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Abstract Background Barth syndrome (BS) is a life-threatening genetic disease caused by abnormal lipids in the mitochondria of cells and mostly affects young males. Those living with BS have severe exercise intolerance, lethargy and fatigue due to muscle disease which affect their daily life. Previous research suggests a need for qualitative exploration of self-regulation in BS and the inter-personal processes at play in family life. Therefore this study aimed to explore self-regulation and coping strategies and inter-personal responses in individuals and families affected by Barth syndrome. A multi-perspective qualitative study based on face to face, semi-structured, in-depth interviews with 11 participants (9–27 years, mean 15 years) with BS and/or their parents participating in a randomised double-blind clinical drug trial (CARDIOMAN). Interviews were transcribed verbatim and managed in NVivo prior to conducting a thematic analysis (AS and GH). Results Four key themes were identified: diagnosis and treatment, social support, identity and social integration, symptoms and self-regulation. The present findings suggest that self-regulation and coping in boys with BS was interpersonal and contingent on parental awareness such that parents were aware that their child had a limited energy reserve and that had to be managed due to the implications of fatigue for daily living. Conclusion The findings support previous quantitative work demonstrating that children and parents tend to share a coherent view of BS. However, there is a need for greater awareness from others within the wider context of social and employment networks to minimise adverse implications for future life choices.

Patients with Barth syndrome (BTHS) can present with cardiomyopathy. BTHS subjects are at risk for cardiac adverse outcomes throughout life, including malignant arrhythmias and death. Electrocardiogram (ECG) parameters have never been assessed as a tool to predict adverse outcomes in individuals with BTHS. The purpose of this study was to identify any ECG parameters, including QRS fragmentation, presence of arrhythmia, or abnormal intervals, that could predict adverse outcomes and cardiac death among the BTHS population. We performed a retrospective case referent study on subjects with BTHS (n = 43) and compared them with our reference group, subjects with idiopathic dilated cardiomyopathy (DCM) from a single institution (n = 53) from 2007 to 2021. BTHS data was obtained from subjects attending the biennial Barth Syndrome Foundation International Scientific, Medical, and Family Conferences (BSFISMFC) from 2002 to 2018. ECG data from the first and last available ECGs prior to an adverse event or cardiac death was analyzed. Then, multivariable regression was performed to determine odd ratios between ECG characteristics and adverse events/cardiac death. No ECG variables were statistically significant predictors of adverse events or cardiac death in the BTHS group. Last ECG QRS fragmentation trended to statistically significance (OR 13.3, p = 0.12) in predicting adverse events in the DCM group. No ECG parameters, including QRS fragmentation, presence of arrhythmia, or abnormal interval values, predict adverse events or cardiac death among BTHS patients. QRS fragmentation may be a predictor of adverse events in the DCM population. • Barth syndrome patients are at risk for malignant arrhythmias and death. • No ECG variables predict adverse events or cardiac death in Barth syndrome. • QRS fragmentation predicts adverse events in children with dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

A mood-stabilizing anticonvulsant valproic acid (VPA) is a drug with a pleiotropic effect on cells. Here, we describe the impact of VPA on the metabolic function of human HAP1 cells. We show that VPA altered the biosynthetic pathway of cardiolipin (CL) and affected the activities of mitochondrial enzymes such as pyruvate dehydrogenase, α-ketoglutarate dehydrogenase and NADH dehydrogenase. We demonstrate that a therapeutic dose of VPA (0.6 mM) has a harmful effect on cell growth and increases the production of reactive oxygen species and superoxides. On the contrary, less concentrated VPA (0.06 mM) increased the activities of CL-dependent enzymes leading to an increased level of oxidative phosphorylation and ATP production. The effect of VPA was also tested on the Barth syndrome model, which is characterized by a reduced amount of CL and an increased level of monolyso-CL. In this model, VPA treatment slightly attenuated the mitochondrial defects by altering the activities of CL-dependent enzymes. However, the presence of CL was essential for the increase in ATP production by VPA. Our findings highlight the potential therapeutic role of VPA in normalizing mitochondrial function in BTHS and shed light on the intricate interplay between lipid metabolism and mitochondrial physiology in health and disease. This study investigates the dose-dependent effect of valproate, a mood-stabilizing drug, on mitochondrial function. The therapeutic concentration reduced overall cellular metabolic activity, while a subtherapeutic concentration notably improved the function of cardiolipin-dependent proteins within mitochondria. These findings shed light on novel aspects of valproate's effect and suggest potential practical applications for its use. By elucidating the differential effects of valproate doses on mitochondrial activity, this research underscores the drug's multifaceted role in cellular metabolism and highlights avenues for further exploration in therapeutic interventions. [Display omitted] • The TAFFAZIN mutation causes multiple lipid changes. • The effect of valproic acid on cellular metabolism is dose-dependent. • Valproic acid alters mitochondrial enzyme activities. • Cardiolipin plays an important role in the molecular mechanism of valproic acid. [ABSTRACT FROM AUTHOR]

Background: Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (BTHS) to provide further analysis of the efficacy of elamipretide observed in an open-label extension (OLE) phase of the TAZPOWER trial, a clinical trial that tested the efficacy of 40 mg daily of elamipretide in patients with BTHS.Methods: This was a retrospective, non-interventional study. A propensity score model was used to compare elamipretide-treated patients and NHCs. The analysis included 8 patients from the TAZPOWER OLE and 19 untreated NHCs (including 12 with serial echocardiographic assessments).Results: For the 6-min walk test (6MWT, primary endpoint), the least squares (LS) mean difference between groups was 79.7 m (P = 0.0004) at week 64 and 91.0 m (P = 0.0005) at week 76 in favor of elamipretide. Significant improvements in muscle strength (secondary endpoint), as assessed by handheld dynamometry (HHD) were also observed with elamipretide, with LS mean differences of 40.8 Newtons at 64 weeks (P = 0.0002) and 56.7 Newtons at 76 weeks (P = 0.0005). Patients continuously treated with elamipretide also experienced statistically significant improvements in other secondary endpoints (i.e., 5 times sit-to-stand [5XSST], multi-domain responder index [MDRI]). The functional improvements were robust to sensitivity analyses. Left ventricular stroke volume increased from baseline in patients with elamipretide but decreased in NHCs.Conclusions: Overall, the study established a NHC for use in assessing the efficacy of therapeutic interventions in patients with BTHS and the results suggest that elamipretide may improve natural history of BTHS at least in part by attenuating the natural decline in heart function and provide meaningful improvements in heart function and functional capacity in patients with BTHS compared to NHCs.Highlights: A matched Natural History Control (NHC) was used to evaluate elamipretide in BTHS Elamipretide may improve natural history of BTHS by attenuating natural decline in heart function Elamipretide was associated with meaningful clinical improvements in skeletal muscle and cardiovascular parameters that were not observed in NHCs The study established a NHC for use in assessing the efficacy of therapeutic interventions in BTHS. [ABSTRACT FROM AUTHOR]

Barth syndrome is a rare and potentially fatal X-linked disease characterized by cardiomyopathy, skeletal muscle weakness, growth delays, and cyclic neutropenia. Patients with Barth syndrome are prone to high risk of mortality in infancy and the development of cardiomyopathy with severe weakening of the immune system. Elamipretide is a water-soluble, aromatic-cationic, mitochondria-targeting tetrapeptide that readily penetrates and transiently localizes to the inner mitochondrial membrane. Therapy with elamipretide facilitates cell health by improving energy production and inhibiting excessive formation of reactive oxygen species, thus alleviating oxidative stress. Elamipretide crosses the outer membrane of the mitochondrion and becomes associated with cardiolipin, a constituent phospholipid of the inner membrane. Elamipretide improves mitochondrial bioenergetics and morphology rapidly in induced pluripotent stem cells from patients with Barth syndrome and other genetically related diseases characterized by pediatric cardiomyopathy. Data with elamipretide across multiple models of disease are especially promising, with results from several studies supporting the use of elamipretide as potential therapy for patients with Barth syndrome, particularly where there is a confirmed diagnosis of cardiomyopathy. This review highlights the challenges and opportunities presented in treating Barth syndrome cardiomyopathy patients with elamipretide and addresses evidence supporting the durability of effect of elamipretide as a therapeutic agent for Barth syndrome, especially its likely durable effects on progression of cardiomyopathy following the cessation of drug treatment and the capability of elamipretide to structurally reverse remodel the failing left ventricle at the global, cellular, and molecular level in a gradual manner through specific targeting of the mitochondrial inner membrane. [ABSTRACT FROM AUTHOR]

Tafazzin--an acyltransferase--is involved in cardiolipin (CL) remodeling. CL is associated with mitochondrial function, structure and more recently with cell proliferation. Various tafazzin isoforms exist in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study was to investigate if specific isoforms like Δ5 can restore the wild type phenotype with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aimed to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and (Ingenuity Pathway Analyis) IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ-cells could fully restore CL composition and--as proven for Δ5--this is naturally associated with restoration of mitochondrial respiration. A similar restoration of CL-composition could not be observed after re-expression of an enzymatically dead full-length rat TAZ (H69L; TAZMut). Re-expression of only rat full length TAZ could restore proliferation rate. Surprisingly, the Δ5 variant failed to restore wild-type proliferation. Further, as expected, re-expression of the TAZMut variant completely failed to reverse the gene expression changes, whereas re-expression of the TAZ-FL variant largely did so and the Δ5 variant to somewhat less extent. Very likely TAZ-deficiency provokes substantial long-lasting changes in cellular lipid metabolism which contribute to changes in proliferation and gene expression, and are not or only very slowly reversible. [ABSTRACT FROM AUTHOR]

Barth Syndrome (BTHS) is an X-linked mitochondrial cardioskeletal myopathy caused by defects in TAFAZZIN, a gene responsible for cardiolipin remodeling. Altered mitochondrial levels of cardiolipin lead to cardiomyopathy (CM), muscle weakness, exercise intolerance, and mortality. Cardiac risk factors predicting outcome are unknown. Therefore, we conducted a longitudinal observational study to determine risk factors for outcome in BTHS. Subjects with minimum two evaluations (or one followed by death or transplant) were included. Cardiac size, function, and QTc data were measured by echocardiography and electrocardiography at 7 time points from 2002 to 2018. Analysis included baseline, continuous, and categorical variables. Categorical risk factors included prolonged QTc, abnormal right ventricle fractional area change (RV FAC), left ventricle (LV) or RV non-compaction, and restrictive CM phenotype. The association between variables and cardiac death or transplant (CD/TX) was assessed. Median enrollment age was 7 years (range 0.5–22; n = 44). Transplant-free survival (TFS) was 74.4% at 15 years from first evaluation. The cohort demonstrated longitudinal declines in LV size and stroke volume z-scores (end-diastolic volume, p = 0.0002; stroke volume p < 0.0001), worsening RV FAC (p = 0.0405), and global longitudinal strain (GLS) (p = 0.0001) with stable ejection (EF) and shortening (FS) fraction. CD/TX subjects (n = 9) displayed worsening LV dilation (p = 0.0066), EF (p ≤ 0.0001), FS (p = 0.0028), and RV FAC (p =.0032) versus stability in TFS. Having ≥ 2 categorical risk factors predicted CD/TX (p = 0.0073). Over 15 years, 25% of BTHS subjects progressed to CD/TX. Those with progressive LV enlargement, dysfunction, and multiple cardiac risk factors warrant increased surveillance and intense therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Barth Syndrome (BTHS) is a rare genetic disorder that presents as a complex of debilitating symptoms and reduced life expectancy. Well-developed, BTHS-specific assessments measuring primary signs and symptoms of BTHS are not currently available, making it difficult to evaluate treatment effects in BTHS clinical studies. The objective of this research was to develop symptom-focused patient-reported outcome (PRO) measures for use in clinical studies with adolescents and adults with BTHS. Methods Concept elicitation interviews (CEIs) with pediatric (n = 18, age

Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.

Tafazzin—an acyltransferase—is involved in cardiolipin (CL) remodeling. CL is associated with mitochondrial function, structure and more recently with cell proliferation. Various tafazzin isoforms exist in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study was to investigate if specific isoforms like Δ5 can restore the wild type phenotype with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aimed to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and (Ingenuity Pathway Analyis) IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ- cells could fully restore CL composition and—as proven for Δ5—this is naturally associated with restoration of mitochondrial respiration. A similar restoration of CL-composition could not be observed after re-expression of an enzymatically dead full-length rat TAZ (H69L; TAZMut). Re-expression of only rat full length TAZ could restore proliferation rate. Surprisingly, the Δ5 variant failed to restore wild-type proliferation. Further, as expected, re-expression of the TAZMut variant completely failed to reverse the gene expression changes, whereas re-expression of the TAZ-FL variant largely did so and the Δ5 variant to somewhat less extent. Very likely TAZ-deficiency provokes substantial long-lasting changes in cellular lipid metabolism which contribute to changes in proliferation and gene expression, and are not or only very slowly reversible.

The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ.

Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies. [ABSTRACT FROM AUTHOR]

Abstract Barth syndrome is a rare X‐linked recessive disorder characterized by a broad spectrum of clinical features including cardiac and skeletal myopathy, neutropenia, exercise intolerance, and growth delay. Most affected patients are diagnosed during childhood, and mortality is highest in the first years of life. As a consequence, Barth syndrome is often considered a paediatric disease. Here, we report a case where the diagnosis was established in a 39‐year‐old patient with left ventricular non‐compaction and neutropenia. The clinical course of the patient presented here was relatively benign. This suggests that the prevalence of Barth syndrome in adults may be underestimated. Barth syndrome should be considered in the differential diagnosis of male patients with cardiomyopathy and neutropenia.

Barth syndrome (BTHS, OMIM 302060) is a genetic disorder caused by variants of the TAFAZZIN gene (G 4.5, OMIM 300394). This debilitating disorder is characterized by cardio- and skeletal myopathy, exercise intolerance, and neutropenia. TAFAZZIN is a transacylase that catalyzes the second step in the cardiolipin (CL) remodeling pathway, preferentially converting saturated CL species into unsaturated CLs that are susceptible to oxidation. As a hallmark mitochondrial membrane lipid, CL has been shown to be essential in a myriad of pathways, including oxidative phosphorylation, the electron transport chain, intermediary metabolism, and intrinsic apoptosis. The pathological severity of BTHS varies substantially from one patient to another, even in individuals bearing the same TAFAZZIN variant. The physiological modifier(s) leading to this disparity, along with the exact molecular mechanism linking CL to the various pathologies, remain largely unknown. Elevated levels of reactive oxygen species (ROS) have been identified in numerous BTHS models, ranging from yeast to human cell lines, suggesting that cellular ROS accumulation may participate in the pathogenesis of BTHS. Although the exact mechanism of how oxidative stress leads to pathogenesis is unknown, it is likely that CL oxidation plays an important role. In this review, we outline what is known about CL oxidation and provide a new perspective linking the functional relevance of CL remodeling and oxidation to ROS mitigation in the context of BTHS.

Barth syndrome (BTHS) is an X‐linked disorder that results from mutations in the TAFAZZIN gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age‐ and sex‐matched patients with idiopathic dilated cardiomyopathy (DCM) and nonfailing controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso‐) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long‐chain fatty acid oxidation enzymes and the tissue acyl‐CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta‐oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids, and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy. [ABSTRACT FROM AUTHOR]

Barth Syndrome is an X‐linked disorder of mitochondrial cardiolipin metabolism caused by pathogenic variants in TAFAZZIN with pleiotropic effects including cardiomyopathy, neutropenia, growth delay, and skeletal myopathy. Management requires a multidisciplinary approach to the organ‐specific manifestations including specialists from cardiology, hematology, nutrition, physical therapy, genetics, and metabolism. Currently, treatment is centered on management of specific clinical features, and is not targeted toward remediating the underlying biochemical defect. However, two clinical trials have been recently undertaken which target the mitochondrial pathology of this disease: a study to examine the effects of elamipretide, a cardiolipin targeted agent, and a study to examine the effects of bezafibrate, a peroxisome proliferator‐activated receptor (PPAR) agonist. Treatments to directly target the defective TAFAZZIN pathway are under development, including enzyme and gene therapies. [ABSTRACT FROM AUTHOR]

Barth syndrome (BTHS) is a rare inherited metabolic disease resulting from mutations in the gene of the enzyme tafazzin, which catalyzes the acyl chain remodeling of the mitochondrial‐specific lipid cardiolipin (CL). Tissue samples of individuals with BTHS present abnormalities in the level and the molecular species of CL. In addition, in tissues of a tafazzin knockdown mouse as well as in cells derived from BTHS patients it has been shown that plasmalogens, a subclass of glycerophospholipids, also have abnormal levels. Likewise, administration of a plasmalogen precursor to cells derived from BTHS patients led to an increase in plasmalogen and to some extent CL levels. These results indicate an interplay between CL and plasmalogens in BTHS. This interdependence is supported by the concomitant loss in these lipids in different pathological conditions. However, currently the molecular mechanism linking CL and plasmalogens is not fully understood. Here, a review of the evidence showing the linkage between the levels of CL and plasmalogens is presented. In addition, putative mechanisms that might play a role in this interplay are proposed. Finally, the opportunity of therapeutic approaches based on the regulation of plasmalogens as new therapies for the treatment of BTHS is discussed. [ABSTRACT FROM AUTHOR]

Cardiolipin (CL) is the signature phospholipid (PL) of mitochondria and plays a pivotal role in mitochondrial and cellular function. Disruption of the CL remodeling gene tafazzin (TAZ) causes the severe genetic disorder Barth syndrome (BTHS). Our current understanding of the function of CL and the mechanism underlying the disease has greatly benefited from studies utilizing the powerful yeast model Saccharomyces cerevisiae. In this review, we discuss important findings on the function of CL and its remodeling from yeast studies and the implications of these findings for BTHS, highlighting the potential physiological modifiers that may contribute to the disparities in clinical presentation among BTHS patients. [ABSTRACT FROM AUTHOR]

Deficiency of the transacylase tafazzin due to loss of function variants in the X‐chromosomal TAFAZZIN gene causes Barth syndrome (BTHS) with severe neonatal or infantile cardiomyopathy, neutropenia, myopathy, and short stature. The condition is characterized by drastic changes in the composition of cardiolipins, a mitochondria‐specific class of phospholipids. Studies examining the impact of tafazzin deficiency on the metabolism of other phospholipids have so far generated inhomogeneous and partly conflicting results. Recent studies showed that the cardiolipin composition in cells and different murine tissues is highly dependent on the surrounding lipid environment. In order to study the relevance of different lipid states and tafazzin function for cardiolipin and phospholipid homeostasis we conducted systematic modulation experiments in a CRISPR/Cas9 knock‐out model for BTHS. We found that—irrespective of tafazzin function—the composition of cardiolipins strongly depends on the nutritionally available lipid pool. Tafazzin deficiency causes a consistent shift towards cardiolipin species with more saturated and shorter acyl chains. Interestingly, the typical biochemical BTHS phenotype in phospholipid profiles of HEK 293T TAZ knock‐out cells strongly depends on the cellular lipid context. In response to altered nutritional lipid compositions, we measured more pronounced changes on phospholipids that were largely masked under standard cell culturing conditions, therewith giving a possible explanation for the conflicting results reported so far on BTHS lipid phenotypes. [ABSTRACT FROM AUTHOR]

Energy‐demanding organs like the heart are strongly dependent on oxidative phosphorylation in mitochondria. Oxidative phosphorylation is governed by the respiratory chain located in the inner mitochondrial membrane. The inner mitochondrial membrane is the only cellular membrane with significant amounts of the phospholipid cardiolipin, and cardiolipin was found to directly interact with a number of essential protein complexes, including respiratory chain complexes I to V. An inherited defect in the biogenesis of cardiolipin causes Barth syndrome, which is associated with cardiomyopathy, skeletal myopathy, neutropenia and growth retardation. Energy conversion is dependent on reducing equivalents, which are replenished by oxidative metabolism in the Krebs cycle. Cardiolipin deficiency in Barth syndrome also affects Krebs cycle activity, metabolite transport and mitochondrial morphology. During excitation‐contraction coupling, calcium (Ca2+) released from the sarcoplasmic reticulum drives sarcomeric contraction. At the same time, Ca2+ influx into mitochondria drives the activation of Krebs cycle dehydrogenases and the regeneration of reducing equivalents. Reducing equivalents are essential not only for energy conversion, but also for maintaining a redox buffer, which is required to detoxify reactive oxygen species (ROS). Defects in CL may also affect Ca2+ uptake into mitochondria and thereby hamper energy supply and demand matching, but also detoxification of ROS. Here, we review the impact of cardiolipin deficiency on mitochondrial function in Barth syndrome and discuss potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Barth syndrome is an X‐linked disorder characterized by cardiomyopathy, skeletal myopathy, and neutropenia, caused by deleterious variants in TAFAZZIN. This gene encodes a phospholipid‐lysophospholipid transacylase that is required for the remodeling of the mitochondrial phospholipid cardiolipin (CL). Biochemically, individuals with Barth syndrome have a deficiency of mature CL and accumulation of the remodeling intermediate monolysocardiolipin (MLCL). Diagnosis typically relies on mass spectrometric measurement of CL and MLCL in cells or tissues, and we previously described a method in blood spot that uses a specific MLCL/CL ratio as diagnostic biomarker. Here, we describe the evolution of our blood spot assay that is based on the implementation of reversed phase‐UHPLC separation followed by full scan high resolution mass spectrometry. In addition to the MLCL/CL ratio, our improved method also generates a complete CL spectrum allowing the interrogation of the CL fatty acid composition, which considerably enhances the diagnostic reliability. This addition negates the need for a confirmatory test in lymphocytes thereby providing a shorter turn‐around‐time while achieving a more certain test result. As one of the few laboratories that offer this assay, we also evaluated the diagnostic yield and performance from 2006 to 2021 encompassing the use of both the original and improved assay. In this period, we performed 796 diagnostic analyses of which 117 (15%) were characteristic of Barth syndrome. In total, we diagnosed 93 unique individuals with Barth syndrome, including three females, which together amounts to about 40% of all reported individuals with Barth syndrome in the world. [ABSTRACT FROM AUTHOR]

Mutation of the gene Tafazzin (TAZ) causes Barth syndrome, an X‐linked disorder characterized by cardiomyopathy, skeletal muscle weakness, and neutropenia. TAZ is an acyltransferase that catalyzes the remodeling of cardiolipin, the signature phospholipid of the inner mitochondrial membrane. Here, we review the major model systems that have been established to study the role of cardiolipin remodeling in mitochondrial function and the pathogenesis of Barth syndrome. We summarize key features of each model and provide examples of how each has contributed to advance our understanding of TAZ function and Barth syndrome pathophysiology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Barth syndrome (BTHS) is an X-linked mitochondrial disease caused by mutations in the gene encoding for tafazzin (TAZ), a key enzyme in the remodeling of cardiolipin. Mice with a germline deficiency in Taz have been generated (Taz-KO) but not yet fully characterized. We performed physiological assessments of 3-, 6-, and 12-month-old male Taz-KO mice, including measures of perinatal survival, growth, lifespan, gross anatomy, whole-body energy and substrate metabolism, glucose homeostasis, and exercise capacity. Taz-KO mice displayed reduced viability, with lower-than-expected numbers of mice recorded at 4 weeks of age, and a shortened lifespan due to disease progression. At all ages, Taz-KO mice had lower body weights compared with wild-type (Wt) littermates despite similar absolute food intakes. This finding was attributed to reduced adiposity and diminutive organs and tissues, including heart and skeletal muscles. Although there were no differences in basal levels of locomotion between age-matched genotypes, indirect calorimetry studies showed higher energy expenditure measures and respiratory exchange ratios in Taz-KO mice. At the youngest age, Taz-KO mice had comparable glucose tolerance and insulin action to Wt mice, but while these measures indicated metabolic impairments in Wt mice with advancing age that were likely associated with increasing adiposity, Taz-KO mice were protected. Comparisons across the three age-cohorts revealed a significant and more severe deterioration of exercise capacity in Taz-KO mice than in their Wt littermate controls. The Taz-KO mouse model faithfully recapitulates important aspects of BTHS, and thus provides an important new tool to investigate pathophysiological mechanisms and potential therapies.

Saccharomyces cerevisiae, commonly known as baker’s yeast, is one of the most comprehensively studied model organisms in science. Yeast has been used to study a wide variety of human diseases, and the yeast model system has proved to be an especially amenable tool for the study of lipids and lipid-related pathophysiologies, a topic that has gained considerable attention in recent years. This review focuses on how yeast has contributed to our understanding of the mitochondrial phospholipid cardiolipin (CL) and its role in Barth syndrome (BTHS), a genetic disorder characterized by partial or complete loss of function of the CL remodeling enzyme tafazzin. Defective tafazzin causes perturbation of CL metabolism, resulting in many downstream cellular consequences and clinical pathologies that are discussed herein. The influence of yeast research in the lipid-related pathophysiologies of Alzheimer’s and Parkinson’s diseases is also summarized.

Mitochondrial cristae are extraordinarily crowded with proteins, which puts stress on the bilayer organization of lipids. We tested the hypothesis that the high concentration of proteins drives the tafazzin‐catalyzed remodeling of fatty acids in cardiolipin, thereby reducing bilayer stress in the membrane. Specifically, we tested whether protein crowding induces cardiolipin remodeling and whether the lack of cardiolipin remodeling prevents the membrane from accumulating proteins. In vitro, the incorporation of large amounts of proteins into liposomes altered the outcome of the remodeling reaction. In yeast, the concentration of proteins involved in oxidative phosphorylation (OXPHOS) correlated with the cardiolipin composition. Genetic ablation of either remodeling or biosynthesis of cardiolipin caused a substantial drop in the surface density of OXPHOS proteins in the inner membrane of the mouse heart and Drosophila flight muscle mitochondria. Our data suggest that OXPHOS protein crowding induces cardiolipin remodelling and that remodeled cardiolipin supports the high concentration of these proteins in the inner mitochondrial membrane. SYNOPSIS: In mitochondrial cristae, proteins are packaged at uniquely high density, imposing stress on the membrane lipid composition. This work uncovers acyl group remodeling of the membrane phospholipid cardiolipin as a precondition for concentrating oxidative phosphorylation (OXPHOS) proteins in the inner mitochondrial membrane. Protein crowding affects fatty acid remodeling of cardiolipin in vitro.The surface concentration of OXPHOS proteins correlates with the molecular species composition of cardiolipin.Ablation of cardiolipin remodeling or biosynthesis decreases surface concentration of OXPHOS proteins in mice and flies. [ABSTRACT FROM AUTHOR]

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise, and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Because mitochondrial function and ROS formation are regulated by excitation-contraction coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. Methods: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin (Taz -KD) compared with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo. Results: Taz -KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+-ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter protein that prevented Ca2+-induced activation of the Krebs cycle during [beta]-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo, Taz -KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to [beta]-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export through the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. Conclusions: Downregulation of mitochondrial Ca2+ uniporter, increased myofilament Ca2+ affinity, and preactivated sarcoplasmic reticulum Ca2+-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease. What Is New? * Barth syndrome cardiomyopathy in tafazzin-knockdown mice is characterized by early and progressive diastolic dysfunction induced by slowed cross-bridge cycling and increased myofilament Ca2+ sensitivity. * The inherited defect in cardiolipin remodeling leads to the loss of mitochondrial Ca2+ uniporter protein in cardiac, but not skeletal muscle. * Defective mitochondrial Ca2+ uptake prevents Krebs cycle activation during [beta]-adrenergic stimulation, abolishes NADH regeneration for ATP production, and lowers antioxidative NADPH. * Mitochondrial Ca2+ deficiency provides trigger and substrate for ventricular arrhythmias and contributes to blunted inotropic reserve during [beta]-adrenergic stimulation. * These changes occur without any increase of reactive oxygen species formation in or emission from mitochondria. What Are the Clinical Implications? * Beyond the first months of life, when systolic dysfunction dominates, Barth syndrome cardiomyopathy is reminiscent of heart failure with preserved rather than reduced ejection fraction, presenting with progressive diastolic and moderate systolic dysfunction without relevant left ventricular dilation. * Defective mitochondrial Ca2+ uptake contributes to inability of patients with Barth syndrome to increase stroke volume during exertion and their vulnerability to ventricular arrhythmias. * Treatment with cardiac glycosides, which could favor mechano-energetic uncoupling, should be discouraged in patients with Barth syndrome and left ventricular ejection fraction >40%. * Instead, treatments with the potential to improve mechano-energetic coupling should be explored in future studies. [ABSTRACT FROM AUTHOR]

• Barth syndrome (BTHS) is a rare X-linked multisystem mitochondrial disease. • It is caused by variants of the TAFAZZIN gene leading to abnormal cardiolipin. • Normal cardiolipin is crucial for proper mitochondrial structure and function. • We review the little-discussed, but significant neuro/psychological aspects of BTHS. • We discuss potential pathogenic mechanisms and propose avenues for further research. Barth syndrome is a rare X-linked multisystem mitochondrial disease that is caused by variants in the tafazzin gene leading to deficient and abnormal cardiolipin. Previous research has focused on the cardiomyopathy and neutropenia in individuals with Barth syndrome, yet just as common are the least explored neurological aspects of Barth syndrome. This review focuses on the major neuropsychological and neurophysiological phenotypes that affect the quality of life of individuals with Barth syndrome, including difficulties in sensory perception and feeding, fatigue, and cognitive and psychological challenges. We propose selected pathogenetic mechanisms underlying these phenotypes and draw parallels to other relevant disorders. Finally, avenues for future research are also suggested. [ABSTRACT FROM AUTHOR]

Saccharomyces cerevisiae , commonly known as baker's yeast, is one of the most comprehensively studied model organisms in science. Yeast has been used to study a wide variety of human diseases, and the yeast model system has proved to be an especially amenable tool for the study of lipids and lipid-related pathophysiologies, a topic that has gained considerable attention in recent years. This review focuses on how yeast has contributed to our understanding of the mitochondrial phospholipid cardiolipin (CL) and its role in Barth syndrome (BTHS), a genetic disorder characterized by partial or complete loss of function of the CL remodeling enzyme tafazzin. Defective tafazzin causes perturbation of CL metabolism, resulting in many downstream cellular consequences and clinical pathologies that are discussed herein. The influence of yeast research in the lipid-related pathophysiologies of Alzheimer's and Parkinson's diseases is also summarized. [ABSTRACT FROM AUTHOR]

Barth Syndrome (BTHS) is a rare, X-linked disease characterized by cardioskeletal myopathy and neutropenia. Comparative outcomes after heart transplantation have not been reported. We identified BTHS recipients across 3 registries (Pediatric Heart Transplant Study Registry [PHTS], Barth Syndrome Research Registry and Repository, and Scientific Registry of Transplant Recipient-Pediatric Health Information System) and matched them 1:4 to non-BTHS, male heart transplant (HT) recipients listed with dilated cardiomyopathy in PHTS. Demographics and survival data were analyzed for all recipients, whereas post-HT infection, malignancy, allograft vasculopathy, and acute rejection were only available for analysis for individuals with PHTS data. Forty-seven BTHS individuals with 51 listings and 43 HTs (including 2 re-transplants) were identified. Age at primary HT was 1.7 years (IQR: 0.6-4.5). Mechanical circulatory support at HT was common (ventricular assist device 29%, extracorporeal membrane oxygenation 5%). Over a median follow-up of 4.5 years (IQR 2.7-9.1), survival for BTHS HT recipients was no different than non-BTHS HT recipients (HR 0.91, 95% CI 0.40-2.12, p = 0.85). Among those with PHTS data (n = 28), BTHS HT recipients showed no difference in freedom from infection (HR 0.64, 0.34-1.22; p = 0.18), malignancy (HR 0.22, 0.02-2.01, p = 0.18), and allograft vasculopathy (HR 0.58, 0.16-2.1, p = 0.41). Freedom from acute rejection (HR 0.39, 0.17-0.86, p = 0.02) was greater for BTHS HT recipients despite similar use of induction (61 vs 73%, p = 0.20), steroids at 30-days (75 vs 62%, p = 0.27), and dual/triple drug immunosuppression at 1-year (80 vs 84%, p = 0.55). In this largest cohort yet reported, individuals with BTHS have equivalent survival with less acute rejection and no difference in infection or malignancy after HT. When indicated, HT for individuals with BTHS is appropriate. [ABSTRACT FROM AUTHOR]

Date Presented 03/23/24 This study used a phone app to capture fatigue and an activity tracker to assess energy expenditure in individuals with and without Barth syndrome (BTHS). We found that the BTHS group reported fatigue after expending less energy compared to controls. Primary Author and Speaker: Marina Nguyen Additional Authors and Speakers: Alyssa Tsui, Virginia W. Chu, Stacey Reynolds Contributing Authors: Sanamtha Payne, Hannah Ikenberry, Mackenzie Hunter [ABSTRACT FROM AUTHOR]

Date Presented 03/21/24 This study applied a propensity score matching method to improve methodological rigor in examining the psychometric properties of the PedsQL Family Impact Module with parents of children with Barth syndrome in the field of OT. Primary Author and Speaker: Yoonjeong Lim Additional Authors and Speakers: Ickpyo Hong, Areum Han [ABSTRACT FROM AUTHOR]

Abstract Background Barth syndrome (BTHS, OMIM 302060) is a rare, life-threatening, x-linked genetic disorder that occurs almost exclusively in males and is characterized by cardiomyopathy, neutropenia, skeletal muscle myopathy primarily affecting larger muscles, and shorter stature in youth. A greater number of individuals with BTHS are now surviving into adulthood due to advancements in diagnosis and disease management. Given these improvements in life expectancy, understanding the disease experience over time has become increasingly important to individuals with the condition, treatment developers, and regulatory agencies. A study was conducted to explore the experience of BTHS from the perspective of adult males at least 35 years of age with the condition via in-depth qualitative interviews. Results Findings showed that adults with BTHS experienced a variety of signs/symptoms with variable onset and severity throughout their lives, the most frequently reported being the symptoms of tiredness, muscle weakness, and a fast and/or irregular heart rate, and the sign of short stature in youth. These signs/symptoms negatively impacted individuals’ emotional, physical, social, and role functioning. Tiredness and weakness impacted some individuals’ physical functioning from an early age and into adulthood. These symptoms generally worsened over time, increasingly interfering with individuals’ ability to fully participate in paid and unpaid labor and to partake in family and leisure activities. Conclusions This research complements recent studies characterizing the potentially degenerative and progressive nature of BTHS and can encourage future research into the natural history and progression of BTHS in untreated individuals. Participants’ interview responses revealed a range of symptoms and the potential for multiple impacts on individuals’ physical, social, emotional, and role functioning as a result of BTHS symptoms, yet also revealed variability in severity of experience as well as the possibility of resilience and adaptation to the condition.

Josef FinstererKrankenanstalt Rudolfstiftung, Messerli Institute, Vienna, AustriaObjectives: Barth syndrome is an ultra-rare, infantile-onset, X-linked recessive mitochondrial disorder, primarily affecting males, due to variants in TAZ encoding for the cardiolipin transacylase tafazzin. This review aimed to summarize and discuss recent and earlier findings concerning the etiology, pathogenesis, clinical presentation, diagnosis, treatment, and outcome of Barth syndrome.Method: A literature review was undertaken through a MEDLINE search.Results: The phenotype of Barth syndrome is highly variable but most frequently patients present with hypertrophic/dilated/non-compaction cardiomyopathy, fibroelastosis, arrhythmias, neutropenia, mitochondrial myopathy, growth retardation, dysmorphism, cognitive impairment, and other, rarer features. Lactic acid and creatine kinase, and blood and urine organic acids, particularly 3-methylglutaconic acid and monolysocardiolipin, are often elevated. Cardiolipin is decreased. Biochemical investigations may show decreased activity of various respiratory chain complexes. The diagnosis is confirmed by documentation of a causative TAZ variant. Treatment is symptomatic and directed toward treating heart failure, arrhythmias, neutropenia, and mitochondrial myopathy.Conclusions: Although Barth syndrome is still an orphan disease, with fewer than 200 cases described so far, there is extensive ongoing research with regard to its pathomechanism and new therapeutic approaches. Although most of these approaches are still experimental, it can be expected that causative strategies will be developed in the near future.Keywords: Barth syndrome, tafazzin, TAZ, cardiomyopathy, non-compaction, X-linked

Background: Barth syndrome (BTHS) is a rare X-linked genetic disease that affects multiple systems and leads to complex clinical manifestations. Although a considerable amount of research has focused on the physical aspects of the disease, less has focused on the psychosocial impact and quality of life (QoL) in BTHS. Methods: The current study investigated caregiver- (n = 10) and self-reported (n = 16) psychological well-being and QoL in a cohort of BTHS-affected patients and families. Participants completed the depression and anxiety components of the Patient-Reported Outcomes Information System (PROMIS) Short Form 8A and Health-related quality of life (HRQoL) surveys at enrollment and again during a follow-up period ranging from 6 to 36 months after baseline. Results: Quality of life changed significantly over time and the various domains with some improvement and some decline. Among the available caregiver-patient dyad data, there was a trend toward discordance between caregiver and self-reported outcomes. Most notably, patients reported improvement in HRQoL, while caregivers reported declines. This suggests that there may be differences in perceived quality of life between the patients and parents, though our study is limited by small sample size. Conclusion: Our study provides valuable insights into the impacts of psychosocial and mental health aspects of BTHS. Implications of these findings include incorporating longitudinal assessment of QoL and screening for psychological symptoms in BTHS care to identify interventions that may drastically impact health status and the course of the disease.

Background: Barth syndrome (BS) is a life-threatening genetic disease caused by abnormal lipids in the mitochondria of cells and mostly affects young males. Those living with BS have severe exercise intolerance, lethargy and fatigue due to muscle disease which affect their daily life. Previous research suggests a need for qualitative exploration of self-regulation in BS and the inter-personal processes at play in family life. Therefore this study aimed to explore self-regulation and coping strategies and inter-personal responses in individuals and families affected by Barth syndrome. A multi-perspective qualitative study based on face to face, semi-structured, in-depth interviews with 11 participants (9-27 years, mean 15 years) with BS and/or their parents participating in a randomised double-blind clinical drug trial (CARDIOMAN). Interviews were transcribed verbatim and managed in NVivo prior to conducting a thematic analysis (AS and GH).Results: Four key themes were identified: diagnosis and treatment, social support, identity and social integration, symptoms and self-regulation. The present findings suggest that self-regulation and coping in boys with BS was interpersonal and contingent on parental awareness such that parents were aware that their child had a limited energy reserve and that had to be managed due to the implications of fatigue for daily living.Conclusion: The findings support previous quantitative work demonstrating that children and parents tend to share a coherent view of BS. However, there is a need for greater awareness from others within the wider context of social and employment networks to minimise adverse implications for future life choices. [ABSTRACT FROM AUTHOR]

To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ-deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. With careful metabolic management with l-arginine supplementation, overnight corn starch, and a prescribed exercise program, our patient's strength, endurance, level of physical activity and body composition improved significantly by age six years. [ABSTRACT FROM AUTHOR]

Background Barth syndrome (BTHS) is a rare X-linked recessive disorder characterized by clinical features including cardiomyopathy, skeletal myopathy, neutropenia, growth delay, and exercise intolerance. It is often considered to be a paediatric disease, owing to most cases being diagnosed during childhood and mortality being the highest during the first few years of life. Case summary We report a case of dilated cardiomyopathy due to BTHS in a 27-year-old adult male patient, who initially presented with lightheadedness, dyspnoea, orthopnoea, and bilateral lower extremity oedema. Key findings from investigations included leukopenia, prolonged QTc interval, reduced left ventricular ejection fraction (LVEF), global enlargement of all heart chambers, patent coronary arteries, and mild pulmonary hypertension. The patient was diuresed to euvolemia and discharged with a LifeVest. Guideline-directed medical therapy was initiated and uptitrated as an outpatient. A repeat echocardiogram 2 years after initial presentation showed marked improvement in LVEF. Discussion It is possible that there are adult patients with idiopathic cardiomyopathy, which may be attributable to BTHS. In the absence of an obvious underlying cause, with the appropriate historical information, clinical exam, laboratory investigations, and imaging findings, BTHS should be considered as a likely cause of non-ischaemic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Mutations in the mitochondrial transacylase tafazzin, Taz1p, in Saccharomyces cerevisiae cause Barth syndrome, a disease of defective cardiolipin remodeling. Taz1p is an interfacial membrane protein that localizes to both the outer and inner membranes, lining the intermembrane space. Pathogenic point mutations in Taz1p that alter import and membrane insertion result in accumulation of monolysocardiolipin. In this study, we used yeast as a model to investigate the biogenesis of Taz1p. We show that to achieve this unique topology in mitochondria, Taz1p follows a novel import pathway in which it crosses the outer membrane via the translocase of the outer membrane and then uses the Tim9p-Tim10p complex of the intermembrane space to insert into the mitochondrial outer membrane. Taz1p is then transported to membranes of an intermediate density to reach a location in the inner membrane. Moreover, a pathogenic mutation within the membrane anchor (V224R) alters Taz1p import so that it bypasses the Tim9p-Tim10p complex and interacts with the translocase of the inner membrane, TIM23, to reach the matrix. Critical targeting information for Taz1p resides in the membrane anchor and flanking sequences, which are often mutated in Barth syndrome patients. These studies suggest that altering the mitochondrial import pathway of Taz1p may be important in understanding the molecular basis of Barth syndrome.

Background: Barth Syndrome (BTHS) is a rare genetic disorder that presents as a complex of debilitating symptoms and reduced life expectancy. Well-developed, BTHS-specific assessments measuring primary signs and symptoms of BTHS are not currently available, making it difficult to evaluate treatment effects in BTHS clinical studies. The objective of this research was to develop symptom-focused patient-reported outcome (PRO) measures for use in clinical studies with adolescents and adults with BTHS.Methods: Concept elicitation interviews (CEIs) with pediatric (n = 18, age < 16 years) and adult (n = 15, age ≥ 16 years) individuals with BTHS and/or their caregivers were conducted to identify signs and symptoms relevant to BTHS and important to individuals with the condition. Based on CEI results, questionnaire construction activities were conducted to create unique adolescent and adult versions of the Barth Syndrome-Symptom Assessment (BTHS-SA). The questionnaires were evaluated in cognitive debriefing interviews (CDIs) with adolescents (n = 12; age 12- < 16 years) and adults (n = 12; age ≥ 16 years) with BTHS to assess relevance and readability of the tools.Results: During the CEIs, a total of 48 and 40 signs and symptoms were reported by the pediatric and adult groups, respectively; 31 were reported by both age groups. Fatigue/tiredness and muscle weakness were the symptoms most frequently reported by both pediatric and adult patients with BTHS as important to improve with an effective treatment. The CEI results informed construction of a nine-item version of the BTHS-SA for adolescents and an eight-item version for adults. Developed for daily administration, each version asks respondents to rate symptom severity "at its worst" over the 24 h prior to administration. CDIs with both adolescents and adults with BTHS demonstrated that each BTHS-SA version was reflective of the disease experience and that respondents could interpret the questionnaire as intended and provide responses that accurately reflected their symptom experience.Conclusions: The BTHS-SA adolescent and adult versions are content-valid PRO measures that can be used to evaluate severity of disease-specific symptoms in future clinical trials. Given the lack of available and well-developed assessments in this underserved therapeutic area, these tools fulfill a need for clinical researchers developing treatments for individuals with BTHS. [ABSTRACT FROM AUTHOR]

Heart failure presents as the leading cause of infant mortality in individuals with Barth syndrome (BTHS), a rare genetic disorder due to mutations in the tafazzin (TAZ) gene affecting mitochondrial structure and function. Investigations into the perturbed bioenergetics in the BTHS heart remain limited. Hence, our objective was to identify the potential alterations in myocardial energy metabolism and molecular underpinnings that may contribute to the early cardiomyopathy and heart failure development in BTHS. Cardiac function and myocardial energy metabolism were assessed via ultrasound echocardiography and isolated working heart perfusions, respectively, in a mouse model of BTHS [doxycycline-inducible Taz knockdown (TazKD) mice]. In addition, we also performed mRNA/protein expression profiling for key regulators of energy metabolism in hearts from TazKD mice and their wild-type (WT) littermates. TazKD mice developed hypertrophic cardiomyopathy as evidenced by increased left ventricular anterior and posterior wall thickness, as well as increased cardiac myocyte cross-sectional area, though no functional impairments were observed. Glucose oxidation rates were markedly reduced in isolated working hearts from TazKD mice compared with their WT littermates in the presence of insulin, which was associated with decreased pyruvate dehydrogenase activity. Conversely, myocardial fatty acid oxidation rates were elevated in TazKD mice, whereas no differences in glycolytic flux or ketone body oxidation rates were observed. Our findings demonstrate that myocardial glucose oxidation is impaired before the development of overt cardiac dysfunction in TazKD mice, and may thus represent a pharmacological target for mitigating the development of cardiomyopathy in BTHS. NEW & NOTEWORTHY Barth syndrome (BTHS) is a rare genetic disorder due to mutations in tafazzin that is frequently associated with infantile-onset cardiomyopathy and subsequent heart failure. Although previous studies have provided evidence of perturbed myocardial energy metabolism in BTHS, actual measurements of flux are lacking. We now report a complete energy metabolism profile that quantifies flux in isolated working hearts from a murine model of BTHS, demonstrating that BTHS is associated with a reduction in glucose oxidation. [ABSTRACT FROM AUTHOR]