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NCT Number: NCT01603446

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.

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Key information

Conditions

MELAS Syndrome Brain Diseases Brain Diseases, Metabolic Brain Diseases, Metabolic, Inborn Cardiovascular Diseases Central Nervous System Diseases Cerebral Small Vessel Diseases Cerebrovascular Disorders Congenital, Hereditary, and Neonatal Diseases and Abnormalities Genetic Diseases, Inborn Metabolic Diseases Metabolism, Inborn Errors Mitochondrial Diseases Mitochondrial Encephalomyopathies Mitochondrial Myopathies Muscular Diseases Musculoskeletal Diseases Nervous System Diseases Neuromuscular Diseases Nutritional and Metabolic Diseases Vascular Diseases

Age range

17 year–23 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

The Hospital for Sick Children

Toronto, Ontario, M5V1X8, Canada

About this study

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.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

L-arginine

Drug

NOW® L-Arginine powder

Primary outcomes

  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 outcomes

  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

Sponsors and collaborators

Lead sponsor

The Hospital for Sick Children

Other

Registry information

Official study title

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

Important dates

Study start
2012
Primary completion
2013
Study completion
2013
First posted
May 22, 2012
Registry last updated
Dec 17, 2013

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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