Abstract 1469: 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), synthesised from GTP by the rate-limiting enzyme GTP cyclohydrolase I (GTPCH-1), is a co-factor for nitric oxide and catecholamine synthesis. Acquired BH4 deficiency is involved in the endothelial dysfunction, the sympathetic regulation of vascular tone and may be associated with right ventricular hypertrophy. Lack of specific GTPCH-1 inhibitor, has limited understanding of the role of BH4 in vascular, sympathetic and cardiac function. Genetic deficiency of BH4 due to rare mutations in GTPCH-1 manifests as a movement disorder known as dopa responsive dystonia (DRD). Assessment of autonomic, cardiac and endothelial function in these patients could provide an insight into the neurovascular role of BH4.
Methods We measured plasma biopterin with HPLC, in 16 DRD patients and 16 age and sex matched controls. Endothelial function was assessed by flow-mediated dilatation (FMD) in presence and absence of NOS inhibitor of monomethyl-L-arginine (L-NMMA) 4μmol/ml infused intra-arterially. Sympathetic autonomic function was assessed by means of heart rate and blood pressure response to tilt, mental arithmetic, deep breathing, isometric exercise, and cold pressor stimuli. Plasma noradrenaline (NA) and Adrenaline (A) concentrations were also measured. Cardiac function was assessed by transthoracic echocardiography (TTE).
Results Plasma biopterin concentration was lower in DRD patients than controls (9.8[1.5] v 5.7[0.5] nmol/L; p=0.057). Despite this difference, FMD response was the same between the two groups (7.7[0.8]% v 7.8[0.9]%; p=0.9). However in DRD patients but not controls, FMD was insensitive to NOS inhibition. TTE and sympathetic responses did not differ in DRD patients and controls despite significantly lower concentrations of A (34.9 v 17.8 pg/ml; p=0.03) and NA (263 v 227 pg/ml; p=0.006).
Conclusion Sympathetic, cardiac function and endothelial function are preserved in patients with GTPCH-1 mutations despite the presence of a neurological phenotype, reduced plasma biopterin, A and NA concentrations. The presence of a non-NO dependent dilator response to flow suggests developmental adaptation involving up-regulation of other dilator systems in the DRD patients