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Metabolic disorders 

Metabolic disorders
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date: 27 February 2021

The inborn errors of metabolism are those inherited diseases in which the phenotype includes a characteristic constellation of biochemical abnormalities related to an alteration in the catalytic activity of a single specific enzyme, activator, or transport protein. Mechanism of diseases—mutations in the proteins giving rise to the inborn errors of metabolism affect primary, secondary, tertiary, or quaternary structure. This can lead to an enormous variety of consequences. Clinical presentation—the manifestations of metabolic disease are protean and may seem nondescript, especially in adults, hence a high level of suspicion may be required to make a correct diagnosis. Prevention and screening—there is a strong case for mass population screening for some inborn errors of metabolism at the presymptomatic stage to allow early detection and introduction of proven treatment before irreversible damage occurs. Management—definitive cure of the underlying abnormality is available for a few disorders, but precise characterization of the biochemical disturbance often permits rational treatment to be organized and provides the basis for further therapeutic endeavours. General approaches include (1) restriction of a substrate that cannot be metabolized including molecules derived from the diet; (2) replacement of a missing metabolic product; (3) removal of poisonous metabolites or rebalancing overproduction of toxic intermediates; (4) administering pharmacological doses of a cofactor, sometimes a vitamin, that may also stabilize a mutant enzyme; (5) replacement of a missing gene product, usually by enzymatic augmentation therapy or pharmacological chaperones, to prevent premature aggregation and denaturation; (6) repression of an overproduced protein or metabolite by stable RNA inhibition; (7) transplantation of cells or organs as a ‘gene replacement therapy’; and (8) activation of a poorly functioning protein.

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