Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: a seven years experience

Abstract

Background: Phenylketonuria (PKU) is an autosomal recessive disorder caused by the deficiency of phenylalanine hydroxylase that catalyzes the conversion of phenylalanine to tyrosine, using tetrahydrobiopterin (BH4) as coenzyme. Besides dietary phenylalanine restriction, new therapeutic options are emerging, such as the treatment with BH4 in subgroups of PKU patients responding to a loading test with BH4.

Methods: A no-profit open-label interventional trial with long-term oral BH4 therapy, sponsored by the Italian Medicines Agency (AIFA), was performed in a group of 17 PKU patients resulted as BH4 responders among 46 subjects analyzed for BH4-responsiveness (prot. FARM5MATC7). We report on efficacy and safety data of BH4 therapy and analyze factors predicting BH4-responsiveness and long-term response to BH4. A BH4-withdrawal test was used as a proof of the efficacy of long-term therapy with BH4.

Results: Forty-four percent of the patients responded to the 48 h-long loading test with BH4. All the phenotypic classes were represented. Genotype was the best predictor of responsiveness, along with lower phenylalanine levels at diagnosis, higher tolerance and lower phenylalanine/tyrosine ratio before the test. In BH4 responder patients, long-term BH4 therapy resulted safe and effective in increasing tolerance while maintaining a good metabolic control. The BH4 withdrawal test, performed in a subset of patients, showed that improved tolerance was directly dependent on BH4 assumption. Tolerance to phenylalanine was re-evaluated in 43.5% of patients and was longitudinally analyzed in 5 patients.

Conclusions: Long-term treatment with BH4 is safe and effective in increasing tolerance to phenylalanine. There is real need to assess the actual tolerance to phenylalanine in PKU patients to ameliorate quality of life, improve nutritional status, avoiding unnecessarily restricted diets, and interpret the effects of new therapies for PKU.

Figure 1

Results of the 48 h-BH4 loading test (20 mg/kg/day) of the 19 HPA responder subjects according to their phenotypic class. Cumulative data at each time-point are shown as mean ± SD, except for the 2 cPKU patients where only mean value is represented.

Figure 2

BH4 withdrawal test in 7 patients. Median Phe before BH4 therapy was calculated on Phe values collected during the 5 years prior to the enrolment into the trial (Baseline). Values reported in BH4-1 and Withdrawal represent the mean values of the Phe concentration at -10 and -5, and at +5 and +10 days from BH4 withdrawal, respectively. Patients were finally asked to re-start BH4 and to control plasma Phe levels 10 days later (day +20) (BH4-2). Numbers reported in the bars represent the daily Phe intake (mg/day) before BH4 therapy (white column) and the dietary Phe intake during the withdrawal test (dark columns). The dashed line indicates the plasma Phe upper value of the target range for the age group (600 micromol/L).