**7. Barth Syndrome**

– dehydrogenase, isocitrate dehydrogenase and α BTHS patients have a quite variable clinical presentation of cardiomyopathy ranging from milder cases to severe cases, which require cardiac transplantation. BTHS patients present with a dilated or hypertrophic cardiomyopathy and left ventricular non-compaction [109–112]. The left ventricular ejection fraction (LVEF) was only moderately reduced—50 ± 10% (normal LVEF 50–70%, mild dysfunction LVEF 40–49%, moderate dysfunction LVEF 30–39% and severe dysfunction LVEF <30%) [111,112]. Despite preserved LVEF, many patients show an inability to increase cardiac output during exercise [113]. A very common symptom is skeletal muscle fatigue and exercise intolerance [110,113]. BTHS patients also manifest metabolic abnormalities in the degradation pathway of branched amino acids and show lactic acidosis during exercise as well as an elevated excretion of 3-Methylglutaconic acid (3-MGA) in urine [113,114] (Figure 5). Defects in the immune system include persistent or intermittent neutropenia causing recurrent infections. A growth deficiency during childhood is compensated by a delayed growth spurt after 12–14 years of age in BTHS [111,112,115].

– BTHS is frequently associated with a severe exercise intolerance, which makes it difficult to perform activities of daily living and drastically reduces quality of life. Skeletal muscle impairments include harmed functional exercise capacity, diminished extensor strength, and lowered daily activity [116]. Exercise intolerance is thought to be a consequence of cardiac impairment and decreased skeletal muscle oxygen utilization [113]. Changes in CL levels also in the skeletal muscle of Barth syndrome patients cause the destabilization of respirasomes, reduction in respiration, excessive production of reactive oxygen, abnormal mitochondrial morphology and defects in ATP production [115,117,118]. The development of a cardiac-specific knockout model recapitulated cardiomyopathy with reduced

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fractional shortening, increased hypertrophy and left ventricular dilatation. A constitutive knockout of Taz, however, resulted in very poor survival. Interestingly, the low survival rates were rescued, upon skeletal muscle-specific virus transmitted gene replacement therapy, indicating a particular contribution of skeletal myopathy to the reduced survival of the mice [39].

**Figure 5.** Clinical alterations, caused by a defect in the CL pool: Colors indicate clinical symptoms matching Sengers syndrome (blue), Barth syndrome (yellow) and dilated cardiomyopathy with ataxia (DCMA, green).

Using <sup>31</sup>P nuclear magnetic resonance (NMR) spectroscopy, a higher content of glycolytic fibers (type 2, fast-twitch) and a smaller fraction of oxidative fibers (type 1, slow-twitch) has been documented in the skeletal muscle of BTHS patients [119,120]. This finding suggests that BTHS patients rely on glycolytic metabolism to a greater extent than control individuals. Moreover, a higher respiratory exchange ratio during exercise and a greater glucose rate of disposal during a hyperinsulinemic–euglycemic clamp procedure indicate higher glucose usage to compensate for the impaired mitochondrial capacity to generate ATP [113,121]. Interestingly, exercise intolerance has also been described in patients with chronic acquired heart failure [122].

BTHS is caused by mutations in the X chromosomal gene encoding for Tafazzin (TAZ) [123]. Pathogenic mutations in TAZ include frameshift, splice-site, missense, and non-sense mutations [124]. Mutations are associated with a decrease in the amount of functional enzymes, mislocalization of the protein in the cell, protein aggregation or altered macromolecular complex assembly [124,125]. Protein levels and messenger RNA of cardiolipin synthase (CLS), Tafazzin (TAZ) and acyl-CoA:lysocardiolipin acyltransferase-1 (ALCAT-1) are affected in cardiac tissue of BTHS patients. Loss of Tafazzin function causes a significant alteration in the CL pool including a reduction in mature forms of CL and an increase in MLCL, which also serves as a diagnostic marker for BTHS [126,127]. Decreased respiration and reduced activity of single respiratory enzymes have been confirmed in several models of BTHS, including BTHS patient-derived fibroblasts and lymphoblasts as well as cellular and animal models [36,40,128].

BTHS patients have a significantly lower body weight and fat free mass [121]. When measured under resting conditions, the fatty acid oxidation rate related to body mass in BTHS patients was comparable to the control group. However, under exercise conditions the elevated fatty acid oxidation rate was severely blunted in BTHS [121]. In turn, glucose turnover was already increased at rest. Therefore, the metabolic derangements, in particular the inability to upregulate fatty acid metabolism, reflect the exercise inability of BTHS patients [129]. Abnormal blood levels of amino acids were determined in BTHS patient [94,130]—in particular, amino acids, which are associated with anaplerosis in the intermediate metabolism (arginine, ornithine and citrulline), were consistently lower. This strongly supports the hypothesis of alterations in the energy metabolism in BTHS. Increased levels of tyrosine, proline, and asparagine compared to the control were found under starvation conditions [94,130]. Considering that the lower lean and skeletal muscle mass of BTHS patients, the unchanged rates of appearance of the ketogenic amino acid leucine upon starvation is remarkable and led to the hypothesis of a higher proteolysis rate in BTHS patients in order to use amino acids for energy needs [121].
