The effectiveness of correcting abnormal metabolic profiles

Inborn errors of metabolism cause disease because of accumulation of a metabolite before the blocked step or deficiency of an essential metabolite downstream of the block. Treatments can be directed at reducing the levels of a toxic metabolite or correcting a metabolite deficiency. Many disorders have been treated successfully first in a single patient because we can measure the metabolites and adjust treatment to get them as close as possible to the normal range. Examples are drawn from Komrower's description of treatment of homocystinuria and the author's trials of treatment in bile acid synthesis disorders (3β‐hydroxy‐Δ(5)‐C(27)‐steroid dehydrogenase deficiency and Δ(4)‐3‐oxosteroid 5β‐reductase deficiency), neurotransmitter amine disorders (aromatic L‐amino acid decarboxylase [AADC] and tyrosine hydroxylase deficiencies), and vitamin B6 disorders (pyridox(am)ine phosphate oxidase deficiency and pyridoxine‐dependent epilepsy [ALDH7A1 deficiency]). Sometimes follow‐up shows there are milder and more severe forms of the disease and even variable clinical manifestations but by measuring the metabolites we can adjust the treatment to get the metabolites into the normal range. Biochemical measurements are not subject to placebo effects and will also show if the disorder is improving spontaneously. The hypothesis that can then be tested for clinical outcome is whether getting metabolite(s) into a target range leads to an improvement in an outcome parameter such as abnormal liver function tests, hypokinesia, epilepsy control etc. The metabolite‐guided approach to treatment is an example of personalized medicine and is a better way of determining efficacy for disorders of variable severity than a randomized controlled clinical trial.