L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome

Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.

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.

Study Overview

• Status: Completed
• Conditions: MELAS Syndrome
• Intervention / Treatment: Drug: L-Arginine

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5V1X8
      • The Hospital For Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 23 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MELAS Patients; Three siblings with MELAS (A3243G) syndrome (1 male; 2 females) aged 17-23 years, followed or previously followed in the Neurometabolic Clinic at the Hospital for Sick Children will be studied.	Drug: L-Arginine; NOW® L-Arginine powder
No Intervention: Control Group; Four age- and sex-matched controls and female controls will be matched according to phase in menstrual cycle corresponding with their age-matched MELAS subjects

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle function investigation via 31P-Magnetic resonance spectroscopy	We will study exercising quadriceps using our MR-compatible up-down ergometer and our well established aerobic exercise protocol at 65 % of maximal voluntary contraction.	60 to 105 minutes post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total body maximal aerobic capacity	Maximal incremental cycle ergometry is conducted in our CardioRespiratory Exercise Lab at HSC by our established protocols (26). Serum CK and quantitative AA (for arginine, ornithine and citrulline) will be measured pre- and post- exercise as well as eNO in order to correlate aerobic exercise parameters with serum arg and eNO levels..	60-75 mins post dose
CerebroVascular Reactivity	Functional MRI-Blood oxygen level dependent (BOLD) of brain	75-105 mins post dose
Exhaled Nitric Oxide (eNO)	eNO will be measured using single breath on-line measurements for the assessment of lower airway Nitric Oxide	75 mins pre dose, 75 mins post dose

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Investigators: Principal Investigator: Ingrid Tein, MD, The Hospital For Sick Children

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: May 18, 2012
• First Submitted That Met QC Criteria: May 21, 2012
• First Posted (Estimate): May 22, 2012

Study Record Updates

• Last Update Posted (Estimate): December 17, 2013
• Last Update Submitted That Met QC Criteria: December 13, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: pediatric; MELAS; mechanism of action of L-arginine
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Mitochondrial Diseases; Brain Diseases, Metabolic, Inborn; Cerebral Small Vessel Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Syndrome; MELAS Syndrome
• Other Study ID Numbers: 1000023405