Heart and Muscle Metabolism in Barth Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2012 by Washington University School of Medicine
Sponsor:
Collaborator:
University of Florida
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01625663
First received: June 19, 2012
Last updated: June 21, 2012
Last verified: June 2012
  Purpose

Barth syndrome (BTHS) is an X-linked disorder caused by abnormal cardiolipin metabolism and is characterized by skeletal and cardiomyopathy and high mortality rates. Through clinical metabolism and imaging studies and pluripotent stem cell induction and molecular techniques on skin biopsy samples, this project will produce novel translational information regarding the pathogenesis of BTHS, reveal potential targets for interventions and provide unique data regarding nutrient metabolism and abnormal cardiolipin and mitochondrial function. This project has the potential to provide information that could significantly improve morbidity and mortality in children and young adults with BTHS and may have relevance to other non-BTHS related conditions such as aging and adult heart failure.


Condition
Barth Syndrome

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Cross-Sectional
Official Title: Heart and Skeletal Muscle Metabolism, Energetics and Function in Barth Syndrome

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Whole-body fatty acid oxidation rate [ Time Frame: baseline ] [ Designated as safety issue: No ]
    Whole-body fatty acid oxidation rate will be measured by 13C-labeled fatty acid stable isotope tracer infusion and mass spectrometry

  • Myocardial fatty acid oxidation rate [ Time Frame: baseline ] [ Designated as safety issue: No ]
    Myocardial fatty acid oxidation rate will be measured by radio-isotope tracer infusion and PET imaging

  • left ventricular systolic strain [ Time Frame: baseline ] [ Designated as safety issue: No ]
    Left ventricular systolic strain will be measured by tissue Doppler echocardiography


Secondary Outcome Measures:
  • whole-body amino acid oxidation rate [ Time Frame: baseline ] [ Designated as safety issue: No ]
    whole-body amino acid oxidation rate will be measured by 13C leucine stable isotope tracer infusion and mass spectrometry

  • cardiac energetics [ Time Frame: baseline ] [ Designated as safety issue: No ]
    cardiac energetics will be measured by 31P magnetic resonance spectroscopy of the heart

  • skeletal muscle energetics [ Time Frame: baseline ] [ Designated as safety issue: No ]
    skeletal muscle energetics will be measured by 31P magnetic resonance spectroscopy


Biospecimen Retention:   Samples With DNA

Serum, skin biopsy, breath


Estimated Enrollment: 60
Study Start Date: June 2012
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Groups/Cohorts
Barth syndrome
Children (8-17 yrs) and adults (18-35 yrs)
Controls
Children (8-15 yrs) and adults (18-35 yrs)

Detailed Description:

Barth syndrome (BTHS) is an X-linked disorder characterized by abnormal cardiolipin metabolism, mitochondrial dysfunction, muscle wasting and heart failure. BTHS is a particularly significant disease as it is often fatal in childhood and there are no approved therapies for BTHS other than the standard treatment of heart failure. Therefore novel areas of research and platforms in which to test new therapies are highly needed. Through state-of-the-art and innovative methodologies, this project will focus on the novel role of skeletal muscle and heart nutrient (glucose, fatty acid, and amino acid) metabolism in the pathogenesis of BTHS. Phenotypic information regarding skeletal muscle and heart nutrient metabolism in BTHS and how it may relate to energy production and function of these organs is lacking and is significant as this may advance our understanding of the underlying pathogenesis of BTHS. With this understanding, safe and efficacious therapies can be targeted for BTHS. The investigators' overall hypothesis is that impaired fatty acid metabolism in skeletal muscle and the heart produces a fuel deficit in these organs leading to impaired energy production, exercise intolerance and heart failure. Further, as a consequence of impaired fatty acid metabolism in skeletal muscle and the heart, protein breakdown (wasting) in skeletal muscle and the heart occurs to provide amino acids as compensation for this inadequate fatty acid energy supply, thereby worsening heart and skeletal muscle function in BTHS. The investigators' aims to address this hypothesis in 30 young adults and children with BTHS and 30 healthy, age, puberty stage and activity level matched controls ages 8-35 years are:

1) To characterize skeletal muscle and heart nutrient metabolism and 2) To examine the relationship between skeletal muscle and heart nutrient metabolism, energy production and function (exercise tolerance and heart function). As an exploratory aim, we will examine mechanistic molecular pathways of nutrient metabolism; specifically protein breakdown, mitochondrial function and fatty acid metabolism, in human myocytes derived from inducible pluripotent stem cells (from skin fibroblasts) obtained from adults and children with BTHS and from adult controls. Skeletal muscle nutrient metabolism will be quantified by stable-isotope tracer methodology and mass spectrometry, heart nutrient metabolism using radio-isotope tracer methodology and PET imaging, skeletal muscle and heart energy production using magnetic resonance spectroscopy, skeletal muscle function by graded exercise testing and indirect calorimetry, heart function by echocardiography, and myocyte nutrient pathway mechanism examination by pluripotent stem cell induction and protein and RNA expression analyses.

  Eligibility

Ages Eligible for Study:   8 Years to 35 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Children and adults ages 8-13 yrs with Barth syndrome and healthy controls.

Criteria

Inclusion Criteria:

  1. confirmed diagnosis of BTHS or healthy control
  2. age 8-35 years
  3. sedentary (physically active less than 2x/wk)
  4. stable on medications for ≥ 3 months including ß-blockers, ACE inhibitors, digoxin
  5. lives in North America, the UK, Europe, South Africa or other locations feasible for travel to the US

Exclusion Criteria:

  1. current unstable heart disease
  2. diabetes or other known concurrent disease that may affect nutrient metabolism
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01625663

Contacts
Contact: William T Cade, PT, PhD 314-286-1432 tcade@wustl.edu
Contact: Kay Bohnert, MS 314-362-2407 bohnertk@wusm.wustl.edu

Locations
United States, Missouri
Washington University Recruiting
St. Louis, Missouri, United States, 63110
Principal Investigator: William T Cade, PT, PhD         
Sponsors and Collaborators
Washington University School of Medicine
University of Florida
Investigators
Principal Investigator: William T Cade, PT, PhD Washington University Early Recognition Center
  More Information

No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01625663     History of Changes
Other Study ID Numbers: 201202004
Study First Received: June 19, 2012
Last Updated: June 21, 2012
Health Authority: United States: Data and Safety Monitoring Board

Keywords provided by Washington University School of Medicine:
barth syndrome
heart failure
mitochondria
metabolism
amino acid

Additional relevant MeSH terms:
Syndrome
Barth Syndrome
Disease
Pathologic Processes
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Metabolic Diseases

ClinicalTrials.gov processed this record on September 18, 2014