Abstract
Background. The diagnosis of autosomal dominant GTP-cyclohydrolase deficiency relies on the examination of the GCH1 gene and/or pterins and neurotransmitters in CSF. The aim of the study was to assess the diagnostic value, if any, of pterins in urine and blood phenylalanine (Phe) and tyrosine (Tyr) under oral Phe loading test. Methods. We report on two new pedigrees with four symptomatic and four asymptomatic carriers whose pattern of urinary pterins and blood Phe/Tyr ratio under oral Phe loading pointed to GTP-cyclohydrolase deficiency. The study was then extended to 3 further patients and 90 controls. The diagnostic specificity and sensitivity of these metabolic markers were analysed by backwards logistic analysis. Results. Two genetic alterations segregated alternatively in Family 1 (c.631-632 del AT and c.671A > G), while exon 1 deletion was transmitted along three generations in Family 2. Neopterin and biopterin concentrations in urine clustered differently in controls under and over the age of 15. Therefore patients and controls were sub grouped according to this age. Neopterin was significantly reduced in GCH1 mutated subjects younger than 15, and both neopterin and biopterin in those older than 15. Moreover, the Phe/Tyr ratios at the second and third hour were both significantly higher in patients than in controls. Backwards logistic regression demonstrated the high diagnostic sensitivity and specificity of combined values of neopterin concentration and Phe/Tyr ratio at the second hour. Conclusions. Pterins in urine and Phe loading test are non-invasive and reliable tools for the biochemical diagnosis of GTP-cyclohydrolase deficiency.