Inborn errors of metabolism

Published on 01/03/2015 by admin

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80

Inborn errors of metabolism

The spectrum of genetic disorders is wide and encompasses chromosomal disorders as well as many common diseases in which multiple genes confer susceptibility to the effects of environmental influences. ‘Classical’ genetic diseases result from single gene mutations that result either in reduced synthesis of a particular protein, or the synthesis of a defective protein. In 1909 Garrod first defined the concept of inborn errors of metabolism, where blocks in specific metabolic pathways result from defects in particular enzymes. Certainly, in most inborn errors, the defective or absent protein is an enzyme; exceptions include familial hypercholesterolaemia, cystinuria and Hartnup disease, where the affected proteins are either receptors or are otherwise involved in transport processes.

Patterns of inheritance

Inborn errors can be autosomal (involving a chromosome other than X or Y) or X-linked, and the genetic defect can be either dominant or recessive. In dominant disorders, everyone who carries the gene is affected by the disease, so every affected individual has at least one affected parent. If the defective gene is recessive, it will be silent unless both copies (maternal and paternal) of the gene carry the mutation, i.e. affected individuals must be homozygous; parents carrying only one copy of the affected gene (heterozygotes) are carriers and are not clinically affected. These patterns of inheritance are illustrated in Figure 80.1.

Establishing pedigrees may not be straightforward. One reason for this is that the severity of the disease can vary widely between individuals even within the same family. Sometimes the clinical manifestations may be so mild that the disease cannot be detected, even though the defective gene is present. When this occurs the disease is said to be non-penetrant. Thus, dominant diseases may clinically appear to ‘skip’ generations.

Clinical diagnosis

Several problems confront the clinician suspecting an inborn error of metabolism. Firstly, the clinical presentation is often non-specific. In an infant, the symptoms may include poor feeding, lethargy and vomiting, which are seen with any significant illness; in older children, failure to thrive or developmental delay may be the only presentation. Secondly, the range of specialist tests used to diagnose inborn errors is extensive and, for many, bewildering. Useful clues that should increase the index of suspicion include:

One useful classification of inborn errors includes both clinical and laboratory features (Table 80.2).

Table 80.2

Classification of inborn errors of metabolism on basis of clinical and laboratory features

Presentation Most likely diagnoses
‘Intoxication’, ketoacidosis (blood H+ not ↑↑) Maple syrup urine disease (amino acid disorder)
‘Intoxication’, ketoacidosis Organic acid disorders
‘Energy deficiency’, lactic acidosis Congenital lactic acidoses
‘Intoxication’, high ammonia, no ketoacidosis Urea cycle defects
‘Energy deficiency’, no metabolic disturbance Peroxisomal disorders
Non-ketotic hyperglycinaemia
Storage disorders, no metabolic disturbance Lysosomal storage diseases
Hypoglycaemia, hepatomegaly, abnormal LFTs Glycogen storage diseases

‘Intoxication’ and ‘energy deficiency’ are contrasting clinical manifestations of neurological distress in the neonatal period. ‘Intoxication’ is characterized by a symptom-free interval, then onset of lethargy or coma. ‘Energy deficiency’ is often associated with hypotonia, dysmorphic features. Lethargy and coma are rarely the initial signs, and often there is no symptom-free interval.

Laboratory diagnosis

Clearly if there is a clinical basis for suspecting a particular inborn error of metabolism, specific investigations should be requested. For example, the presence of cataracts should make one suspect galactosaemia, for which the appropriate investigation is measurement of galactose-1-phosphate uridyl transferase in red blood cells. More often, however, there are no specific features. Routine laboratory investigations may help point the direction of further investigations by suggesting particular groups of metabolic disorders (see Table 80.3). In the acute situation, in the absence of clues, the following investigations should always be considered, and performed urgently if indicated:

image Plasma ammonia. Indicated particularly when there is neurological distress/intoxication; grossly elevated levels are most frequently due to urea cycle disorders.

image Organic acids (urine) and amino acids (urine and plasma). Organic and amino acid disorders collectively comprise a large group of inborn errors of metabolism.

image Plasma lactate. Should be measured especially if there is acidosis, hypoglycaemia or neurological distress. This test is readily available in most laboratories.

image Galactose-1-phosphate uridyl transferase. Unusual in this list in being specific to one disorder (galactosaemia). However, this is easily treated by excluding galactose from the diet, is frequently fatal if unrecognized (especially in neonates), and is sufficiently common that it is included in some population screening programmes.

image Clinical note

Making the diagnosis of an inborn error post mortem is not pointless: it may permit genetic counselling and may save the life of a future sibling. Where possible, blood and urine samples should be collected after discussion with a specialist laboratory. Inborn errors are also diagnosed sometimes using samples of skin, liver or vitreous humour.

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