**2. Etiology**

More than 1000 mutations result in PKU [16], and more than 100 mutations result in HT1, and most of them are missense mutations [7]. In the *PAH* gene, 60.5% of mutations are missense mutations, and in the *FAH* gene, 45% of mutations are missense mutations [8,9]. The severity of a mutation depends on its effect on the resulting enzyme's conformation and function. In other words, the genotypic effect on the clinical phenotype is variable [3,33]. Most of the mutations causing PKU and HT1 result in PAH and FAH instability, leading to misfolding and loss of function [20,22,33–35].

Because both enzymes are biallelic, it is possible to have many disease-causing mutations, resulting in a compound heterozygote [36,37]. Mutations in the *PAH* and *FAH* genes are known to decrease catalytic activity and reduce the kinetic stability of the enzymes, inducing accelerated degradation [7,38].
