Heart and Muscle Metabolism in Barth Syndrome
Condition: Barth Syndrome
MeSH terms: Barth Syndrome; Syndrome
Study type: Observational

Summary: 
      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.
    

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.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Children and adults ages 8-35 yrs with Barth syndrome and healthy controls.
      
Biospecimen description: 
      Serum, skin biopsy, breath, urine
    
Keywords: barth syndrome; heart failure; mitochondria; metabolism; amino acid