DIFFERENTIAL-DIAGNOSIS OF HYPERPHENYLALANINEMIA BY A COMBINED PHENYLALANINE-TETRAHYDROBIOPTERIN LOADING TEST

We describe a new fully reliable method for the differential diagnosis of tetrahydrobiopterin-dependent hyperphenylalaninaemia (HPA). The me thod comprises the combined phenylalanine (Phe) plus tetrahydrobiopter in (BH4) oral loading test and enables the selective screening of BH4 deficiency when pterin analysis is not available or when a clear diagn osis has not been previously made. It should be performed together wit h the measurement of dihydropteridine reductase (DHPR) activity in blo od. The new combined loading test was performed in nine patients with primary HPA, three with classical phenylketonuria (PKU), three with DH PR deficiency, and three with 6-pyruvoyl tetrahydropterin synthase (PT PS) deficiency. Three hours after oral Phe loading (100 mg/kg body wei ght), synthetic BH4 was administered orally at doses of either 7.5 or 20 mg/kg body weight. Amino acid (Phe and tyrosine) and pterin (neopte rin and biopterin) metabolism and kinetics were analysed. By exploitin g the decrease in serum Phe 4 and 8 h after administration, a clear re sponse was obtained with the higher BH4 dose (20 mg/kg body weight), a llowing detection of all cases of BH4 deficiency, as well as different iation of BH4 synthesis from regeneration defects. Since DHPR deficien t patients who were previously shown to be non-responsive to the simpl e BH4 loading test gave a positive response, the combined Phe plus BH4 loading test can be used as a more reliable tool for the differential diagnosis of HPA in these patients. Moreover, it takes advantage of b eing performed while patients are on a Phe-restricted diet.