Garrod identified the first inborn error of metabolism in 1902 when he described the symptoms that had been observed in patients with alkaptonuria as being due to an inherited enzyme deficiency. Since that time over 400 disorders have been described that are due to an enzyme deficiency in the catabolic pathways of proteins, fatty acids, and carbohydrates. The resulting accumulation of toxic intermediates and, in some cases, the depletion of a necessary end product cause a variety of metabolic derangements, often with significant neurological sequelae. The severity and the age of onset of symptoms usually, although not always, depend on the amount of residual enzyme activity.
The vast majority of these disorders are inherited in an autosomal recessive fashion. While the individual inborn errors of metabolism are rare, based on recent results of expanded newborn screening programs (in which over 30 disorders can be detected), the overall incidence is approximately 1 in 5000 live births worldwide. The incidence of disorders may vary across populations because of the 'founder effect', where a specific mutation arises and is maintained in subsequent generations, and may be higher where there is a higher incidence of consanguinity.
With a few exceptions, infants are normal at birth because the placenta efficiently eliminates the toxic metabolites.
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