Figure 1.

Kitchen sink model for IEM caused by toxic metabolite accumulation. As the majority of IEMs appear to be caused by the accumulation of the substrate of the enzyme that is impaired by the underlying mutation, the pathology and treatment can be conceptualized as a sink. Using phenylketonuria as an example, the loss of function mutation in phenylalanine hydroxylase leaves individuals unable to metabolite phenylalanine; thus, the drain of the sink is blocked and leads to an overflow of phenylalanine in the individual and accumulation of toxic phenylalanine byproducts. Importantly, dietary restriction of phenylalanine prevents the pathology, just as turning off the faucet prevents an overflow. This general sink mechanic appears to be in play in the majority of amino acid breakdown disorders, as described in this review. PAH: phenylalanine hydroxylase.