Overview of the classification of inborn errors of metabolism

INTRODUCTION

Metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite. The concept of a single enzyme deficiency resulting in lifelong disease was recognized first by Sir Archibald Garrod in 1902, when he described alkaptonuria [1,2]. In this disorder, the activity of the enzyme homogentisic acid oxidase is deficient and blood concentrations of homogentisic acid are elevated, causing the clinical phenotype. Since Garrod's initial description, hundreds of inborn errors of metabolism (IEM) have been described [3], and new disorders continue to be identified.

The major classes of IEM and their characteristic clinical and biochemical features will be described below. The clinical presentation and evaluation of IEM are discussed separately, as are specific disorders. (See "Presenting features of inborn errors of metabolism" and "Overview of the evaluation of inborn errors of metabolism in children", ) See individual topic reviews on specific disorders. (See "Overview of maple syrup urine disease".)

PATHOGENESIS

Metabolic disorders can be caused by several mechanisms. Most metabolic disorders are caused by a single enzyme deficiency that disrupts one step of a metabolic pathway. This disruption may lead to the accumulation of metabolites preceding the interrupted step, as in alkaptonuria, or the inability to make certain intermediates or end- products of a specific metabolic pathway, such as ketoacids during fasting in patients with medium chain acyl-CoA dehydrogenase (MCAD) deficiency [4].

Less frequently, alterations that result in abnormalities of more than one enzyme can affect several metabolic steps. An example is multiple sulfatase deficiency, a lysosomal storage disorder that is caused by impaired posttranslational modification of sulfatases. Disorders of cofactors also can affect multiple enzymes. As an example, defects of cobalamin (vitamin B12) transport and synthesis may lead to accumulation of both methylmalonic acid and homocysteine. (See "Organic acidemias".)

In most cases, metabolic disorders result from single mutations, deletions, or other genetic changes. However, a single enzyme, such as mitochondrial trifunctional protein, can be composed of multiple subunits encoded by different genes and catalyze more than one metabolic reaction. In addition, defects in different enzymes can result in a similar clinical phenotype (eg, elevated total plasma hymocysteine may result from either deficiency of the enzyme cystathione beta-synthetase or from a cobalamin processing defect [complementation group G]).