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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01603446
Recruitment Status : Completed
First Posted : May 22, 2012
Last Update Posted : December 17, 2013
Information provided by (Responsible Party):
Ingrid Tein, 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.

Condition or disease Intervention/treatment Phase
MELAS Syndrome Drug: L-Arginine Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Study to Investigate the Efficacy of L-arginine Therapy on Endothelium-dependent Vasodilation & Mitochondrial Metabolism in MELAS Syndrome.
Study Start Date : May 2012
Actual Primary Completion Date : May 2013
Actual Study Completion Date : December 2013

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

Primary Outcome Measures :
  1. Muscle function investigation via 31P-Magnetic resonance spectroscopy [ Time Frame: 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 :
  1. Total body maximal aerobic capacity [ Time Frame: 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..

  2. CerebroVascular Reactivity [ Time Frame: 75-105 mins post dose ]
    Functional MRI-Blood oxygen level dependent (BOLD) of brain

  3. Exhaled Nitric Oxide (eNO) [ Time Frame: 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

Information from the National Library of Medicine

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Ages Eligible for Study:   17 Years to 23 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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.


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

Exclusion Criteria:


  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01603446

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Canada, Ontario
The Hospital for Sick Children
Toronto, Ontario, Canada, M5V1X8
Sponsors and Collaborators
The Hospital for Sick Children
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Principal Investigator: Ingrid Tein, MD The Hospital for Sick Children

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Ingrid Tein, Staff Neurologist, The Hospital for Sick Children Identifier: NCT01603446     History of Changes
Other Study ID Numbers: 1000023405
First Posted: May 22, 2012    Key Record Dates
Last Update Posted: December 17, 2013
Last Verified: December 2013
Keywords provided by Ingrid Tein, The Hospital for Sick Children:
mechanism of action of L-arginine
Additional relevant MeSH terms:
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MELAS Syndrome
Pathologic Processes
Mitochondrial Encephalomyopathies
Mitochondrial Myopathies
Muscular Diseases
Musculoskeletal Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Cerebral Small Vessel Diseases
Cerebrovascular Disorders
Neuromuscular Diseases
Vascular Diseases
Cardiovascular Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Mitochondrial Diseases