Plasma concentration of
asymmetric dimethylarginine (ADMA), an endogenous inhibitor of
nitric oxide (NO) synthesis from
L-arginine and a cardiovascular risk factor, was found to be elevated in plasma of homocysteinemic adults. Enhanced cardiovascular risk due to
homocystinuria and impaired renal function has been found in patients with
phenylketonuria (PKU) on
protein-restricted diet. However, it is still unknown whether ADMA synthesis is also elevated in children with
homocystinuria due to
cystathionine beta-synthase deficiency (classical
homocystinuria), and whether ADMA may play a role in
phenylketonuria in childhood. In the present study, we investigated the status of the
L-arginine/NO pathway in six young patients with
homocystinuria, in 52 young
phenylketonuria patients on natural
protein-restricted diet, and in age- and gender-matched healthy children serving as controls. ADMA in plasma and urine was determined by GC-MS/MS. The NO metabolites
nitrate and
nitrite in plasma and urine, and urinary
dimethylamine (DMA), the
dimethylarginine dimethylaminohydrolase (DDAH) metabolite of ADMA, were measured by GC-MS. Unlike urine ADMA excretion, plasma ADMA concentration in patients with
homocystinuria was significantly higher than in controls (660±158 vs. 475±77 nM, P=0.035). DMA excretion rate was considerably higher in children with
homocystinuria as compared to controls (62.2±24.5 vs. 6.5±2.9 μmol/mmol
creatinine, P=0.068), indicating enhanced DDAH activity in this disease. In contrast and unexpectedly,
phenylketonuria patients had significantly lower ADMA plasma concentrations compared to controls (512±136 vs. 585±125 nM, P=0.009).
Phenylketonuria patients and controls had similar
L-arginine/ADMA molar ratios in plasma. Urinary
nitrite excretion was significantly higher in
phenylketonuria as compared to healthy controls (1.7±1.7 vs. 0.7±1.2 μmol/mmol
creatinine, P=0.003). Our study shows that the
L-arginine/NO pathway is differently altered in children with
phenylketonuria and
homocystinuria. Analogous to hyperhomocysteinemic adults, elevated ADMA plasma concentrations could be a cardiovascular risk factor in children with
homocystinuria. In
phenylketonuria, the
L-arginine/NO pathway seems not be altered. Delineation of the role of ADMA in childhood
phenylketonuria and
homocystinuria demands further investigation.