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

NCT ID: NCT01603446

Last Updated: 2013-12-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-05-31
• Study Completion Date: 2013-12-31

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.

Conditions

MELAS Syndrome

Keywords

pediatric; MELAS; mechanism of action of L-arginine

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

L-Arginine

Intervention Type: DRUG

NOW® L-Arginine powder

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

L-Arginine

NOW® L-Arginine powder

Intervention Type: DRUG

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.

• Minimum Eligible Age: 17 Years
• Maximum Eligible Age: 23 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

The Hospital for Sick Children

OTHER

Sponsor Role: lead

Responsible Party

Ingrid Tein

Staff Neurologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ingrid Tein, MD

Role: PRINCIPAL_INVESTIGATOR

The Hospital for Sick Children

Locations

The Hospital for Sick Children

Toronto, Ontario, Canada

Countries

Canada

References

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.

Reference Type: DERIVED

PMID: 32881886 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25993630 (View on PubMed)

Other Identifiers

1000023405

Identifier Type: -

Identifier Source: org_study_id