Introduction

Inborn errors of metabolism are a diverse group of disorders that result from a defect or absence of an enzyme or transport system. The presenting symptoms and signs are equally diverse; however, there are a number of common features that can alert the clinician to their presence. This chapter will concentrate on those metabolic conditions that present acutely to the emergency department (ED), but will also touch on those with more chronic presentations which could easily go unrecognised.

The majority of patients presenting with acute metabolic conditions to the emergency department will have already been diagnosed, particularly given the advent of extended newborn screening (see end of chapter). However, not all conditions can be screened for and some can be missed by screening, thus children and, indeed, adults can still present acutely with an undiagnosed metabolic condition.

Physiology and pathogenesis

The process by which living matter is built up (anabolism) or broken down (catabolism) is termed metabolism. Strictly speaking, an inborn error of metabolism (IEM) is an inherited defect in a metabolic pathway or enzyme. Generally, there is a defect in an enzyme that catalyses the conversion of one organic compound to another. However, not all defects in metabolic pathways give rise to pathology. Figure 10.1.1 shows that compound A is converted to B. If the enzyme that catalyses the reaction is not present or is functioning poorly, this can affect the body in any one of the following ways.

There is accumulation of A, which is toxic – example: phenylketonuria.

There is a deficiency of B, which results in cellular dysfunction – example: Smith–Lemli–Opitz syndrome, a disorder of cholesterol biosynthesis.

Excess A is converted to C via an alternate pathway which is toxic – example: tyrosinaemia type 1.

Excess A results in accumulation of metabolite E earlier in the pathway, which is toxic – example: maple syrup urine disease.

Excess A is excreted by reacting/conjugating with D, which results in deficiency of D – example: carnitine deficiency in fatty acid oxidation defects.

Fig. 10.1.1 Pathogenic mechanisms in IEM; refer to text for a full explanation.

The pathology seen in an IEM can result from any of the processes outlined in Figure 10.1.1, but in fact most IEM are the result of more than one mechanism. Genetic defects can also occur in the support processes of metabolic pathways such as transport proteins, enzyme chaperones and enzyme complex assembly proteins, which result in the block of a metabolic process and thus pathology.

Clinical features

The clinical features and presentations of IEM are many and varied due to the diverse nature of the enzymes and processes affected; however, Table 10.1.1 shows that there are a number of common features that should alert the clinician to the possibility of an IEM.

Table 10.1.2 can be used as a guide to identifying an IEM in the ED:

An IEM should be considered if there is both a clinical and a biochemical feature from each of the lists; however, considering an IEM should never take the place of the work up and treatment for more common causes of the above presentations, the most important being sepsis.

IEM are broken down into a number of groups of conditions, all of which affect a common metabolic pathway. The groups of IEM that are likely to present to the ED are outlined in Table 10.1.1, including the common presenting features of each.