After reading this chapter you should:
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know the biochemical features of metabolic diseases
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be able to undertake and interpret relevant metabolic investigations
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understand the clinical presentation and prognosis of metabolic diseases
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know the screening procedures for inherited metabolic conditions
Metabolic medicine cares for those children who present with conditions resulting from absence or disruption of metabolic cellular processes. These processes are dependent upon the specific actions of enzymes and, if these are deficient or absent, then cell activity becomes dysfunctional. Conditions which are the result of defective enzymes are usually the result of single gene abnormalities and are known as ‘Inborn Errors of Metabolism’.
In clinical terms, inborn errors of metabolism can present at any age with varying degrees of severity depending upon the degree of enzymatic dysfunction. In broad terms, the more enzymatic dysfunction present, the earlier and more severe the presentation. A total absence of enzymatic function may not be compatible with life. Children with metabolic disease often present acutely with poor feeding, altered conscious states or seizure activity or, on investigation, are found to have hypoglycaemia or a metabolic acidosis. However, there are a significant number where presentation is more insidious with growth failure, developmental delay, learning disability or dysmorphism.
The management of such children requires an understanding of the underlying abnormality and the effect of the defect on the body. It will be important for the clinician to know how to address any immediate problems along with management of short-term and long-term consequences of the illness. Most children will be under the care of specially trained paediatricians in tertiary centres or general paediatricians with further training in metabolic medicine who work closely with a tertiary team.
Biochemical features of metabolic diseases
Modes of presentation for metabolic disease:
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hypoglycaemia
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metabolic acidosis
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altered consciousness
Hypoglycaemia
Hypoglycaemia is a common finding in children and is seen in many clinical scenarios. It is seen in the immediate newborn period, particularly in infants who are preterm or growth restricted or who are infants of diabetic mothers and those who are seriously ill with sepsis. If significant hypoglycaemia occurs within the first 72 hours after birth or is recurrent in older infants and children, then investigations should be undertaken to identify an underlying metabolic condition.
Glucose homeostasis is vital in maintaining health. The body generates glucose by the process of gluconeogenesis whereby the body can generate glucose from nonglucose precursors. Glycolysis is the process of the conversion of glucose to pyruvate which enters the tricarboxylic acid cycle to produce ATP. When there is excess glucose available, glycogenesis converts glucose to glycogen for storage in the liver and muscles. At times of increased glucose demand, as in illness, fasting or exercise, the glycogen is converted to glucose by the process of glycogenolysis. If the demand for glucose cannot be met through glycogenolysis alone the body switches to fat metabolism with the subsequent production of free fatty acids and the ketone bodies beta-hydroxybutyrate and acetoacetate ( Table 30.1 ).
| Term | Definition |
|---|---|
| Hypoglycaemia | a true blood glucose <2.6 mmol/l |
| Gluconeogenesis | synthesis of glucose from nonglucose precursors in liver, kidney and intestinal epithelium |
| Glycolysis | oxidation of glucose to pyruvate with generation of ATP |
| Glycogenesis | conversion of excess glucose to glycogen |
| Glycogenolysis | degradation of glycogen to glucose |
Hypoglycaemia may produce pallor, sweating and irritability in babies and infants prior to being fed. In older children, who have a relatively long overnight fast, early morning lethargy or bad moods should lead to the assessment of a blood glucose. Any baby or child with a profound hypoglycaemia may present with seizures.
Investigations
When a metabolic cause is considered in the differential diagnosis a range of investigations to investigate the cause of the hypoglycaemia will be needed and are outlined below ( Tables 30.2 and 30.3 ).
| Investigation | Rationale for investigation |
|---|---|
| Insulin | should reflect the expected normal pattern in response to hypoglycaemia—low with low blood glucose. High levels indicate pathological production |
| C-peptide | C-peptide connects the two insulin sections together in the pre-insulin molecule and is cleaved from each endogenous insulin molecule. Measured values should be the same as measured insulin values and, if significantly lower, indicates administration of exogenous insulin |
| Growth hormone | promotes gluconeogenesis in the liver so elevated levels can induce hypoglycaemia |
| Free fatty acids | produced in lipolysis and increases with prolonged hypoglycaemia |
| Ketone bodies | should be produced when child becomes hypoglycaemic as an alternative energy source for brain and other tissues. A non-ketotic hypoglycaemia requires more detailed investigation |
| Cortisol | has an effect on gluconeogenesis and aims to increase glucose |
| Investigation | Rationale for investigation |
|---|---|
| Acylcarnitine | specific patterns seen in fatty acid oxidation disorders, e.g. raised C8:C10 ratio in MCADD |
| Ammonia | raised in hepatic encephalopathy which may lead to hypoglycaemia |
| Lactate | produced in excess when body unable to mobilise stored glycogen |
Treatment and management
Immediate management should aim to correct the hypoglycaemia by the administration of glucose or dextrose following APLS protocols. The route of administration will be dictated by the conscious level of the child, the age of the child and whether the child can tolerate oral administration. Underlying causes may become evident when results of investigations are available and will direct further management.
Metabolic acidosis
Acidosis is a common finding in the acutely unwell baby or child and it is important to determine if this has a metabolic or respiratory cause. Many such children will have a degree of circulatory failure due to sepsis and the diagnosis and management will follow the usual course, but it is important to investigate alternative causes of an acidosis if it is persistent and unresolved ( Table 30.4 ).
| Abnormality | Primary disturbance | Effect on | Base excess | Compensatory response | |
|---|---|---|---|---|---|
| pH | pCO2 | ||||
| respiratory acidosis | ↑ pCO2 | ↓ | ↑ | negative | ↑ [HCO3-] |
| metabolic acidosis | ↓ [HCO3-] | ↓ | N or ↓ | negative | ↓pCO2 |
| respiratory alkalosis | ↓ pCO2 | ↑ | N or ↓ | positive | ↓[HCO3-] |
| metabolic alkalosis | ↑ [HCO3-] | ↑ | N or ↑ | positive | ↑pCO2 |
Children with a metabolic acidosis can present with a combination of:
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vomiting
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poor feeding
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reduced conscious level
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tachypnoea (hyperventilation to reduce CO 2 levels)
Investigations
An initial calculation of the anion gap will indicate if there is an excess acid present and, if raised, the acid must be identified. This may be obvious, for example in DKA where a ketoacidosis is present, but in metabolic disease specialist tests will be required ( Table 30.5 ).
anion gap = [Na + ] + [K + ] – [HCO 3 – ] + [Cl – ]
Normal value = less than 10–14
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although there may be some small variations in this range between laboratories
| Metabolic acidosis with raised anion gap (due to addition of ‘acids’ to plasma) | Metabolic acidosis with normal anion gap (due to loss of bicar bonate—renal or GI) |
|---|---|
| lactic acidosis ingestion, e.g. ethanol, salicylate renal failure acid-producing metabolic disorder diabetic ketoacidosis | renal tubular acidosis Addison disease acetazolamide severe diarrhoea post-ureteric diversion into large bowel |
Further investigations will be needed to clarify the underlying metabolic cause identified at presentation. The tests would include ( Table 30.6 ):
| Investigation | Rationale for investigation |
|---|---|
| blood gas | identifies metabolic acidosis |
| ammonia | can be raised in organic acidaemia, hepatic encephalopathy and urea cycle disorders |
| lactate | raised in any acutely unwell child. In congenital lactic acidosis may improve but fails to entirely resolve |
| ketone bodies | present if child hypoglycaemic but level out of keeping with the degree of hypoglycaemia |
| acylcarnitine | abnormal in organic acidaemias and fatty acid oxidation disorders |
| plasma amino acids | indicative of mitochondrial disease, amino acidaemia and urea cycle disorders |
| urine organic acids | identifies organic acidaemias |
Treatment and management
Children who are unwell at presentation will require standard APLS resuscitation. If a metabolic cause is considered, then the child should be placed nil by mouth and intravenous dextrose commenced. Dextrose stops catabolism by relieving stress on metabolic pathways and so stopping metabolic decompensation. In severe acidosis there may be a need for sodium bicarbonate although administration of this needs to be undertaken after consultation and with caution.
Metabolic diseases
Idiopathic ketotic hypoglycaemia
Idiopathic ketotic hypoglycaemia is the commonest cause of hypoglycaemia in children. It is a recognised condition with uncertain aetiology although inadequate carbohydrate intake or excessive level of exercise may contribute to the problem. It is, however, a diagnosis of exclusion and an underlying metabolic or endocrine cause must be sought in the first instance.
The condition typically presents between 1–3 years of age with an episode of hypoglycaemia either during an intercurrent illness with reduced oral intake or on waking after the long overnight fast. The crucial finding is the presence of ketones in the urine as the body turns to ketogenesis as an energy source. Children may have a single episode or recurrent episodes but, in the majority, the condition improves between the ages of 5–8 years.
Treatment and management
Carers of the children should be provided with an emergency regimen for use at times of illness. This consists of a glucose polymer drink they must take every 2 hours during the day and every 3 hours at night. The children must avoid long periods of fasting and some may require a long-acting carbohydrate to be taken before sleep.
Glycogen storage disease (GSD)
Glycogen storage disorders are a diverse group of conditions which are the result of dysfunctional or absent enzymes in the glucogenesis, glycolysis or gluconeogenesis pathways. They can be divided into two broad groups, those affecting the liver and those affecting the muscles. The result is an inability to metabolise, mobilise or store glucose which then impacts on blood glucose levels. Stored glycogen in organs and tissues, particularly liver, kidneys and small intestines, will accumulate over time and disrupt their normal function.
Glycogen storage disease type 1 (GSD type 1) is the most common GSD of the hepatic group and is an autosomal recessively inherited condition. The underlying abnormality is a deficiency of glucose-6-phosphatase which facilitates the conversion of glycogen to glucose.
A child with GSD type 1 will usually present before the age of 2 years with the consequences of recurrent and prolonged episodes of hypoglycaemia—seizures, growth retardation or developmental concerns. There are two recognised subtypes—GSD-1a and GSD-1b—and both will present in similar ways although children in the latter group also have chronic neutropenia and suffer with recurrent infections, typically of the skin. Examination of the child will identify a distended abdomen due to hepatomegaly caused by the increasing stores of glycogen. The hepatomegaly can be easily missed as the liver feels very soft.
Investigations
Classical laboratory findings are:
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episodic hypoglycaemia
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persistently raised lactate—anaerobic activities due to low supply of glucose
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raised ketones
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raised lipid levels
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neutropenia—in type 1b but can by cyclical
The raised lactate and ketones can produce a metabolic acidosis and consequently, the child may be hyperventilating when seen.
Treatment and management
The aim of treatment for children with GSD type 1 is to maintain normoglycaemia. This is achieved by the administration of frequent feeds during the day and often continuous gastric feeds overnight. This will allow the child to grow and prevent further accumulation of glycogen. At times of illness the child will have an emergency regime. Children with GSD type 1 may have normal growth and development if periods of profound hypoglycaemia can be avoided. Those with some of the other GSD variants may experience growth failure and developmental delay but only if not treated.
Galactosaemia
Lactose (milk disaccharide) is formed of glucose and galactose. Once cleaved the galactose is converted to UDP-galactose by the enzyme galactose-1-phosphate uridyl transferase (GALT) and then to glucose. It is the absence of this enzyme which leads to classical galactosaemia. There is therefore an accumulation of galactose which is converted to a toxic alcohol-based molecule.
Classical galactosaemia presents in the first week of life as milk feeds are introduced although it can present at a slightly later stage. It is associated with Escherichia coli sepsis and this may be the main presenting problem although the explanation for this association is unclear. The condition is inherited in an autosomal recessive manner and is known to be more common within certain populations—Irish travelling families being one such group.
The majority of babies present with:
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jaundice
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poor feeding
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oozing from venepuncture sites due to coagulopathy
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cataracts (in some children though most will develop them if left untreated)
Investigations
Initial investigations will show:
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conjugated hyperbilirubinaemia—liver failure
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abnormal coagulation studies—liver failure
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metabolic acidosis
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urinary reducing substances—galactose
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glycosuria, aminoaciduria and albuminuria
A more detailed assessment will show near complete absence of galactose-1-phosphate uridyl transferase (GALT) activity in red blood cells and the consequent elevated levels of galactose-1-phosphate in plasma and red blood cell.
Treatment and management
Immediate treatment must address the acute problems of liver failure, coagulopathy and sepsis but must also remove galactose-containing formula feeds from the diet. All children who have survived the acute metabolic decompensation must adhere to a lifelong diet with minimal galactose although many will have learning disabilities despite treatment. Any cataracts which have formed will usually resolve with treatment. The majority of females with galactosaemia will be infertile due to ovarian dysgenesis and must be referred to a paediatric endocrinologist at around 10 years of age.
Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
This is the result of a deficiency in the enzyme medium chain acyl-CoA dehydrogenase, which is responsible for the breakdown of stored medium chain fats to create the energy source Acyl-CoA. This leads to affected individuals being unable to meet an increase in energy demands after glycogen stores are depleted. The consequence is the characteristic findings of hypoglycaemia with very low or absent ketones.
Most infants are identified through the UK neonatal screening programme and consequently acute presentations are now uncommon. They may, however, present before they have undergone screening due to a failure to establish breast feeding and classically are nonspecifically unwell with hypoglycaemia and possible seizures. There is the possibility of coma or sudden death if profound hypoglycaemia develops.
Investigations
Investigations will reveal a hypoglycaemia without the expected elevation of ketones (non-ketotic hypoglycaemia).
Treatment and management
Avoidance of long periods of fasting, particularly overnight or during intercurrent illness, is important. As the child grows, they will be able to tolerate a longer fast, but the maximum time allowed should be 12 hours. Families must be given a written emergency regimen which can be shown to medical staff at times of illness. Children with MCADD who are identified on neonatal screening and treated appropriately can expect normal development and growth.
Mucopolysaccharidoses
This is a group of disorders that arise due to the absence or dysfunction of lysosomal enzymes. These enzymes break down molecules known as glycosaminoglycans (GAGs—previously known as mucopolysaccharides) which are found in cells forming bone, cartilage, tendons, connective tissue and corneas. Currently, seven different clinical types are recognised and each has a different presentation and prognosis. Most are recessively inherited although MPS type II is x-linked.
The clinical features are similar across the different types of the disease although they may differ in severity. The symptoms may not be evident in the first few months of life, but concerns about early developmental may lead to referral. Characteristic signs include:
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coarse facial features with corneal clouding ( Figures 30.1 and 30.2 )
