Assessment of tetrahydrobiopterin (BH(4))-responsiveness and spontaneous phenylalanine reduction in a phenylalanine hydroxylase deficiency population.

A BH(4) loading test was performed in 36 patients from 34 unrelated families. The patients had 29 different genotypes, and previous data on only eight of them were found in the BIOPKU database. Thirteen patients were classified as classic PKU (35.1%), 14 as mild PKU (37.8%) and 9 as MHP (27.0%). Blood Phe levels were shown to reach a plateau after three full days of increased natural protein ingestion. Measuring the 24-hour blood Phe levels (T(-24), T(-16), T(0)) on the fourth day of increased protein ingestion before BH(4) administration showed that within 24h Phe on average increased by 2.4% in MHP patients, decreased by 2.7% in mild PKU patients and increased by 9.7% in classic PKU patients (NS for all comparisons); Phe only slightly decreased in responders by 0.2% but increased in non-responders by 7.8% (P>0.05). Altogether, 16 of 36 (44.4%) patients represented by 12 of 29 (41.4%) different genotypes were proven to be BH(4) responders, and four (10.8%) were slow-responders. Responders were 6/9 (66.7%) MHP patients, 10/14 (71.4%) mild PKU patients and 0/13 classic PKU patients. Twenty of the 29 (68.9%) genotypes harbored at least one mutation with a known PRA of 10% or more but only 11 (55%) of them were BH(4)-responsive. Spontaneous reduction of blood Phe levels within 24h on the fourth day of natural protein loading was observed only in mild PKU patients and was shown not to be an important part of the BH(4)-response. 73.3% of genotypes containing at least one allele with a PRA of at least 30% were found to be BH(4) responsive; a PRA of at least 15.5% was needed for the responder genotype in our population.