Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency: possible regulation of gene expression in a patient with the homozygous L48S mutation.

To the Editor: Tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency is a recently recognized variant of hyperphenylalaninemia (HPA) characterized by a positive response to a BH4-loading test (1). Up to the present time, 11 different mutations have been described which are associated with mild HPA (Table 1) and all patients have been shown to be compound heterozygotes (1–6). They respond to an oral challenge with BH4 (10–20 mg/ kg) in that plasma phenylalanine concentrations normalize within 4–8 h after administration and they can be treated with BH4 monotherapy instead of a low-phenylalanine diet. It has been speculated that some of mutations in the PAH gene result in a Km variant of the PAH enzyme in which enhancement of the residual activity can be achieved by supplementation of BH4. These mutations, located in the DNA region encoding for the catalytic domain (exons 6 to 12) of the enzyme, may potentially alter the tertiary structure. Most of these mutations, when expressed recombinantly in eukaryotic cells, showed at least 25% residual activity (7). However, Lindner et al. (4) showed that BH4-responsiveness may differ between patients with the same genotype and suggested that the difference must be due to other as yet unknown factors. Only one out of three patients with the common R408W/Y414C mutations responded to the loading with 20 mg BH4/kg body weight. Recently, a patient with a BH4-responsive PAH deficiency, whose plasma phenylalanine normalized within 8 h from 726 to 120 mol/L after oral administration of BH4 (20 mg/kg/day), was diagnosed at the Children’s Hospital of Reutlingen. Surprisingly, he was found to be a homozygote for the Leu to Ser