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

Phase 2

Completed

• Conditions: MELAS Syndrome
• Interventions: Drug: L-Arginine

• Registration Number: NCT01603446
• Lead Sponsor: The Hospital for Sick Children

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.

Study Timeline

• Study Start: 2012-05
• Study First Submitted: 2012-05-18
• Study First Submitted QC: 2012-05-21
• Study First Posted: 2012-05-22
• Primary Completion: 2013-05
• Status Verified: 2013-12
• Study Completion: 2013-12
• Last Update Submitted: 2013-12-13
• Last Update Posted: 2013-12-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 7

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MELAS Patients	L-Arginine	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.

Primary Outcome Measures

Name	Time	Method
Muscle function investigation via 31P-Magnetic resonance spectroscopy	60 to 105 minutes post dose	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.

Secondary Outcome Measures

Name	Time	Method
Total body maximal aerobic capacity	60-75 mins post dose	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..
CerebroVascular Reactivity	75-105 mins post dose	Functional MRI-Blood oxygen level dependent (BOLD) of brain
Exhaled Nitric Oxide (eNO)	75 mins pre dose, 75 mins post dose	eNO will be measured using single breath on-line measurements for the assessment of lower airway Nitric Oxide

Trial Locations

Locations (1)

The Hospital for Sick Children; 🇨🇦 Toronto, Ontario, Canada