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Nutrition in metabolic disease
SYMPOSIUM: NUTRITION
Nutrition in metabolic disease
(b) Preventing the accumulation of a substrate to toxic levels e.g. by restricting the intake of phenylalanine in phenylketonuria (PKU). (c) Supplying adequate energy and thereby preventing catabolism. By increasing the flux through the affected pathway, catabolism can cause the accumulation of a toxic substrate even in patients on an appropriate dietary restriction. We will consider each of these three dietary strategies in this article.
Elisabeth Jameson Andrew A M Morris
Abstract
Supply of a deficient metabolic product
Many inborn errors of metabolism are treated by dietary modification. There are three main strategies. 1. Some disorders lead to deficiency of a crucial product, which can be supplied by a special diet. This is illustrated by the need for a continuous enteral supply of glucose in hepatic glycogen storage diseases. 2. In other disorders, dietary restriction can prevent the accumulation of a substrate to toxic levels. Examples include the use of a low-phenylalanine diet in phenylketonuria and a minimalgalactose diet in galactosaemia. 3. In many disorders, catabolism during minor illnesses can lead to acute problems. These can usually be prevented by maintaining a high intake of glucose, either orally or intravenously. For inborn errors without specific dietary treatment, nutritional support is still important and may include tube feeding through a gastrostomy.
In a few inborn errors, the main problem is a lack of the product of the affected pathway. Most frequently, the deficient product is glucose. In the hepatic GSDs, reduced hepatic glucose production leads to hypoglycaemia. In fatty acid oxidation disorders (FAODs) decreased use of fat fuels can cause excessive glucose consumption and hypoglycaemia. In GLUT1 deficiency, a defect of glucose transport across the blood-brain-barrier leads to low cerebrospinal fluid (CSF) glucose concentrations. Glycogen storage diseases Glycogen is stored in liver and muscle; there is a risk of hypoglycaemia in the hepatic GSDs, predominantly types I, III, VI and IX. The fasting tolerance varies with the type of GSD; it is shortest in GSD type I because the defect prevents the release of glucose derived from gluconeogenesis as well as glycogenolysis. Typically, GSD I patients need to be fed every two to two and a half hours to prevent hypoglycaemia and families cannot sustain this, day and night, in the long-term. A continuous overnight feed (or glucose infusion) is, therefore, given through a gastrostomy or a nasogastric tube. During the day, the interval between feeds can be extended by giving uncooked corn starch (UCCS). This is digested by pancreatic amylase and acts as a slow release form of glucose. It is seldom tolerated before the age of 2 years; in older children, it usually achieves normoglycaemia for four and a half hours. The duration of normoglycaemia is longer in adults, who often substitute one or two UCCS doses for the overnight glucose infusion. In GSD types III, VI and IX, management is tailored to
Keywords catabolism; emergency regimen; encephalopathy; inborn errors of metabolism; ketogenic diet; low-protein diet; protein exchange; protein supplements
Introduction Inborn errors of metabolism are rare disorders but collectively their incidence is at least three in a thousand. They fall into three broad categories, as shown in Table 1. Neurological handicap, feeding difficulties and vomiting occur in many metabolic disorders, including mitochondrial, lysosomal and peroxisomal disorders. Feeding problems are particularly common in SmitheLemlieOpitz syndrome, an inborn error of cholesterol synthesis associated with microcephaly and malformations of variable severity. Nutritional support is important in all these patients and may include tube feeding through a gastrostomy. In many disorders of energy metabolism and intoxication, dietary treatment has an additional specific role in minimizing the consequences of the metabolic block (Figure 1). It can achieve this in three main ways by: (a) Supplying a deficient product e.g. glucose in the hepatic glycogen storage diseases (GSDs).
Catabolism Body stores A
B
D
Diet C Elisabeth Jameson MBBCh BSc MRCPCH is ST7 Paediatric inborn errors of metabolism in the Biochemical Genetics Unit at St Mary’s Hospital, Oxford Road Manchester, UK. Conflict of interest: none.
Figure 1 Schematic representation of an inborn error of metabolism. The metabolic block results from a deficiency of the enzyme or co-enzyme or, occasionally, from a transport defect. It leads to a deficiency of the product, D, and accumulation of the substrate, B, and related chemicals, A and C. Catabolism increases the flux through breakdown pathways and so increases the accumulation of the chemicals before the metabolic block, A, B and C.
Andrew A M Morris FRCPCH PhD is Consultant in Paediatric inborn errors of metabolism in the Biochemical Genetics Unit, St Mary’s Hospital, Oxford Road Manchester, UK. Conflict of interest: none.
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SYMPOSIUM: NUTRITION
Categories of metabolic disease Disorders of intoxication
Disorders of energy metabolism
Disorders of complex molecules
Amino acid disorders (e.g. phenylketonuria, homocystinuria, maple syrup urine disease) Organic acidaemias (e.g. propionic & methylmalonic) Urea cycle disorders (e.g. ornithine transcarbamylase deficiency, citrullinaemia) Sugar intolerances (e.g. Galactosaemia, Hereditary fructose intolerance)
Glycogen storage disorders Fat oxidation disorders (e.g. medium chain acyl-CoA dehydrogenase deficiency) Ketogenesis and ketolysis disorders GLUT1 deficiency Glutaric aciduria type 1 Mitochondrial disorders
Lysosomal disorders Peroxisomal disorders (e.g. Zellweger syndrome, X-linked adreno-leukodystrophy) Congenital disorders of glycosylation Sterol synthesis disorders (e.g. Smith-LemliOpitz syndrome) Lipoprotein disorders (e.g. familial hypercholesterolaemia, abetalipoproteinaemia)
Table 1
the fasting tolerance. An intravenous glucose infusion is generally needed during acute illnesses associated with vomiting.
galactose and related metabolites and they resolve when the milk is changed to a galactose-free formula, usually derived from soya. There is substantial intrinsic production of galactose within the body that cannot be eliminated. It is, therefore, unnecessary to avoid foods that contain very small quantities of galactose; indeed some older patients have returned to a normal diet without adverse consequences. Patients with galactosaemia often require calcium supplementation. Unfortunately, most patients with galactosaemia have some educational problems and premature ovarian failure that is not prevented by galactose restriction.
Fatty acid oxidation disorders There are many FAODs of varying severity. The commonest disorder is medium chain acyl-CoA dehydrogenase deficiency (MCADD) and this has recently been added to the UK newborn blood-spot screening programme. Patients with MCADD are well most of the time, provided that prolonged fasting is avoided. Infections can, however, lead to encephalopathy or sudden death, due to hypoglycaemia and the accumulation of fatty acid metabolites. These disasters can be prevented by maintaining a regular intake of glucose by mouth or intravenously (see below, Prevention of catabolism and acute encephalopathy). The same is true for many other FAODs, though some also require long-term dietary modification and in others the main problem is myopathy.
Hereditary fructose intolerance These patients develop symptoms of poor feeding, failure to thrive and vomiting when they start consuming fructose. This usually occurs during the weaning process because breast and formula milks do not contain fructose. The greatest source of fructose is from sucrose containing foods. Treatment is lifelong avoidance of fructose, sucrose and sorbitol from the diet. Patients are at risk of vitamin C and folic acid deficiency because of the exclusion of fruits and vegetables, so supplements may be required.
GLUT1 deficiency GLUT1 is responsible for glucose transport across the bloodbrain-barrier. Patients with GLUT1 deficiency have mutations in one allele of the gene, leading to a reduced number of transporters and a low CSF to blood glucose ratio. They present with seizures, developmental delay and a movement disorder. Ketone body transport into the brain is unaffected and can provide an alternative fuel. Treatment with a ketogenic diet usually controls the seizures but many patients continue to have cognitive problems. The classical ketogenic diet and the medium chain triglyceride (MCT)-based diet are both effective. In the latter, 60% energy is derived from MCT and 40% from saturated fat þ carbohydrate þ protein; in the classical diet, 4 g of fat are consumed for every one gram protein þ carbohydrate. Side effects include constipation, mild hyperlipidaemia, platelet dysfunction and, very rarely, kidney stones or pancreatitis.
Urea cycle disorders and branched chain organic acidaemias Amino acid degradation leads to the production of ammonia. This is normally converted to urea in the liver but it accumulates in patients with urea cycle disorders. The breakdown of certain amino acids also gives rise to branched chain organic acids, which accumulate in patients with propionic, methylmalonic and isovaleric acidaemias. Ammonia and the branched chain organic acids are toxic to the brain and can cause acute encephalopathy and irreversible brain damage. There may also be adverse effects on other organs, including the kidney, pancreas and heart in organic acidaemias. Drugs, such as sodium benzoate, sodium phenylbutyrate and arginine can promote the excretion of nitrogen in urea cycle disorders and carnitine therapy may increase the excretion of the organic acids. Dietary protein restriction is another crucial part of the management for both groups of disorders. This reduces the flux through the affected pathway and the accumulation of the toxic chemicals. It is important for the protein intake to provide sufficient amino acids for growth and, ideally, the protein should be from a high biological value source to prevent essential amino acid deficiency. Most patients are given the minimum safe protein intake but some will tolerate more, depending on their
Restriction of a dietary component that cannot be broken down The commonest dietary strategy is to restrict the intake of the nutrient whose degradation is prevented by the inborn error. Certain disorders of carbohydrate metabolism, as well as amino acid and lipoprotein metabolism are managed in this way. Galactosaemia Galactosaemia classically presents at 4e10 days of age with jaundice, failure to thrive, liver dysfunction and, sometimes, cataracts. The problems result from the accumulation of
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SYMPOSIUM: NUTRITION
e A phenylalanine-free amino acid mixture (or ‘protein substitute’) that brings the total protein intake up into the safe range. The palatability of the protein substitutes has improved over the years but many children still require considerable persuasion to take them. e Very low-protein foods, which may be natural (some fruits and vegetables) or synthetic (artificial low-protein bread, pasta, biscuits, milk-substitutes etc, which can be obtained on prescription in the UK). e Vitamin and mineral supplements, which are incorporated into many of the protein substitutes. Infancy and childhood are the vital times to follow the diet strictly, as this is the critical period for brain development. Some patients come off diet in adulthood with no adverse effects, others feel slightly ‘slow witted’ off diet. High phenylalanine levels during pregnancy cause the baby to have severe learning difficulties and an increased risk of congenital malformations, especially affecting the heart. It is, therefore, crucial that women have strict control of their phenylalanine levels throughout pregnancy (preferably starting prior to conception).
residual enzyme activity and growth rate. Many patients require vitamin, mineral, trace element and essential fatty acid supplementation. In these disorders, most problems are caused by acute rises in the concentrations of toxic chemicals. The acute rises are usually caused by catabolism and it is, therefore, essential to minimize catabolism; this is considered in the final section of this article. Aminoacidopathies In phenylketonuria, homocystinuria and maple syrup urine disease, specific amino acids accumulate to toxic levels. Moreover, in all three disorders, the concentrations of the relevant amino acid(s) remain unacceptably high, even on the minimum safe intake of natural protein. Management, therefore, requires a diet extremely low in natural protein, and supplements of all the other amino acids; the amino acid mixture is often called a ‘protein substitute’ and examples are shown in Figure 2. Blood concentrations of the relevant amino acid(s) need to be monitored regularly and the diet is adjusted accordingly. Phenylketonuria PKU is due to a deficiency of phenylalanine hydroxylase, which results in high phenylalanine levels. Untreated, it results in microcephaly, developmental delay and seizures. In most developed countries, patients are diagnosed by 2 weeks of age following newborn screening. The diet is semi-synthetic and consists of: e Small measured amounts of natural protein that provide the necessary phenylalanine for growth and protein turnover. These are known as the phenylalanine exchanges; the phenylalanine tolerance varies depending on the amount of residual enzyme activity and the daily number of exchanges is adjusted according to the blood phenylalanine levels.
MSUD
Homocystinuria Classical homocystinuria (HCU) is caused by deficiency of cystathionine b-synthase (Figure 3). The raised concentrations of homocysteine lead to complications that include learning difficulties, lens dislocation, osteoporosis and thromboembolism. Other less commonly seen complications include dystonia, sagittal sinus thrombosis and psychiatric disturbance. Homocysteine is not found in the diet but is derived from the amino acid, methionine. Plasma homocysteine concentrations can, therefore, be controlled by a low-methionine diet. This is directly analogous to the low-phenylalanine diet for PKU, the protein substitute this time consisting of a methionine-free amino acid
HCU
PKU
Figure 2 Examples of protein substitutes.
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SYMPOSIUM: NUTRITION
Familial hypercholesterolaemia This autosomal dominant condition is the commonest inborn error of metabolism, with an incidence of 1:500. Most patients have a mutation in the gene for the low-density lipoprotein (LDL) receptor, which reduces the hepatic uptake of LDLs and increases cholesterol synthesis. A diet low in saturated fat will lower the plasma cholesterol concentration but usually only by about 15%. Much larger reductions can be achieved with the statin drugs, which are licensed from 8 years of age in the UK. The National Institute of Clinical Excellence has published guidelines on the management of familial hypercholesterolaemia, however their guidance on paediatric management is limited.
Diet Methionine Dimethylglycine Vitamin B12 and folate
Methyl group Betaine Homocysteine
Pyridoxine
Abetalipoproteinaemia This is an autosomal recessive disease characterized by the absence of chylomicrons, very low-density lipoproteins (VLDLs) and LDLs. It is caused by a defect in the transfer of lipid to apolipoprotein B. Patients present with malabsorption in infancy; without treatment, vitamin E deficiency leads to neurological symptoms, starting in adolescence. Management is with a very low fat diet, supplements of essential fatty acids and fat-soluble vitamins; huge doses of vitamin E are needed.
Pyridoxal-phosphate Cystathionine
Cysteine Figure 3 Simplified metabolic pathways relevant to the treatment of classical homocystinuria.
mixture. Unfortunately, there is no screening program for homocystinuria in the UK and patients are only diagnosed at the age of a few years after developing clinical problems. It is much harder to introduce the difficult diet at this age than in babies. Other forms of treatment are also worth trying. A sub-group of HCU patients respond to pharmacological doses of pyridoxine; sometimes the response is so good that no additional treatment is required. There are two pathways for the remethylation of homocysteine to methionine (Figure 2). One depends on vitamin B12 and folate, and good levels of these vitamins should be maintained to maximize flux through this pathway. The other pathway depends on betaine, which is normally only present in the body at low concentrations. Treatment with betaine can reduce homocysteine concentrations substantially and is particularly useful in patients with poor dietary compliance.
Prevention of catabolism and acute encephalopathy This is particularly important in disorders where metabolic disturbance can lead to acute problems, such as encephalopathy or cardiomyopathy, see Table 2. Such disorders include the urea cycle disorders, organic acidaemias, and MSUD. Catabolism in these disorders leads to high concentrations of the toxic chemical that causes the acute problems. In fatty acid oxidation disorders, the clinical problems result from the accumulation of fatty acid metabolites and from hypoglycaemia. Catabolism can be caused by many different stresses, including exercise. In patients with inborn errors, acute problems are usually triggered by the stress of being born, fasting or infections. These patients are instructed to avoid prolonged fasting but all children suffer minor infections from time to time. During infections, catabolism is minimized by stopping the normal diet and substituting glucose, orally or intravenously. Supplying glucose will lead to insulin secretion and reduce catabolism. Oral glucose is preferred during minor infections, unless the patient is vomiting, because it can be started at home without delay; moreover, higher concentrations of glucose can be given by mouth than into a peripheral vein. Glucose polymer (e.g. CaloreenÒ, PolycoseÒ, MaxijulÒ, PolycalÒ, VitajouleÒ) is generally used because it is less sticky than an equivalent concentration of glucose. The concentration and volume are adjusted according to the patient’s age. The glucose polymer drinks are often referred to as the patient’s ‘emergency regimen’. It is important to start the drinks promptly, as vomiting is an early feature of metabolic encephalopathy. The emergency regimen is, therefore, started at the first sign of a possible illness and the child is reviewed 2 h later. If it was a false alarm, the normal diet is resumed. Otherwise, the drinks are continued every 2 h day and night until the child is on the road to recovery. Normal diet should generally be reintroduced within 48 h to avoid malnutrition. Patients who vomit or refuse to take their emergency regimen or deteriorate despite taking it, should go to hospital for
Maple syrup urine disease (MSUD) MSUD is caused by a defect in the metabolism of the branched chain amino acids (BCAA) leucine, valine and isoleucine. Leucine is the most toxic of these: long-standing moderate elevation can lead to demyelination, whilst very high concentrations result in acute encephalopathy, with ataxia, drowsiness and cerebral oedema. This contrasts with PKU and HCU, in which the problems are caused by sustained high levels of the toxic amino acids and brief rises are relatively harmless. The long-term dietary management of MSUD resembles that for PKU but, this time, the protein substitute is an amino acid mixture free of all three BCAA. The natural protein intake is adjusted according to the plasma leucine concentrations and supplements of valine and isoleucine may be added, depending on their plasma levels. In addition to the long-term management, extra treatment is needed during illnesses to prevent acute encephalopathy (discussed below in the section on catabolism). If patients do become encephalopathic, dialysis may be needed to reduce the leucine concentrations. Dialysis is usually needed during the initial presentation, which often occurs in the newborn period.
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SYMPOSIUM: NUTRITION
Conditions requiring an emergency regimen Condition
Emergency regimen components
Organic acidaemias
Glucose polymer þ continuation of metabolic medications if the child is on them. These may need to be given intravenously if vomiting or refusal of them Glucose polymer þ continuation of metabolic medications which may need to be given intravenously if there is vomiting or refusal of them Glucose polymer þ continuation of protein substitute either orally or via a nasogastric tube. It is vital the latter is continued to promote reduction in leucine levels Glucose polymer Glucose polymer
Urea cycle disorders Maple syrup urine disease Fatty acid oxidation disorders Glycogen storage disorders Table 2
assessment and, usually, intravenous management. To prevent catabolism, the infusion should supply 6e12 mg/kg/min of glucose, depending on age, and the fluid should generally be 10% glucose with 0.45% saline and potassium as required. If patients become hyperglycaemic, an insulin infusion should be started with appropriate monitoring rather than reducing the concentration of the glucose infusion. Additional measures may be needed to make patients anabolic and bring down the concentrations of toxic metabolites. In MSUD, acute encephalopathy is caused by toxic levels of the BCAA, especially leucine. These can only be lowered by incorporating them into new protein synthesis (or by dialysis). To promote protein synthesis, a mixture of all the other amino acids is given with the glucose polymer in the oral emergency regimen. In other conditions, non-dietary measures are needed. In the urea cycle disorders, drugs (sodium benzoate, sodium phenylbutyrate and arginine) can help to lower ammonia concentrations. Haemodialysis or haemofiltration is often the best treatment for patients with severe acute metabolic disturbances (such as neonatal hyperammonaemia).
team, ensuring that the diet is safe and adequate for growth, whilst also trying to minimize the impact on the patient and their family.
Funding
FURTHER READING Emergency management protocols are available on the British Inherited Metabolic Disease Group website, http://www.bimdg.org.uk Fernandes J, Saudubray JM, van den Berghe G, Walter JH, eds. Inborn metabolic diseases. 4th Edn. Heidelberg: Springer-Verlag, 2006. NICE hypercholesterolaemia guidelines: http://www.nice.org.uk Shaw V, Lawson M, eds. Clinical paediatric dietetics. 3rd Edn. Oxford: Blackwell, 2007.
Practice points C
Summary
C
This review highlights the importance of diet in the acute and chronic management of many inborn errors of metabolism. For many disorders, a dietary emergency regimen is crucial to prevent acute decompensation during intercurrent illnesses; it is at least as important as any medication. Long-term dietary management is also needed in many disorders, restricting the accumulation of toxic chemicals and supplying essential nutrients. The specialist dietician is a vital member of the metabolic
PAEDIATRICS AND CHILD HEALTH 21:9
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None.
C
C
C
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Dietary manipulation is needed for the acute and long-term management of many inborn errors of metabolism. A high calorie dietary emergency regime is vital during infections in certain inborn errors to prevent catabolism and subsequent clinical deterioration. Intravenous treatment should be started promptly if the emergency regime is not tolerated. Nutritional supplements are needed in many disorders and should be regarded as a medication. A specialist dietician is crucial for successful management.
Ó 2011 Elsevier Ltd. All rights reserved.
Nutrition in metabolic disease
(b) Preventing the accumulation of a substrate to toxic levels e.g. by restricting the intake of phenylalanine in phenylketonuria (PKU). (c) Supplying adequate energy and thereby preventing catabolism. By increasing the flux through the affected pathway, catabolism can cause the accumulation of a toxic substrate even in patients on an appropriate dietary restriction. We will consider each of these three dietary strategies in this article.
Elisabeth Jameson Andrew A M Morris
Abstract
Supply of a deficient metabolic product
Many inborn errors of metabolism are treated by dietary modification. There are three main strategies. 1. Some disorders lead to deficiency of a crucial product, which can be supplied by a special diet. This is illustrated by the need for a continuous enteral supply of glucose in hepatic glycogen storage diseases. 2. In other disorders, dietary restriction can prevent the accumulation of a substrate to toxic levels. Examples include the use of a low-phenylalanine diet in phenylketonuria and a minimalgalactose diet in galactosaemia. 3. In many disorders, catabolism during minor illnesses can lead to acute problems. These can usually be prevented by maintaining a high intake of glucose, either orally or intravenously. For inborn errors without specific dietary treatment, nutritional support is still important and may include tube feeding through a gastrostomy.
In a few inborn errors, the main problem is a lack of the product of the affected pathway. Most frequently, the deficient product is glucose. In the hepatic GSDs, reduced hepatic glucose production leads to hypoglycaemia. In fatty acid oxidation disorders (FAODs) decreased use of fat fuels can cause excessive glucose consumption and hypoglycaemia. In GLUT1 deficiency, a defect of glucose transport across the blood-brain-barrier leads to low cerebrospinal fluid (CSF) glucose concentrations. Glycogen storage diseases Glycogen is stored in liver and muscle; there is a risk of hypoglycaemia in the hepatic GSDs, predominantly types I, III, VI and IX. The fasting tolerance varies with the type of GSD; it is shortest in GSD type I because the defect prevents the release of glucose derived from gluconeogenesis as well as glycogenolysis. Typically, GSD I patients need to be fed every two to two and a half hours to prevent hypoglycaemia and families cannot sustain this, day and night, in the long-term. A continuous overnight feed (or glucose infusion) is, therefore, given through a gastrostomy or a nasogastric tube. During the day, the interval between feeds can be extended by giving uncooked corn starch (UCCS). This is digested by pancreatic amylase and acts as a slow release form of glucose. It is seldom tolerated before the age of 2 years; in older children, it usually achieves normoglycaemia for four and a half hours. The duration of normoglycaemia is longer in adults, who often substitute one or two UCCS doses for the overnight glucose infusion. In GSD types III, VI and IX, management is tailored to
Keywords catabolism; emergency regimen; encephalopathy; inborn errors of metabolism; ketogenic diet; low-protein diet; protein exchange; protein supplements
Introduction Inborn errors of metabolism are rare disorders but collectively their incidence is at least three in a thousand. They fall into three broad categories, as shown in Table 1. Neurological handicap, feeding difficulties and vomiting occur in many metabolic disorders, including mitochondrial, lysosomal and peroxisomal disorders. Feeding problems are particularly common in SmitheLemlieOpitz syndrome, an inborn error of cholesterol synthesis associated with microcephaly and malformations of variable severity. Nutritional support is important in all these patients and may include tube feeding through a gastrostomy. In many disorders of energy metabolism and intoxication, dietary treatment has an additional specific role in minimizing the consequences of the metabolic block (Figure 1). It can achieve this in three main ways by: (a) Supplying a deficient product e.g. glucose in the hepatic glycogen storage diseases (GSDs).
Catabolism Body stores A
B
D
Diet C Elisabeth Jameson MBBCh BSc MRCPCH is ST7 Paediatric inborn errors of metabolism in the Biochemical Genetics Unit at St Mary’s Hospital, Oxford Road Manchester, UK. Conflict of interest: none.
Figure 1 Schematic representation of an inborn error of metabolism. The metabolic block results from a deficiency of the enzyme or co-enzyme or, occasionally, from a transport defect. It leads to a deficiency of the product, D, and accumulation of the substrate, B, and related chemicals, A and C. Catabolism increases the flux through breakdown pathways and so increases the accumulation of the chemicals before the metabolic block, A, B and C.
Andrew A M Morris FRCPCH PhD is Consultant in Paediatric inborn errors of metabolism in the Biochemical Genetics Unit, St Mary’s Hospital, Oxford Road Manchester, UK. Conflict of interest: none.
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SYMPOSIUM: NUTRITION
Categories of metabolic disease Disorders of intoxication
Disorders of energy metabolism
Disorders of complex molecules
Amino acid disorders (e.g. phenylketonuria, homocystinuria, maple syrup urine disease) Organic acidaemias (e.g. propionic & methylmalonic) Urea cycle disorders (e.g. ornithine transcarbamylase deficiency, citrullinaemia) Sugar intolerances (e.g. Galactosaemia, Hereditary fructose intolerance)
Glycogen storage disorders Fat oxidation disorders (e.g. medium chain acyl-CoA dehydrogenase deficiency) Ketogenesis and ketolysis disorders GLUT1 deficiency Glutaric aciduria type 1 Mitochondrial disorders
Lysosomal disorders Peroxisomal disorders (e.g. Zellweger syndrome, X-linked adreno-leukodystrophy) Congenital disorders of glycosylation Sterol synthesis disorders (e.g. Smith-LemliOpitz syndrome) Lipoprotein disorders (e.g. familial hypercholesterolaemia, abetalipoproteinaemia)
Table 1
the fasting tolerance. An intravenous glucose infusion is generally needed during acute illnesses associated with vomiting.
galactose and related metabolites and they resolve when the milk is changed to a galactose-free formula, usually derived from soya. There is substantial intrinsic production of galactose within the body that cannot be eliminated. It is, therefore, unnecessary to avoid foods that contain very small quantities of galactose; indeed some older patients have returned to a normal diet without adverse consequences. Patients with galactosaemia often require calcium supplementation. Unfortunately, most patients with galactosaemia have some educational problems and premature ovarian failure that is not prevented by galactose restriction.
Fatty acid oxidation disorders There are many FAODs of varying severity. The commonest disorder is medium chain acyl-CoA dehydrogenase deficiency (MCADD) and this has recently been added to the UK newborn blood-spot screening programme. Patients with MCADD are well most of the time, provided that prolonged fasting is avoided. Infections can, however, lead to encephalopathy or sudden death, due to hypoglycaemia and the accumulation of fatty acid metabolites. These disasters can be prevented by maintaining a regular intake of glucose by mouth or intravenously (see below, Prevention of catabolism and acute encephalopathy). The same is true for many other FAODs, though some also require long-term dietary modification and in others the main problem is myopathy.
Hereditary fructose intolerance These patients develop symptoms of poor feeding, failure to thrive and vomiting when they start consuming fructose. This usually occurs during the weaning process because breast and formula milks do not contain fructose. The greatest source of fructose is from sucrose containing foods. Treatment is lifelong avoidance of fructose, sucrose and sorbitol from the diet. Patients are at risk of vitamin C and folic acid deficiency because of the exclusion of fruits and vegetables, so supplements may be required.
GLUT1 deficiency GLUT1 is responsible for glucose transport across the bloodbrain-barrier. Patients with GLUT1 deficiency have mutations in one allele of the gene, leading to a reduced number of transporters and a low CSF to blood glucose ratio. They present with seizures, developmental delay and a movement disorder. Ketone body transport into the brain is unaffected and can provide an alternative fuel. Treatment with a ketogenic diet usually controls the seizures but many patients continue to have cognitive problems. The classical ketogenic diet and the medium chain triglyceride (MCT)-based diet are both effective. In the latter, 60% energy is derived from MCT and 40% from saturated fat þ carbohydrate þ protein; in the classical diet, 4 g of fat are consumed for every one gram protein þ carbohydrate. Side effects include constipation, mild hyperlipidaemia, platelet dysfunction and, very rarely, kidney stones or pancreatitis.
Urea cycle disorders and branched chain organic acidaemias Amino acid degradation leads to the production of ammonia. This is normally converted to urea in the liver but it accumulates in patients with urea cycle disorders. The breakdown of certain amino acids also gives rise to branched chain organic acids, which accumulate in patients with propionic, methylmalonic and isovaleric acidaemias. Ammonia and the branched chain organic acids are toxic to the brain and can cause acute encephalopathy and irreversible brain damage. There may also be adverse effects on other organs, including the kidney, pancreas and heart in organic acidaemias. Drugs, such as sodium benzoate, sodium phenylbutyrate and arginine can promote the excretion of nitrogen in urea cycle disorders and carnitine therapy may increase the excretion of the organic acids. Dietary protein restriction is another crucial part of the management for both groups of disorders. This reduces the flux through the affected pathway and the accumulation of the toxic chemicals. It is important for the protein intake to provide sufficient amino acids for growth and, ideally, the protein should be from a high biological value source to prevent essential amino acid deficiency. Most patients are given the minimum safe protein intake but some will tolerate more, depending on their
Restriction of a dietary component that cannot be broken down The commonest dietary strategy is to restrict the intake of the nutrient whose degradation is prevented by the inborn error. Certain disorders of carbohydrate metabolism, as well as amino acid and lipoprotein metabolism are managed in this way. Galactosaemia Galactosaemia classically presents at 4e10 days of age with jaundice, failure to thrive, liver dysfunction and, sometimes, cataracts. The problems result from the accumulation of
PAEDIATRICS AND CHILD HEALTH 21:9
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Ó 2011 Elsevier Ltd. All rights reserved.
SYMPOSIUM: NUTRITION
e A phenylalanine-free amino acid mixture (or ‘protein substitute’) that brings the total protein intake up into the safe range. The palatability of the protein substitutes has improved over the years but many children still require considerable persuasion to take them. e Very low-protein foods, which may be natural (some fruits and vegetables) or synthetic (artificial low-protein bread, pasta, biscuits, milk-substitutes etc, which can be obtained on prescription in the UK). e Vitamin and mineral supplements, which are incorporated into many of the protein substitutes. Infancy and childhood are the vital times to follow the diet strictly, as this is the critical period for brain development. Some patients come off diet in adulthood with no adverse effects, others feel slightly ‘slow witted’ off diet. High phenylalanine levels during pregnancy cause the baby to have severe learning difficulties and an increased risk of congenital malformations, especially affecting the heart. It is, therefore, crucial that women have strict control of their phenylalanine levels throughout pregnancy (preferably starting prior to conception).
residual enzyme activity and growth rate. Many patients require vitamin, mineral, trace element and essential fatty acid supplementation. In these disorders, most problems are caused by acute rises in the concentrations of toxic chemicals. The acute rises are usually caused by catabolism and it is, therefore, essential to minimize catabolism; this is considered in the final section of this article. Aminoacidopathies In phenylketonuria, homocystinuria and maple syrup urine disease, specific amino acids accumulate to toxic levels. Moreover, in all three disorders, the concentrations of the relevant amino acid(s) remain unacceptably high, even on the minimum safe intake of natural protein. Management, therefore, requires a diet extremely low in natural protein, and supplements of all the other amino acids; the amino acid mixture is often called a ‘protein substitute’ and examples are shown in Figure 2. Blood concentrations of the relevant amino acid(s) need to be monitored regularly and the diet is adjusted accordingly. Phenylketonuria PKU is due to a deficiency of phenylalanine hydroxylase, which results in high phenylalanine levels. Untreated, it results in microcephaly, developmental delay and seizures. In most developed countries, patients are diagnosed by 2 weeks of age following newborn screening. The diet is semi-synthetic and consists of: e Small measured amounts of natural protein that provide the necessary phenylalanine for growth and protein turnover. These are known as the phenylalanine exchanges; the phenylalanine tolerance varies depending on the amount of residual enzyme activity and the daily number of exchanges is adjusted according to the blood phenylalanine levels.
MSUD
Homocystinuria Classical homocystinuria (HCU) is caused by deficiency of cystathionine b-synthase (Figure 3). The raised concentrations of homocysteine lead to complications that include learning difficulties, lens dislocation, osteoporosis and thromboembolism. Other less commonly seen complications include dystonia, sagittal sinus thrombosis and psychiatric disturbance. Homocysteine is not found in the diet but is derived from the amino acid, methionine. Plasma homocysteine concentrations can, therefore, be controlled by a low-methionine diet. This is directly analogous to the low-phenylalanine diet for PKU, the protein substitute this time consisting of a methionine-free amino acid
HCU
PKU
Figure 2 Examples of protein substitutes.
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SYMPOSIUM: NUTRITION
Familial hypercholesterolaemia This autosomal dominant condition is the commonest inborn error of metabolism, with an incidence of 1:500. Most patients have a mutation in the gene for the low-density lipoprotein (LDL) receptor, which reduces the hepatic uptake of LDLs and increases cholesterol synthesis. A diet low in saturated fat will lower the plasma cholesterol concentration but usually only by about 15%. Much larger reductions can be achieved with the statin drugs, which are licensed from 8 years of age in the UK. The National Institute of Clinical Excellence has published guidelines on the management of familial hypercholesterolaemia, however their guidance on paediatric management is limited.
Diet Methionine Dimethylglycine Vitamin B12 and folate
Methyl group Betaine Homocysteine
Pyridoxine
Abetalipoproteinaemia This is an autosomal recessive disease characterized by the absence of chylomicrons, very low-density lipoproteins (VLDLs) and LDLs. It is caused by a defect in the transfer of lipid to apolipoprotein B. Patients present with malabsorption in infancy; without treatment, vitamin E deficiency leads to neurological symptoms, starting in adolescence. Management is with a very low fat diet, supplements of essential fatty acids and fat-soluble vitamins; huge doses of vitamin E are needed.
Pyridoxal-phosphate Cystathionine
Cysteine Figure 3 Simplified metabolic pathways relevant to the treatment of classical homocystinuria.
mixture. Unfortunately, there is no screening program for homocystinuria in the UK and patients are only diagnosed at the age of a few years after developing clinical problems. It is much harder to introduce the difficult diet at this age than in babies. Other forms of treatment are also worth trying. A sub-group of HCU patients respond to pharmacological doses of pyridoxine; sometimes the response is so good that no additional treatment is required. There are two pathways for the remethylation of homocysteine to methionine (Figure 2). One depends on vitamin B12 and folate, and good levels of these vitamins should be maintained to maximize flux through this pathway. The other pathway depends on betaine, which is normally only present in the body at low concentrations. Treatment with betaine can reduce homocysteine concentrations substantially and is particularly useful in patients with poor dietary compliance.
Prevention of catabolism and acute encephalopathy This is particularly important in disorders where metabolic disturbance can lead to acute problems, such as encephalopathy or cardiomyopathy, see Table 2. Such disorders include the urea cycle disorders, organic acidaemias, and MSUD. Catabolism in these disorders leads to high concentrations of the toxic chemical that causes the acute problems. In fatty acid oxidation disorders, the clinical problems result from the accumulation of fatty acid metabolites and from hypoglycaemia. Catabolism can be caused by many different stresses, including exercise. In patients with inborn errors, acute problems are usually triggered by the stress of being born, fasting or infections. These patients are instructed to avoid prolonged fasting but all children suffer minor infections from time to time. During infections, catabolism is minimized by stopping the normal diet and substituting glucose, orally or intravenously. Supplying glucose will lead to insulin secretion and reduce catabolism. Oral glucose is preferred during minor infections, unless the patient is vomiting, because it can be started at home without delay; moreover, higher concentrations of glucose can be given by mouth than into a peripheral vein. Glucose polymer (e.g. CaloreenÒ, PolycoseÒ, MaxijulÒ, PolycalÒ, VitajouleÒ) is generally used because it is less sticky than an equivalent concentration of glucose. The concentration and volume are adjusted according to the patient’s age. The glucose polymer drinks are often referred to as the patient’s ‘emergency regimen’. It is important to start the drinks promptly, as vomiting is an early feature of metabolic encephalopathy. The emergency regimen is, therefore, started at the first sign of a possible illness and the child is reviewed 2 h later. If it was a false alarm, the normal diet is resumed. Otherwise, the drinks are continued every 2 h day and night until the child is on the road to recovery. Normal diet should generally be reintroduced within 48 h to avoid malnutrition. Patients who vomit or refuse to take their emergency regimen or deteriorate despite taking it, should go to hospital for
Maple syrup urine disease (MSUD) MSUD is caused by a defect in the metabolism of the branched chain amino acids (BCAA) leucine, valine and isoleucine. Leucine is the most toxic of these: long-standing moderate elevation can lead to demyelination, whilst very high concentrations result in acute encephalopathy, with ataxia, drowsiness and cerebral oedema. This contrasts with PKU and HCU, in which the problems are caused by sustained high levels of the toxic amino acids and brief rises are relatively harmless. The long-term dietary management of MSUD resembles that for PKU but, this time, the protein substitute is an amino acid mixture free of all three BCAA. The natural protein intake is adjusted according to the plasma leucine concentrations and supplements of valine and isoleucine may be added, depending on their plasma levels. In addition to the long-term management, extra treatment is needed during illnesses to prevent acute encephalopathy (discussed below in the section on catabolism). If patients do become encephalopathic, dialysis may be needed to reduce the leucine concentrations. Dialysis is usually needed during the initial presentation, which often occurs in the newborn period.
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SYMPOSIUM: NUTRITION
Conditions requiring an emergency regimen Condition
Emergency regimen components
Organic acidaemias
Glucose polymer þ continuation of metabolic medications if the child is on them. These may need to be given intravenously if vomiting or refusal of them Glucose polymer þ continuation of metabolic medications which may need to be given intravenously if there is vomiting or refusal of them Glucose polymer þ continuation of protein substitute either orally or via a nasogastric tube. It is vital the latter is continued to promote reduction in leucine levels Glucose polymer Glucose polymer
Urea cycle disorders Maple syrup urine disease Fatty acid oxidation disorders Glycogen storage disorders Table 2
assessment and, usually, intravenous management. To prevent catabolism, the infusion should supply 6e12 mg/kg/min of glucose, depending on age, and the fluid should generally be 10% glucose with 0.45% saline and potassium as required. If patients become hyperglycaemic, an insulin infusion should be started with appropriate monitoring rather than reducing the concentration of the glucose infusion. Additional measures may be needed to make patients anabolic and bring down the concentrations of toxic metabolites. In MSUD, acute encephalopathy is caused by toxic levels of the BCAA, especially leucine. These can only be lowered by incorporating them into new protein synthesis (or by dialysis). To promote protein synthesis, a mixture of all the other amino acids is given with the glucose polymer in the oral emergency regimen. In other conditions, non-dietary measures are needed. In the urea cycle disorders, drugs (sodium benzoate, sodium phenylbutyrate and arginine) can help to lower ammonia concentrations. Haemodialysis or haemofiltration is often the best treatment for patients with severe acute metabolic disturbances (such as neonatal hyperammonaemia).
team, ensuring that the diet is safe and adequate for growth, whilst also trying to minimize the impact on the patient and their family.
Funding
FURTHER READING Emergency management protocols are available on the British Inherited Metabolic Disease Group website, http://www.bimdg.org.uk Fernandes J, Saudubray JM, van den Berghe G, Walter JH, eds. Inborn metabolic diseases. 4th Edn. Heidelberg: Springer-Verlag, 2006. NICE hypercholesterolaemia guidelines: http://www.nice.org.uk Shaw V, Lawson M, eds. Clinical paediatric dietetics. 3rd Edn. Oxford: Blackwell, 2007.
Practice points C
Summary
C
This review highlights the importance of diet in the acute and chronic management of many inborn errors of metabolism. For many disorders, a dietary emergency regimen is crucial to prevent acute decompensation during intercurrent illnesses; it is at least as important as any medication. Long-term dietary management is also needed in many disorders, restricting the accumulation of toxic chemicals and supplying essential nutrients. The specialist dietician is a vital member of the metabolic
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None.
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Dietary manipulation is needed for the acute and long-term management of many inborn errors of metabolism. A high calorie dietary emergency regime is vital during infections in certain inborn errors to prevent catabolism and subsequent clinical deterioration. Intravenous treatment should be started promptly if the emergency regime is not tolerated. Nutritional supplements are needed in many disorders and should be regarded as a medication. A specialist dietician is crucial for successful management.
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