Long‐term follow‐up of patients with phenylketonuria receiving tetrahydrobiopterin treatment

Abstract

Treatment with tetrahydrobiopterin (BH4), the natural cofactor of phenylalanine hydroxylase (PAH), can reduce blood phenylalanine (Phe) levels in patients with BH4-responsive phenylketonuria (PKU). A number of studies has reported on the short-term BH4 treatment of patients with PKU, but long-term data are lacking. Here, we describe the effects of long-term treatment with BH4 on 16 patients, who showed a >28% reduction in blood Phe following testing for BH4 overload. The mean dose of BH4 was 16 mg/kg body weight (range 5-36 mg/kg body weight). The mean treatment duration was 56 months (range 24-110 months). Of 16 patients, 14 achieved long-term Phe control with BH4 treatment, with a mean blood Phe concentration of 321 ± 236 µmol/l. The mean decrease from baseline in blood Phe levels in these 14 patients was 54.6%. Of the seven patients who required continued dietary restriction, Phe intake increased from 200-300 mg/day to 800-1000 mg/day. Factors that may cause fluctuation of Phe levels in BH4-treated patients include patients' PAH genotype, Phe intake, changes in protein catabolism or anabolism, and periods of illness or infection.

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

“…This percentage is similar to that of other studies (Trefz et al 2010). Other authors obtained a far superior rate of response, 62%, (Vernon et al 2010); this may be because the loading test experiments are performed under dietary supplementation with a low-phe food.…”

“…Although this formulation has been used extensively in experimental studies, it has not been evaluated in formal clinical trials and was not recorded. A newer formulation of BH4 (sapropterin dihydrochloride, Kuvan ® ) for the treatment of PKU that is more stable at room temperature has been available in the USA and Europe (Burnett 2007) Burton et al 2011;Blau et al 2010;Vernon et al 2010;Trefz et al 2010). No serious adverse events with BH4 treatment were reported in medical literature (Belanger-Quintana et al 2005;Nielsen et al 2010); headache, upper respiratory tract infections, and rhinorrhea were the side effects observed in sapropterin-treated patients with PKU in clinical trials (Kuvan Trefz et al 2009a).…”

Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: A semi-mechanistically-based, nonlinear mixed-effect modeling

“…with our model, including all patients with blood Phe levels >180 µmol/L, was similar to that reported in a study of 24 patients with PKU that included adolescents with poor dietary control and neonates with HPA (50-54%) [29]. The better response observed in newborns may be because it is easier achieve compliance in infants than in older children.…”

Long-term treatment with tetrahydrobiopterin in phenylketonuria: Treatment strategies and prediction of long-term responders

“…In 1999, the treatment of PKU patients with tetrahydrobiopterin (BH4), the cofactor of PAH, has been described for the first time [2]. Since then, multiple studies reported on the effect of BH4 in PKU patients with PAH deficiency [3][4][5][6][7][8][9][10][11].…”