New targets for monitoring and therapy in Barth syndrome

Thompson, William; DeCroes, Brittany; McClellan, Rebecca; Rubens, Jessica; Vaz, Frédéric M.; Kristaponis, Kara; Avramopoulos, Dimitrios; Vernon, Hilary J.

doi:10.1038/gim.2015.204

Cited by 36 publications

(42 citation statements)

References 40 publications

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“…; Thompson et al. ). Skeletal myopathy leads to easy fatigability, which is exaggerated by the cardiovascular complications associated with Barth syndrome (Spencer et al.…”

Section: Discussionmentioning

confidence: 97%

“…Most patients diagnosed with Barth syndrome are widely recognized by pronounced skeletal myopathy, low muscle mass, delayed gross motor development, exercise intolerance, and muscle weakness (Barth et al 1983;Spencer et al 2006;Thompson et al 2016). Skeletal myopathy leads to easy fatigability, which is exaggerated by the cardiovascular complications associated with Barth syndrome (Spencer et al 2011).…”

Section: Discussionmentioning

confidence: 99%

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Drosophila tafazzinmutants have impaired exercise capacity

2018

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Cardiolipin (CL) is a mitochondrial phospholipid that helps maintain normal structure of the inner mitochondrial membrane and stabilize the protein complexes of the electron transport chain to promote efficient ATP synthesis. Tafazzin, an acyl‐transferase, is required for synthesis of the mature form of CL. Mutations in the tafazzin (TAZ) gene are associated with a human disorder known as Barth syndrome. Symptoms of Barth syndrome often include muscle weakness and exercise intolerance. Previous work demonstrates that Drosophila Taz mutants exhibit motor weakness, as measured by reduced flying and climbing abilities. However, Drosophila TAZ mutants’ baseline endurance or response to endurance exercise training has not been assessed. Here, we find that TAZ mutants have reduced endurance and do not improve following a stereotypical exercise training paradigm, indicating that loss of TAZ function leads to exercise intolerance in Drosophila. Although cardiac phenotypes are observed in human Barth syndrome patients, TAZ mutants had normal resistance to cardiac pacing. In the future, endurance may be a useful screening tool to identify additional genetic modifiers of tafazzin.

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“…; Thompson et al. ). Skeletal myopathy leads to easy fatigability, which is exaggerated by the cardiovascular complications associated with Barth syndrome (Spencer et al.…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Drosophila tafazzinmutants have impaired exercise capacity

2018

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“…) that can unpredictably decline and improve throughout childhood, adolescence and young adulthood (Thompson et al. ). In this study, we found impaired cardiac bioenergetic reserve (i.e., PCr/ATP) in both children/adolescents and adults with BTHS.…”

Section: Discussionmentioning

confidence: 99%

“…; Thompson et al. ). In addition, cardiac bioenergetics have been shown to respond favorably to interventions (Spoladore et al.…”

Section: Introductionmentioning

confidence: 97%

“…Reduced PCr/ATP ratio is characteristic of failing myocardium (Conway et al 1991) and represents a reduced capacity or reserve to provide ATP to the working heart, especially during stressed conditions (Nascimben et al 1996;Smith et al 2006). Skeletal muscle and cardiac bioenergetics might be useful biomarkers or outcome measures for prospective studies and clinical trials in BTHS as individuals with BTHS frequently have normal resting cardiac function without a predictable natural history (Spencer et al 2006;Thompson et al 2016). In addition, cardiac bioenergetics have been shown to respond favorably to interventions (Spoladore et al 2013) and to be useful predictors of cardiovascular and all-cause mortality in patients with non-BTHS heart failure (Neubauer et al 1997).…”

Section: Introductionmentioning

confidence: 99%

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Impaired cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with Barth syndrome

Bashir

Bohnert

Reeds

et al. 2017

Physiological Reports

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Barth syndrome (BTHS) is an X‐linked condition characterized by altered cardiolipin metabolism and cardioskeletal myopathy. We sought to compare cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardiac function and exercise capacity. Children/adolescents and young adults with BTHS (n = 20) and children/adolescent and young adult control participants (n = 23, total n = 43) underwent 31P magnetic resonance spectroscopy (31P‐MRS) of the lower extremity (calf) and heart for estimation of skeletal muscle and cardiac bioenergetics. Peak exercise testing (VO 2peak) and resting echocardiography were also performed on all participants. Cardiac PCr/ATP ratio was significantly lower in children/adolescents (BTHS: 1.5 ± 0.2 vs. Control: 2.0 ± 0.3, P < 0.01) and adults (BTHS: 1.9 ± 0.2 vs. Control: 2.3 ± 0.2, P < 0.01) with BTHS compared to Control groups. Adults (BTHS: 76.4 ± 31.6 vs. Control: 35.0 ± 7.4 sec, P < 0.01) and children/adolescents (BTHS: 71.5 ± 21.3 vs. Control: 31.4 ± 7.4 sec, P < 0.01) with BTHS had significantly longer calf PCr recovery (τ PCr) postexercise compared to controls. Maximal calf ATP production through oxidative phosphorylation (Qmax‐lin) was significantly lower in children/adolescents (BTHS: 0.5 ± 0.1 vs. Control: 1.1 ± 0.3 mmol/L per sec, P < 0.01) and adults (BTHS: 0.5 ± 0.2 vs. Control: 1.0 ± 0.2 mmol/L sec, P < 0.01) with BTHS compared to controls. Blunted cardiac and skeletal muscle bioenergetics were associated with lower VO2peak but not resting cardiac function. Cardiac and skeletal muscle bioenergetics are impaired and appear to contribute to exercise intolerance in BTHS.

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Clinical presentation and natural history of Barth Syndrome: An overview

Taylor

Rao

Pierre

et al. 2021

J of Inher Metab Disea

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Barth Syndrome is a rare X‐linked disorder caused by pathogenic variants in the gene TAFAZZIN, which encodes for an enzyme involved in the remodeling of cardiolipin, a phospholipid primarily localized to the inner mitochondrial membrane. Barth Syndrome is characterized by cardiomyopathy, skeletal myopathy, neutropenia, and growth abnormalities, among other features. In this review, we will discuss the clinical presentation and natural history of Barth Syndrome, review key features of this disease, and introduce less common clinical associations. Recognition and understanding of the natural history of Barth Syndrome are important for ongoing patient management and developing endpoints for the demonstration of efficacy of new and emerging therapies.

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New targets for monitoring and therapy in Barth syndrome

Cited by 36 publications

References 40 publications

Drosophila tafazzinmutants have impaired exercise capacity

Drosophila tafazzinmutants have impaired exercise capacity

Impaired cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with Barth syndrome

Clinical presentation and natural history of Barth Syndrome: An overview

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