The main purpose of this study is to determine the safest maximum dose of an amino acid, citrulline, which will be used as potential treatment for adult patients with a disorder of energy metabolism called Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). Once established, this dose will be used in a future clinical trial.

The human body is made of many cells and each cell contains many mitochondria. Mitochondria are called the powerhouses of the cell, because they produce the energy needed for a cell to be healthy and function the way it is meant to.

Diseases of the mitochondria affect the way the tissues and cells of the body make and use energy, and can affect almost all the different organs of the body like the brain and the muscles.

MELAS syndrome is one of the mitochondrial diseases; patients with this disease have different complications including stroke like episodes, headache, muscle weakness, fatigue, and hearing loss. One of the factors contributing to complications seen in patients with MELAS syndrome, in particular the stroke like episodes, is decreased amount of an element called nitric oxide. This element is made in the bodies from an amino acid called arginine. Amino acids are the building blocks of proteins. Proteins make the muscles in the bodies, and they are present in meat, chicken and fish.

In this study, the highest acceptable dose of an amino acid called citrulline will be established in participants who have a mitochondrial disorder. Previous research conducted by several groups including Baylor College of Medicine has determined that there is a deficiency of a compound called nitric oxide in patients affected with MELAS.

The lack of nitric oxide could cause constriction of blood vessels in the brain making it easier for these patients to have a metabolic stroke. The amino acid citrulline is a foundation for nitric oxide. In earlier studies, the investigator has found that there is more production of nitric oxide in the body when participants affected with MELAS take L-citrulline.

Inclusion Criteria:

1. Clinical diagnosis of MELAS (stroke-like events, seizures, exercise intolerance or muscle weakness).
2. Subject must be aged 18 to 65 years.
3. The m.3243A>G mutation in the MTTL1 gene.
4. Elevated plasma lactate (>2.2 mmol/L) taken at any point in the screening period (6 months prior to screening visit, including and up to the baseline visit).
5. Negative urine pregnancy test, if applicable.
6. Score of 26 or higher on the Montreal Cognitive Assessment (MOCA). -

Exclusion Criteria:

1. Evidence of acute illness or physical disability that may interfere with their ability to undergo the study.
2. Tobacco use
3. Orthostatic hypotension defined as a decrease in systolic blood pressure of 20 mm Hg, or a decrease in diastolic blood pressure of 10 mm Hg, between one and three minutes of standing when compared with blood pressure from the sitting or supine position at the baseline visit.
4. Presence of the following signs or symptoms in the past 12 months at grade 3 or higher based on the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03: hypotension, syncope, dizziness, blurred vision, fatigue, concentration impairment, nausea, vomiting, diarrhea, hypoglycemia, or headache.
5. > 2 seizures in week prior to baseline visit.
6. Hypotension defined as systolic blood pressure ≤ 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg at the baseline visit.
7. Arginine supplementation within one week prior to baseline visit.
8. Inability to travel to the study site.
9. Subjects with no evidence of neurological disease, muscle weakness, or exercise intolerance.
10. Subjects with evidence of moderate to severe renal impairment ( eGFR < 60 mL/min/1.73 m2 ) at the baseline visit.
11. Subjects with poor cognitive ability to provide consent and to understand and report hypoglycemia.
12. Unwillingness of sexually active female subjects of childbearing age to practice reliable methods of contraception.
13. Intake of drugs that increase NO synthesis, vasodilators, or amino acid supplements that cannot be stopped during the study period.
14. Positive urine pregnancy test.
15. Score of less than 26 on the Montreal Cognitive Assessment (MOCA). -