Clinical trial NCT01603446: L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome
Official title: Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: MELAS Syndrome
Keywords: pediatric
MELAS
mechanism of action of L-arginine
Lead sponsor: The Hospital for Sick Children
Sponsor class: OTHER
First posted: 2012-05-22
Enrollment: 7
Sex: ALL
Minimum age (years): 17
Maximum age (years): 23
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: MELAS patients suffer from exercise intolerance, weakness, poor vision or blindness, poor growth, developmental delay, and deafness. They also have unique 'stroke-like' episodes (SLEs) which are not due to blockages of large or medium arteries. These 'strokes' are thought to be due to energy failure of very small brain blood vessels combined with energy failure in the mitochondria (cell battery) of the brain cells, especially in the back region of the brain in the vision centre. This leads to visual loss and paralysis. The overall goal of this study is to better understand the mechanism of these SLEs at the level of the brain cells and small blood vessels.

Detailed description: We will study a family of 3 siblings, each with different severities of MELAS, using safe, non-invasive tests. We will determine whether there is a decrease in the ability of small brain blood vessels to increase blood flow by dilating in response to certain stimuli such as increased blood carbon dioxide levels or in response to brain cell activation in the vision centre by visual stimuli. We will use a technique called BOLD-fMRI which can detect changes in brain blood flow. As exercising muscle also depends on increased blood flow and mitochondrial energy, we will study different measures of aerobic energy metabolism in exercising muscle using cycle exercise testing and special phosphorus-magnetic resonance spectroscopy which measures the changes in the major chemicals of muscle energy metabolism. The dietary amino acid L-arginine is known to dilate blood vessels increasing blood flow and to decrease toxic free radicals that are generated by dysfunctional mitochondria. We will determine the effect of a single dose and a 6 week trial of oral L-arginine, on brain blood vessel reactivity, brain cell activation and muscle aerobic function to see how useful this would be in the treatment of these patients and other mitochondrial disorders which present with strokes.

Eligibility criteria: Inclusion Criteria:

Experimental Siblings with MELAS (A3243G) syndrome

* 17-23 years
* Followed Neurometabolic Clinic at the Hospital for Sick Children will be studied.
* Normal electrolytes, glucose, renal and liver functions \& no history of gastrointestinal, respiratory or cardiac problems.

Controls

-Aged 17-23- Sex matched to the MELAS subjects

Exclusion Criteria:

Controls

* Experience migraines
* Have a metabolic disorder
* Taking medications predisposing to lactic acidosis or vasodilatation
* Neuromuscular/neurologic condition
* Cardiac or pulmonary disease
* Visual abnormalities
* Hypertension, anemia and prothrombotic state. Control subjects
* Contraindication for MRI (pacemaker, ocular metal, claustrophobia, tattoos) will be excluded from the study.

Primary outcomes:
measure: Muscle function investigation via 31P-Magnetic resonance spectroscopy
timeFrame: 60 to 105 minutes post dose
Secondary outcomes:
measure: Total body maximal aerobic capacity
timeFrame: 60-75 mins post dose
measure: CerebroVascular Reactivity
timeFrame: 75-105 mins post dose
measure: Exhaled Nitric Oxide (eNO)
timeFrame: 75 mins pre dose, 75 mins post dose
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: The Hospital for Sick Children
name: Ingrid Tein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rodan LH, Poublanc J, Fisher JA, Sobczyk O, Mikulis DJ, Tein I. L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome. PLoS One. 2020 Sep 3;15(9):e0238224. doi: 10.1371/journal.pone.0238224. eCollection 2020.
citation: Rodan LH, Wells GD, Banks L, Thompson S, Schneiderman JE, Tein I. L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-Like Episodes) Syndrome. PLoS One. 2015 May 20;10(5):e0127066. doi: 10.1371/journal.pone.0127066. eCollection 2015.