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The inborn errors of metabolism: general aspects 

The inborn errors of metabolism: general aspects

The inborn errors of metabolism: general aspects

Richard W.E. Watts

and T.M. Cox



Significant alterations have been made throughout this chapter to reflect recent developments in our understanding of the genome, inborn errors of metabolism, and potential treatments.

Updated on 28 Nov 2013. The previous version of this content can be found here.
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date: 29 April 2017

Historical perspective—inborn errors of metabolism were first recognized by Archibald Garrod, whose studies illustrated the dynamic aspects of human biochemistry and how unitary hereditary factors caused variation in the turnover of physiological metabolites derived from dietary components. He proposed that the activity of enzymes involved in human metabolism (e.g. of tyrosine degradation) were subject to control by specific genes, and several of the disorders studied by him were subsequently shown to be the result of block at some point in normal metabolism. He also noted the importance of consanguinity in the clinical expression of rare genetic variants which behave as recessive human disease traits.

Definition—the inborn errors of metabolism are those inherited diseases in which the phenotype includes a characteristic constellation of chemical abnormalities related to an alteration in the catalytic activity of a single specific enzyme, activator or transport protein. About 1500 such disorders have been characterized, with an estimated overall birth frequency of 1 in 4000 live births in non-consanguineous popluation groups. While these are now recognized as belonging to the category of ‘rare diseases’, they can also be viewed in an evolutionary context as paradigmatic examples of the interplay between the constitutional and environmental aspects of disease. Sophisticated, and increasingly inexpensive DNA-sequencing technologies, including whole-exome methods, now permit rapid identification of the molecular causation of metabolic diseases occurring in small pedigrees due to rare disabling mutations affecting any of the ~2x104 expressed human genes.

Genetic basis and pathogenesis

Site of mutations—almost all the inborn errors of metabolism arise from mutations in the nuclear genome and have Mendelian patterns of inheritance, but 13 genes are encoded by the mitochondrial genome, and when these are mutated the cognate diseases are thus maternally transmitted.

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, including (1) abolishing, decreasing, or (occasionally) increasing protein activity; (2) affecting activator proteins, or binding of hormones and other ligands to cell surfaces or other structures; (3) impeding intracellular trafficking and folding of proteins, as well as their post-translational modification through e.g. glycosylation, phosphorylation or prenylation, the latter a post-translational modification in which an isoprenyl group is added to a cysteine residue—a process which mediates protein interactions, especially protein-membrane interactions; (4) affecting the transport of metabolites across cellular membranes.

Clinical features and future prospects

Clinical presentation—the symptoms of metabolic disease are protean and may seem non-descript, especially in adults, hence a high index of suspicion may be required to make a correct diagnosis. Inborn errors of metabolism usually come to light in the neonatal period of infancy but can occur at any time, even in mature adults for the first time—and in whom the rate of progression may be indolent. In an appropriate clinical context—e.g. unexplained acute neonatal illness and/or failure to thrive in early infancy, developmental slowing and arrest followed by retrogression, unusual physiognomy—the critical clue often comes from taking an appropriate family history, with specific inquiries about affected siblings, possible parental consanguinity, paternity, miscarriages, perinatal deaths, abortions, about the sexes of possibly affected relatives and their placement on the maternal or paternal side of the family, the ages at death of relatives, as well as the ethnic and geographical origins of the parents. Impaired function of proteins that are localized to the mitochondria, lysosomes, and peroxisomes are associated with particular clinical and biochemical characteristics that reflect the compartmentalized functions of these organelles.

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. Specific methods, including mass spectroscopy and molecular analysis of genomic DNA, are increasingly used identify those at risk.

Treatment—cure of the underlying abnormality is reserved for a few spectacular disorders, but precise characterization of the biochemical disturbance often permits a rational treatment to be developed. 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 as in the case of the statin drugs for hypercholesterolaemia, rebalancing overproduction of toxic intermediates; (4) administering pharmacological doses of a cofactor; (5) replacement of a missing gene product, usually by enzymatic augmentation therapy or pharmacological chaperones to prevent premature aggregation and denaturation; (6) transplantation of cells (e.g. haematopoetic stem cells) or organs (e.g. liver) as a ‘gene replacement therapy’; (7) activation of a poorly functioning protein (e.g. the successful use of an oral agent which serves as an activator of a relatively uncommon mutant cystic fibrosis transmembrane regulator protein, due to the G551D missense variant in patients with the cognate disease).

Future prospects—the developments of treatments for inborn errors of metabolism will continue to be assisted by the recent capacity to develop credible models of specific disorders in genetically modified animals. The concept of pharmacological chaperones—based on the ability of small molecules to bind to mutant proteins to prevent their inactivation by abnormal folding, intracellular aggregation and mistargeting—is receiving much attention, but has yet to produce treatments of clinical utility. Numerous trials of gene therapy are planned and after many vicissitudes there are signs of success in patients suffering from several inborn errors of metabolism including haemophilia B and retinal defects: it is clear that this stratagem will enjoy wider clinical application over the next decade.

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