Heart and Muscle Metabolism in Barth Syndrome

Age Range:8 - 35
Start Date:June 2012
End Date:July 2019
Contact:William T Cade, PT, PhD

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Heart and Skeletal Muscle Metabolism, Energetics and Function in Barth Syndrome

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.

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

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

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
We found this trial at
Saint Louis, Missouri 63110
Principal Investigator: William T Cade, PT, PhD
Saint Louis, MO
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