Endothelial, Sympathetic, and Cardiac Function in Inherited (6R)-L-Erythro-5,6,7,8-Tetrahydro-L-Biopterin Deficiency

Background-(6R)-5,6,7,8-Tetrahydro-L-biopterin (BH4) is a cofactor for enzymes involved in catecholamine and nitric oxide generation whose synthesis is initiated by GTP cyclohydrolase I (GTPCH-1), encoded by GCH1. In the absence of a potent, specific GTPCH-1 inhibitor, natural BH4 deficiency caused by mutations in GCH1 in the rare movement disorder, DOPA-responsive dystonia (OMIM DYT5), offers the opportunity to study the role of endogenous BH4 in humans. Methods and Results-In 16 DOPA-responsive dystonia patients with mutations predicted to affect GTPCH-1 expression or function and in age-and sex-matched control subjects, we measured plasma biopterin and nitrogen oxides by high-performance liquid chromatography and the Griess reaction, respectively, endothelial function by brachial artery flow-mediated dilation (FMD), sympathetic function by measurement of plasma norepinephrine, epinephrine, and heart rate and blood pressure in response. Cardiac function and structure were assessed by echocardiography. Plasma biopterin was lower in patients (5.76 +/- 0.53 versus 8.43 +/- 0.85 nmol/L, P=0.03), but plasma NO(2)(-)/NO(3)(-) (NOx) (median, 9.06 [interquartile range, 5.35 to 11.04] versus 8.40 [interquartile range, 5.28 to 11.44] mu mol/L, P=1) and FMD were not lower (7.7 +/- 0.8% versus 7.9 +/- 0.9%, P=0.91). In patients but not control subjects, FMD was insensitive to nitric oxide synthase inhibition (FMD at baseline, 6.7 +/- 2.1%; FMD during L-NMMA infusion, 6.2 +/- 2.5, P=0.68). The heart rate at rest was higher in patients, but the heart rate and blood pressure response to sympathetic stimulation did not differ in patients and control subjects despite lower concentrations of norepinepherine (264 +/- 8 pg/mL versus 226 +/- 9 pg/mL, P=0.006) and epinephrine (33.8 +/- 5.2 pg/mL versus 17.8 +/- 4.6 pg/mL, P=0.03) in patients. There was also no difference in cardiac function and structure. Conclusions-Sympathetic, cardiac, and endothelial functions are preserved in patients with GCH1 mutations despite a neurological phenotype, reduced plasma biopterin, and norepinepherine and epinephrine concentrations. Lifelong endogenous BH4 deficiency may elicit developmental adaptation through mechanisms that are inaccessible during acquired BH4 deficiency in adulthood. (Circ Cardiovasc Genet. 2010;3:513-522.)