TABLE 1.

Summary of previous studies evaluating the use of Nitric Oxide precursors in patients with mitochondrial disorders.

Authors	Study population	Intervention	Outcome
Koga et al. (2002)	Three patients with MELAS with a total of 16 stroke-like episodes	IV arginine (0.5 g/kg) or placebo administrated within 1 h of onset of stroke-like symptoms	Stroke-like episodes associated symptoms responded to arginine treatment Improved microcirculation as measured by SPECT
Koga et al. (2005)	24 patients with MELAS with total of 34 stroke-like episodes and 72 control subjects	IV arginine (0.5 g/kg) or placebo administrated within 1 h of onset of stroke-like symptoms Six patients were treated by oral administration of oral arginine (0.15–0.3 g/kg/d for 18 months) to prevent stroke-like episodes	All symptoms suggesting stroke dramatically improved Concentrations of lactate and pyruvate, L-arginine, L-citrulline, NO, cGMP, and ADMA returned to interictal-phase concentrations within 24 h After oral arginine supplementation, the frequency and severity of symptoms caused by the stroke decreased dramatically (p < 0.05)
Kitamura et al. (2016)	Two patients with MELAS	IV arginine infusion at acute phase of stroke-like episodes	Resolution of the transient changes observed in brain MRI within 1 week
Koga et al. (2018)	15 patients with MELAS	IV arginine administered within six 6 h of stroke-like episodes in 10 patients Oral administration of arginine at a dose of 0.3–0.5 g/kg/day orally in three divided doses for 2 years to 13 patients	The statistical hypothesis that “the rate of improvement in headache and nausea/vomiting at 2 h after completion of the initial intravenous administration is greater than 30%” was not achieved. Nevertheless, the improvement rates increased with time Chronic arginine administration was not associated with a statistically significant difference in MELAS stroke scale, mitochondrial disease severity scores, or migraine severity score The interictal phases were extended after arginine treatment The maximum plasma arginine concentration was 167 μmol/L when seizures developed
Koga et al. (2006)	15 patients with MELAS and 20 controls	IV arginine (0.5 g/kg)or placebo 0.15–0.3 g/kg/day oral arginine for 24 months.	Two hours after arginine loading, there was no improvement in FMD values in the controls but the values in MELAS patients improved (p < 0.05) FMD values after 2 years of arginine supplementation improved compared to the original values (p < 0.05) and returned to control levels in all MELAS patients
El-Hattab et al. (2012)	10 adults subjects with MELAS and 10 control subjects	Oral arginine (10 g/m2 body surface area/day divided every 4 h for 48 h). Oral citrulline (10 g/m2 body surface area/day divided every 4 h for 48 h).	Increase in plasma arginine and citrulline concentration, increased NO synthesis, increased de novo arginine synthesis (P < 0.05) Citrulline supplementation at the same dose resulted in greater increase in NO synthesis
El-Hattab et al. (2016)	Five children subjects with MELAS and Five control subjects	Oral arginine (10 g/m2 body surface area/day divided every 4 h for 48 h). Oral citrulline (10 g/m2 body surface area/day divided every 4 h for 48 h).	NO production rate increased with arginine (p < 0.05) and to a greater extent with citrulline (p < 0.001) supplementations Plasma arginine concentration increased with arginine (p < 0.001) and citrulline (p < 0.001) supplementations Plasma citrulline concentration did not change with arginine but increased with citrulline (p < 0.05) supplementation
Rodan et al. (2020)	Three siblings with MELAS and four healthy controls	Single dose of oral arginine (100 mg/kg) 6 week oral arginine (100 mg/kg three times daily)	CVR in MELAS subjects after single dose and 6-week arginine course was not significantly different, but there was a trend towards increasing CVR in the frontal cortex and a decrease in the occipital cortex A 29–37% reduction in baseline CBF in one patient following 6 weeks of arginine with a marked increase in functional MRI activation in response to visual cortex toward control values following a single dose and 6 weeks of arginine in the same patient
Al Jasmi et al. (2020)	Nine individuals with variable mitochondrial diseases, less than 18 years of age	Arginine or citrulline (500 mg/kg/day if weight is < 20 kg and 10 g/m2/day if weight is ≥ 20 kg) for 2 weeks followed by 2 weeks washout period and then subjects were crossed over to the other intervention	Average RHI increased 15% and 19% with arginine and citrulline supplementation, respectively

CBF, cerebral blood flow; CVR, cerebrovascular reactivity; FMD, flow-mediated vasodilation; RHI, reactive hyperemic index; SPECT, single-photon emission computed tomography.