Arginine to ornithine ratio as a diagnostic marker in patients with positive newborn screening for hyperargininemia

Abstract

Arginase deficiency is a rare inborn error of metabolism that interrupts the final step of the urea cycle. Untreated individuals often present with episodic hyperammonemia, developmental delay, cognitive impairment, and spasticity in early childhood. The newborn screening (NBS) algorithms for arginase deficiency vary between individual states in the US but often include hyperargininemia and elevated arginine to ornithine (Arg/Orn) ratio. Here, we report 14 arginase deficiency cases, including two patients with positive NBS for hyperargininemia in whom the diagnosis of arginase deficiency was delayed owing to normal or near normal plasma arginine levels on follow-up testing. To improve the detection capability for arginase deficiency, we evaluated plasma Arg/Orn ratio as a secondary diagnostic marker in positive NBS cases for hyperargininemia. We found that plasma Arg/Orn ratio combined with plasma arginine was a better marker than plasma arginine alone to differentiate patients with arginase deficiency from unaffected newborns. In fact, elevated plasma arginine in combination with an Arg/Orn ratio of ≥1.4 identified all 14 arginase deficiency cases. In addition, we examined the impact of age on plasma arginine and ornithine levels. Plasma arginine increased 0.94 μmol/L/day while ornithine was essentially unchanged in the first 31 days of life, which resulted in a similar increasing trend for the Arg/Orn ratio (0.01/day). This study demonstrated that plasma Arg/Orn ratio as a secondary diagnostic marker improved the detection capability for arginase deficiency in newborns with hyperargininemia, which will allow timely detection of arginase deficiency and hence initiation of treatment before developing symptoms.

Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS

“…Another example is the detection of arginase deficiency. Since implementing the use of the ratio Arg/Orn as the main marker for the screening of this disease, the number of FP cases has dramatically decreased, as hyperargininemia resulting from secondary causes (i.e., dietary intake, such as parenteral nutrition [ 31 ]) could be excluded.…”

Mass spectrometry-based metabolomics study of nicotine exposure in THP-1 monocytes

“…Both the absolute and relative levels of several amino acids were signi cantly affected by nicotine exposure (Tables S5a, S5b and S6a). Short-term disturbance of the urea cycle following nicotine exposure was indicated by signi cant effects on the proline-to-citrulline and arginine-toornithine ratio 49,50 . This was detected both in the cell and medium extracts in case of the arginine-to-ornithine ratio, whereas the effect on the proline-tocitrulline ratio was only detected in the medium.…”

Exogenous Proline Optimizes Osmotic Adjustment Substances and Active Oxygen Metabolism of Maize Embryo under Low-Temperature Stress and Metabolomic Analysis

“…At the same time, the ornithine cycle can detoxify ammonia and store ammonia. The ornithine cycle is also linked to the TCA pathway through fumaric acid, which is released to supplement the TCA cycle [93]. Glycine is an effective nitrogen source, which can be transformed into pyruvate and enter the TCA cycle as an amino acid skeleton [94].…”