabry disease. The valve fibrosa contained fibroblasts distended by storage material. There are cardiomyocytes at the base of the valve leaflet that show cytoplasmic distension by particulate inclusions.

10.3.2 Gaucher Disease

This is the most common of the lysosomal storage disorders. Autosomal recessive in inheritance, it is caused by deficiency of the enzyme glucocerebrosidase. The usual clinical presentation is with neurological disease or haematological involvement. The heart is rarely affected [44], but there are individual reports of cardiomyopathy, aortic and mitral valvar calcification and pulmonary arterial hypertension [45].

10.3.3 Niemann–Pick Disease

Niemann–Pick disease comprises a group of autosomal recessive lysosomal storage disorders characterised by accumulation of lipid in brain or viscera. Three major types are recognised:

  • Type A is characterised by hepatomegaly, early central nervous system involvement and death within the first four years of life.

  • Type B is a more chronic form affecting older patients chiefly with hepatosplenomegaly and lung involvement but no neurological involvement. Both types A and B are caused by deficiency of acid sphingomyelinase

  • Type C is caused by deficiency of the enzyme NPC1 or NPC2

Cardiac involvement is very unusual, and only one case has been described in which the heart was affected. This was a 7.5-month-old female with cardiomegaly with left ventricular hypertrophy and endocardial fibroelastosis [46].

10.4 Mucopolysaccharidosis

The mucopolysaccharidoses (MPS) are inherited lysosomal storage disorders caused by the absence of functional enzymes necessary for the degradation of glycosaminoglycans. This leads to progressive accumulation of glycosaminoglycans in multiple organs. There is associated organ dysfunction depending on the particular enzymatic defect [47]. The typical effects of MPS are growth restriction with musculoskeletal abnormalities, dysmorphic facies, nervous involvement with or without cognitive impairment, defects of hearing and vision, hepatomegaly, bowel dysfunction and respiratory difficulty. Table 10.2 lists the various forms with their enzymatic defects and presentations.

Table 10.2 The mucopolysaccharidoses

Name Eponym Inheritance Enzyme lacking Presentation
MPS IH Hurler AR α-L-iduronidase Infancy
MPS IS Scheie AR α-L-iduronidase Early childhood
MPS IH/S Hurler–Scheie AR α-L-iduronidase Late childhood
MPS II Hunter XR Iduronate-2-sulfatase Infancy/early childhood
MPS III (A) Sanfilippo AR Heparan sulfamidase (A) Mid-childhood
MPS III (B) AR N-acetyl-α-D-glucosaminidase (B) Mid-childhood
MPS III (C) AR Acetyl-CoA-α-glucosaminidase N-acetyltransferase (C) Mid-childhood
MPS III (D) AR N-acetylglucosamine-6-sulfatase (D) Mid-childhood
MPS IV A Morquio AR N-acetylgalactosamine-6-sulfatase Early childhood
MPS IV B β-galactosidase Early childhood
MPS VI Marotaux–Lamy AR N-acetylgalactosamine-4-sulfatase Throughout childhood
MPS VII Sly AR β-D-glucuronidase Throughout childhood

AR: autosomal recessive; XR: X-linked recessive.

Involvement of the heart is reported in all forms of mucopolysaccharidosis [48,49]. It is common in MPS I, II and VI. Valvar thickening and dysfunction (more severe for left-sided valves) and myocardial hypertrophy are frequent; conduction abnormalities, coronary artery and other vascular involvement also occur. Cardiac disease contributes to early mortality.

The valvar abnormality [50] is the commonest and the earliest manifestation in the heart. It affects predominantly the left-sided valves and the mitral more frequently than the aortic valve. Regurgitation is more common than stenosis [51]. Macroscopically the valvar leaflets are thickened particularly along their free edges, and the appearance has been likened to cartilage (Figure 10.12). The tendinous chords of the leaflets are thickened and shortened, and the papillary muscles are thick. The valvar annulus may calcify. Histologically the valve leaflets show large numbers of clear cells (Figure 10.13). Similar clear cells are present in the coronary arteries, myocardium and endocardium. The aortic valve shows thickening and rigidity of its leaflets and is poorly mobile (Figure 10.14). Left ventricular hypertrophy with diastolic dysfunction occurs as a result of the valvar regurgitation or stenosis, and ventricular dilatation with systolic dysfunction is a late feature [52].

Figure 10.12 Mucopolysaccharidosis of the heart. Nine-month-old male infant who died of pneumonia while being investigated for neuronal storage disorder. The heart shows diffuse thickening of the aortic and mitral valve leaflets and chordae typical of mucopolysaccharidosis.

(A) Histology shows Alcian blue-positive cells in the connective tissue of the aortic and mitral valves.

(B) Electron microscopy shows laminated inclusions within the cells.

Figure 10.13 Mucopolysaccharidosis.

(A) Five year-old boy with Hunters’s syndrome (MPSII). He underwent aortic valve replacement for aortic regurgitation. The resected aortic valve leaflets show irregular thinning and thickening.

(B) Alcian blue staining shows positive macrophages in the valve fibrosa. Similar cells were also present in the tunica media of the aorta and pulmonary trunk.

Figure 10.14 Mucopolysaccharidosis aortic valve.

The epicardial coronary arteries are involved especially in MPS I and MPS II. There is intimal proliferation containing glycosaminoglycans (Figure 10.15) [53]. There may be narrowing or dilatation of the aorta with coarctation or systemic hypertension.

(A) The epicardial coronary arteries show marked concentric intimal thickening.

(B) The thickening is caused by fibrous tissue that contains vacuolated cells consistent with mucopolysaccharidosis.

Figure 10.15 Mucopolysaccharidosis: coronary artery involvement. One-year-old boy with Hurler’s syndrome (MPSI).

The disease may be treated with enzyme replacement therapy (MPS I, II and VI) or with stem cell transplant.

10.5 Disorders of Fatty Acid Metabolism

Oxidation of fatty acids occurs in the mitochondria. Very-long-chain fatty acids are exclusively oxidised in peroxisomes (54); other specific carboxylic acids, such as branched-chain fatty acids, bile acids and fatty dicarboxylic acids, are also oxidised within peroxisomes. In the liver, in the fasting state, beta-oxidation of fatty acids provides substrate for gluconeogenesis with generation of ketones. In muscle, by contrast, beta-oxidation of fatty acids generates acetyl choline that is used to generate ATP via the Krebs cycle. Adipose tissue stores of triglyceride are the principal source of fatty acids for beta-oxidation in the fasting state. Lipases release free fatty acids into the blood, which are taken up into the cytoplasm of myocytes and hepatocytes. Here they are esterified to coenzyme A (Co-A). Short- and medium-chain fatty acids cross the mitochondrial membrane directly, but long-chain fatty acids are transported across the mitochondrial membrane by a carnitine shuttle where the acyl-Co-A is converted to acyl carnitine, which is transported across the membrane and then reconverted to Acyl-Co-A [55]. This requires the action of three enzymes: carnitine palmitoyltransferase I, carnitine acylcarnitine translocase and carnitine palmitoyltransferase II. Inside the mitochondrion the first step of beta-oxidation requires the enzyme acyl-Co-A dehydrogenase. There are three forms specific for varying lengths of fatty acid molecule: short chain (SCAD), medium chain (MCAD) and very long chain (LCHAD) [56]. The remaining steps are illustrated in Figure 10.16.

Figure 10.16 Overview of lipid metabolism.

Defects of fatty acid oxidation have an overall incidence of approximately 1:9300 [57] and have a variable clinical presentation [58]. In the infant they can result in hypoglycaemia, metabolic acidosis, myopathy, liver dysfunction and cardiomyopathy. Cardiac arrhythmia may be the presenting feature [59]. In older children they may be more neurological or myopathic in their presentation. Neonatal screening of bloodspots has resulted in many being detected early [57]. Pregnancies of affected fetuses may show preeclampsia or HELPP syndrome [60].

There are about 20 distinct disorders of fatty acid oxidation. The more common disorders are MCAD, long-chain 3-hydroxylacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies.

10.5.1 Medium-Chain Acyl Co-A Dehydrogenase Deficiency (MCAD)

The most common mutation associated with MCAD deficiency is the K304E mutation of the ACADM gene [4]. Infants with deficiency of MCAD are usually normal at birth and present in the first months of life only when exposed to periods of fasting, usually precipitated by vomiting caused by active infection. Presentation is with transient episodes of hypoglycaemia occasionally with seizures during periods of stress. Presentation may be early with hypertrophic cardiomyopathy or arrhythmia or later in childhood with myopathy. Biochemically, there is hypoglycaemia and raised liver enzymes. Treatment in the acute episode is with intravenous fluids, dextrose and carnitine. Continued care is centred on avoidance of catabolic stress and urgent medical attention in periods of acute illness. In fatal infantile cases, the heart may be enlarged, pale or yellow (Figure 10.17). Histologically there is fine vacuolation of the myocyte cytoplasm from accumulation of fine droplets of lipid. This is dramatically demonstrated if frozen sections of myocardium are stained with fat stains such as oil-red-O (Figure 10.18). There is accumulation of lipid in liver, muscle and kidney as well as in myocardium (Figure 10.19). As an aside, it should be noted that fat is a normal constituent of the cardiomyocyte, and excess accumulation of lipid can be seen secondary to many disorders including sepsis. A diagnosis of fatty acid oxidation defect should always be confirmed biochemically or genetically.

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