Barth Syndrome Research Articles

Diverse mitochondrial abnormalities in a new cellular model of TAFFAZZIN deficiency are remediated by cardiolipin-interacting small molecules

Barth syndrome (BTHS) is an X-linked disorder of mitochondrial phospholipid metabolism caused by pathogenic variants in TAFFAZIN, which results in abnormal cardiolipin (CL) content in the inner mitochondrial membrane. To identify unappreciated pathways of mitochondrial dysfunction in BTHS, we utilized an unbiased proteomics strategy and identified that complex I (CI) of the mitochondrial respiratory chain and the mitochondrial quality control protease presenilin-associated rhomboid-like protein (PARL) are altered in a new HEK293–based tafazzin-deficiency model. Follow-up studies confirmed decreased steady state levels of specific CI subunits and an assembly factor in the absence of tafazzin; this decrease is in part based on decreased transcription and results in reduced CI assembly and function. PARL, a rhomboid protease associated with the inner mitochondrial membrane with a role in the mitochondrial response to stress, such as mitochondrial membrane depolarization, is increased in tafazzin-deficient cells. The increased abundance of PARL correlates with augmented processing of a downstream target, phosphoglycerate mutase 5, at baseline and in response to mitochondrial depolarization. To clarify the relationship between abnormal CL content, CI levels, and increased PARL expression that occurs when tafazzin is missing, we used blue-native PAGE and gene expression analysis to determine that these defects are remediated by SS-31 and bromoenol lactone, pharmacologic agents that bind CL or inhibit CL deacylation, respectively. These findings have the potential to enhance our understanding of the cardiac pathology of BTHS, where defective mitochondrial quality control and CI dysfunction have well-recognized roles in the pathology of diverse forms of cardiac dysfunction.

High-resolution mass spectrometric analysis of cardiolipin profiles in Barth syndrome

Barth syndrome is an X-linked recessive disorder caused by pathogenic variants in TAZ, which leads to a reduction in cardiolipin with a concomitant elevation of monolysocardiolipins. There is a paucity of studies characterizing changes in individual species of monolysocardiolipins, dilysocardiolipins and cardiolipin in Barth syndrome using high resolution untargeted lipidomics that can accurately annotate and quantify diverse lipids. We confirmed the structural diversity monolysocardiolipins, dilysocardiolipins and cardiolipin and identified individual species that showed previously unreported alterations in BTHS. Development of mass spectrometry-based targeted assays for these lipid biomarkers should provide an important tool for clinical diagnosis of Barth syndrome.

Favorable outcomes after heart transplantation in Barth syndrome

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.

Development and content validity of the Barth Syndrome Symptom Assessment (BTHS-SA) for adolescents and adults

BackgroundBarth 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.MethodsConcept 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.ResultsDuring 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.ConclusionsThe 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.

Cardiolipin Remodeling Defects Impair Mitochondrial Architecture and Function in a Murine Model of Barth Syndrome Cardiomyopathy.

Cardiomyopathy is a major clinical feature in Barth syndrome (BTHS), an X-linked mitochondrial lipid disorder caused by mutations in Tafazzin (TAZ), encoding a mitochondrial acyltransferase required for cardiolipin remodeling. Despite recent description of a mouse model of BTHS cardiomyopathy, an in-depth analysis of specific lipid abnormalities and mitochondrial form and function in an in vivo BTHS cardiomyopathy model is lacking. We performed in-depth assessment of cardiac function, cardiolipin species profiles, and mitochondrial structure and function in our newly generated Taz cardiomyocyte-specific knockout mice and Cre-negative control mice (n≥3 per group). Taz cardiomyocyte-specific knockout mice recapitulate typical features of BTHS and mitochondrial cardiomyopathy. Fewer than 5% of cardiomyocyte-specific knockout mice exhibited lethality before 2 months of age, with significantly enlarged hearts. More than 80% of cardiomyocyte-specific knockout displayed ventricular dilation at 16 weeks of age and survived until 50 weeks of age. Full parameter analysis of cardiac cardiolipin profiles demonstrated lower total cardiolipin concentration, abnormal cardiolipin fatty acyl composition, and elevated monolysocardiolipin to cardiolipin ratios in Taz cardiomyocyte-specific knockout, relative to controls. Mitochondrial contact site and cristae organizing system and F1F0-ATP synthase complexes, required for cristae morphogenesis, were abnormal, resulting in onion-shaped mitochondria. Organization of high molecular weight respiratory chain supercomplexes was also impaired. In keeping with observed mitochondrial abnormalities, seahorse experiments demonstrated impaired mitochondrial respiration capacity. Our mouse model mirrors multiple physiological and biochemical aspects of BTHS cardiomyopathy. Our results give important insights into the underlying cause of BTHS cardiomyopathy and provide a framework for testing therapeutic approaches to BTHS cardiomyopathy, or other mitochondrial-related cardiomyopathies.

Treatment of Barth Syndrome by Cardiolipin Manipulation (CARDIOMAN) With Bezafibrate: Protocol for a Randomized Placebo-Controlled Pilot Trial Conducted in the Nationally Commissioned Barth Syndrome Service.

BackgroundBarth syndrome is a rare, life-threatening, X-linked recessive genetic disease that predominantly affects young males and is caused by abnormal mitochondrial lipid metabolism. Currently, there is no definitive treatment for Barth syndrome other than interventions to ameliorate acute symptoms, such as heart failure, cardiac arrhythmias, neutropenia, and severe muscle fatigue. Previous mechanistic studies have identified the lipid-lowering drug bezafibrate as a promising potential treatment; however, to date, no human trials have been performed in this population.ObjectiveThe aim of this study is to determine whether bezafibrate (and resveratrol in vitro) will increase mitochondrial biogenesis and potentially modify the cellular ratio of monolysocardiolipin (MLCL) to tetralinoleoyl-cardiolipin (L4-CL), ameliorating the disease phenotype in those living with the disease.MethodsThe CARDIOMAN (Cardiolipin Manipulation) study is a UK single-center, double-blinded, randomized, placebo-controlled crossover study investigating the efficacy of bezafibrate in participants with Barth syndrome. Treatment was administered in two 15-week phases with a minimum washout period of 1 month between the phases where no treatment was administered. The primary outcome is peak oxygen consumption (VO2 peak). Secondary outcomes include MLCL/L4-CL ratio and CL profile in blood cells, amino acid expression, phosphocreatine to adenosine triphosphate ratio in cardiac muscle and skeletal muscle oxidative function on phosphorus-31 magnetic resonance spectroscopy, quality of life using the Pediatric Quality of Life Inventory questionnaire, absolute neutrophil count, cardiac function and rhythm profiles at rest and during exercise, and mitochondrial organization and function assessments. Outcomes were assessed at baseline and during the final week of each treatment phase.ResultsA total of 12 patients were scheduled to participate across three consecutive research clinics between March and April 2019. In total, 11 participants were recruited, and the follow-up was completed in January 2020. Data analysis is ongoing, with publication expected in 2021.ConclusionsThis trial was approved by the United Kingdom National Research Ethics Service Committee and the Medicines and Healthcare products Regulatory Agency. The feasibility of the CARDIOMAN study will help to inform the future conduct of randomized controlled trials in rare disease populations as well as testing the efficacy of bezafibrate as a potential treatment for the disease and advancing the mechanistic understanding of Barth syndrome.Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN): 58006579; https://www.isrctn.com/ISRCTN58006579International Registered Report Identifier (IRRID)DERR1-10.2196/22533

Increased Reactive Oxygen Species-Mediated Ca2+/Calmodulin-Dependent Protein Kinase II Activation Contributes to Calcium Handling Abnormalities and Impaired Contraction in Barth Syndrome.

Mutations in tafazzin (TAZ), a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome (BTHS). Cardiomyopathy and risk of sudden cardiac death are prominent features of BTHS, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and arrhythmia are poorly understood. We performed in vivo electrophysiology to define arrhythmia vulnerability in cardiac-specific TAZ knockout mice. Using cardiomyocytes derived from human induced pluripotent stem cells and cardiac-specific TAZ knockout mice as model systems, we investigated the effect of TAZ inactivation on Ca2+ handling. Through genome editing and pharmacology, we defined a molecular link between TAZ mutation and abnormal Ca2+ handling and contractility. A subset of mice with cardiac-specific TAZ inactivation developed arrhythmias, including bidirectional ventricular tachycardia, atrial tachycardia, and complete atrioventricular block. Compared with wild-type controls, BTHS-induced pluripotent stem cell-derived cardiomyocytes had increased diastolic Ca2+ and decreased Ca2+ transient amplitude. BTHS-induced pluripotent stem cell-derived cardiomyocytes had higher levels of mitochondrial and cellular reactive oxygen species than wild-type controls, which activated CaMKII (Ca2+/calmodulin-dependent protein kinase II). Activated CaMKII phosphorylated the RYR2 (ryanodine receptor 2) on serine 2814, increasing Ca2+ leak through RYR2. Inhibition of this reactive oxygen species-CaMKII-RYR2 pathway through pharmacological inhibitors or genome editing normalized aberrant Ca2+ handling in BTHS-induced pluripotent stem cell-derived cardiomyocytes and improved their contractile function. Murine Taz knockout cardiomyocytes also exhibited elevated diastolic Ca2+ and decreased Ca2+ transient amplitude. These abnormalities were ameliorated by Ca2+/calmodulin-dependent protein kinase II or reactive oxygen species inhibition. This study identified a molecular pathway that links TAZ mutation with abnormal Ca2+ handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat BTHS and potentially other diseases with elevated mitochondrial reactive oxygen species production.

Effects of N‐oleoylethanolamide on Lymphoblasts Deficient in Tafazzin

Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in the TAZ gene that encodes for the cardiolipin remodelling enzyme, Tafazzin. This syndrome is characterized by cardiac and skeletal myopathies, as well as immunological deficits that cause significant morbidity and mortality. Study of the molecular pathology of BTHS thus provides insight into the role of cardiolipin and mitochondria in cellular physiology, while addressing a clinically relevant disease. Current treatment options for BTHS are limited, but a recent trial suggests that PPARα activation may be therapeutic. The objective of this study was to quantitatively examine the growth properties and mitochondrial physiology of B-lymphoblasts derived from five donors with BTHS, as well as effects of treatment with oleoylethanolamide (OEA), a bioactive N-acylethanolamine. Cyclic neutropenia is a well-recognized aspect of the pathology of BTHS. We hypothesized that deficits in lymphoblast proliferation would also be evident, and that OEA, which activates receptors including PPARα, would demonstrate therapeutic benefit. One million B-lymphoblasts derived from BTHS donors and age- and sex-matched healthy controls were seeded on day 0 and counted daily for 4 days. On day 4, there were 27.7 ± 4.6% fewer BTHS B-lymphoblasts than control cells (P<0.05), indicating that lymphopenia is likely also a component of BTHS. Treatment of B-lymphoblasts with 1 μM OEA caused no significant effect on control cell numbers, but significantly improved deficits in each of the five BTHS lymphoblast lines, raising the mean cell number on day 4 from 3.74 × 106 to 4.25 × 106 cells, although a full rescue of growth was not achieved. Analysis of electron micrographs of samples from two distinct BTHS B-lymphoblast donors indicated that cells had larger mitochondria as compared with healthy controls (mean of 0.67 ± 0.07 µM2 versus 0.27 ± 0.16 µM2, respectively). OEA decreased mitochondrial size by 53.0 ± 10.9%, while increasing the total mitochondrial number per cell by 92.6 ± 58.6%. OEA reduced the elevated expression of the enzyme CDS1 in BTHS B-lymphoblasts to healthy control levels, suggesting improved cardiolipin levels may play a role. However, an initial donor pair comparison did not show an effect of OEA on cardiolipin content, suggesting other mechanisms should be explored. Higher immunodetectable levels of OPA1, a biomarker of mitochondrial fusion, were found in lymphoblasts from children with BTHS, and were attenuated by OEA. Results from this study newly identify lymphopenia as a probable immunological deficit in BTHS, and suggest that therapies targeting aberrant fission/fusion of the mitochondrial network, rather than cardiolipin content, per se, and may have clinical utility for treatment of this disease.

Tissue‐specific roles of cardiolipin in the control of systemic energy homeostasis

The mitochondrial inner membrane is a dynamic interface that supports bioenergetic processes, intracellular communication, and transport of metabolites, lipids, and ions. The phospholipid, cardiolipin, is one of the defining components of this membrane and is classically ascribed an indispensable role in mitochondrial structure and function. Disruption of cardiolipin biology is causally linked to numerous pathophysiologies, including diabetes, nonalcoholic fatty liver disease, Parkinson's disease, and, most notably, Barth syndrome. Yet how cardiolipin controls the metabolic functions of different tissues and how these tissues respond to loss of cardiolipin remains largely unknown. Therefore, we generated inducible gain and loss-of-function genetic models of cardiolipin synthesis in tissues with predominantly uncoupled (i.e. brown adipose) or coupled (i.e. skeletal muscle) mitochondria. We found that tissue-specific loss of cardiolipin had dramatically different outcomes on respiration and whole-body metabolic homeostasis. Cardiolipin deficiency in brown adipocytes significantly reduced organismal insulin sensitivity and glucose tolerance, whereas loss of cardiolipin in skeletal muscle unexpectedly improved glycemic control. Moreover, in contrast to the dogmatic belief that cardiolipin is ubiquitously required for mitochondrial function, we found that certain skeletal muscle fiber types fully retained respiratory capacity in the face of cardiolipin depletion through adaptive measures. Our collective findings on tissue-specific roles of cardiolipin reshape the fundamental understanding of mitochondrial structure and function with potential therapeutic implications for phospholipid disorders.

Barth syndrome-related cardiomyopathy is associated with a reduction in myocardial glucose oxidation.

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.

EP142 - Barth syndrome caused by a novel TAZ deletion through an alu element-mediated mechanism: a case report

eP142 - Barth syndrome caused by a novel TAZ deletion through an alu element-mediated mechanism: a case report

A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism

PurposeTo evaluate effectiveness of elamipretide in Barth syndrome (BTHS), a genetic condition of defects in TAZ, which causes abnormal cardiolipin on the inner mitochondrial membrane.MethodsWe performed a randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension in BTHS to test the effect of elamipretide, a mitochondrial tetrapeptide that interacts with cardiolipin. In part 1, 12 subjects were randomized to 40 mg per day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and then 12 weeks on the opposite arm. Ten subjects continued on the open-label extension (part 2) of 40 mg per day of elamipretide, with eight subjects reaching 36 weeks. Primary endpoints were improvement on the 6-minute walk test (6MWT) and improvement on a BTHS Symptom Assessment (BTHS-SA) scale.ResultsIn part 1 neither primary endpoint was met. At 36 weeks in part 2, there were significant improvements in 6MWT (+95.9 m, p = 0.024) and BTHS-SA (-2.1 points, p = 0.031). There were also significant improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms, and some cardiac parameters.ConclusionIn this interventional clinical trial in BTHS, daily administration of elamipretide led to improvement in BTHS symptoms.

Barth syndrome: cardiolipin, cellular pathophysiology, management, and novel therapeutic targets.

Barth syndrome is a rare X-linked genetic disease classically characterized by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia, and 3-methylglutaconic aciduria. It is caused by mutations in the tafazzin gene localized to chromosome Xq28.12. Mutations in tafazzin may result in alterations in the level and molecular composition of the mitochondrial phospholipid cardiolipin and result in large elevations in the lysophospholipid monolysocardiolipin. The increased monolysocardiolipin:cardiolipin ratio in blood is diagnostic for the disease, and it leads to disruption in mitochondrial bioenergetics. In this review, we discuss cardiolipin structure, synthesis, and function and provide an overview of the clinical and cellular pathophysiology of Barth Syndrome. We highlight known pharmacological management for treatment of the major pathological features associated with the disease. In addition, we discuss non-pharmacological management. Finally, we highlight the most recent promising therapeutic options for this rare mitochondrial disease including lipid replacement therapy, peroxisome proliferator-activated receptor agonists, tafazzin gene replacement therapy, induced pluripotent stem cells, mitochondria-targeted antioxidants and peptides, and the polyphenolic compound resveratrol.

"I Want That Life a Lot…How on Earth Do I Get That?" Examining Challenges for Men With Barth Syndrome in Their Transitions to Adulthood.

vFor youth with life-limiting chronic illnesses, transitioning to adulthood in line with age-norms may be difficult due to symptom severity and shortened survival. This study explores whether individuals with Barth syndrome (BTHS), a condition uniquely characterized by extreme prognostic uncertainty, experience similar or different challenges compared to youth with other conditions. During focus groups with adults with BTHS (n = 12) and caregivers (n = 13), participants reported that the ability to independently manage one’s health condition, the social/emotional impacts of BTHS, and the ability to set goals in the context of future uncertainty challenge their transition to adulthood. This aligns with prior research, indicating that prognostic uncertainty may hinder long-term goal setting in BTHS. Implications of these findings include providing strategies for identifying meaningful alternative goals for individuals with chronic illnesses to target, promoting increased autonomy earlier in youth, and fostering coping strategies to manage non-disease related impacts.

Barth Syndrome: A Rare Cause of Congestive Heart Failure in Boys

Barth Syndrome: A Rare Cause of Congestive Heart Failure in Boys

Psychometric Properties of the Modified Barthel Index for Children With Rare Disorders

Objective: The Modified Barthel Index (MBI) measures individuals’ level of independence in performing activities of daily living. The purpose of this study was to examine the internal consistency and construct validity of the MBI for children with rare disorders. Methods: The study participants are children with rare disorders who have muscle weakness including Barth syndrome and congenital muscular dystrophy (N = 113). The MBI was completed by participants in either an online format utilizing the UF Qualtrics system or a pencil-and-paper format. Statistical analysis was conducted to examine the psychometric properties of the MBI. Results: The MBI showed excellent internal consistency for children with Barth syndrome (Cronbach’s α = .91) and congenital muscular dystrophy (Cronbach’s α = .93). Construct validity was supported by a significant difference in MBI scores among participants grouped by diagnoses. MBI score was significantly different between the unaffected group and congenital muscular dystrophy (p < .0001) as well as between the unaffected group and Barth syndrome (p < .0001). Conclusion: The psychometric properties of the MBI present good reliability and construct validity suggesting suitability for use as an outcome measure for children with rare disorders.

Dynamic Cardiolipin Synthesis Is Required for CD8+ T Cell Immunity

SummaryMitochondria constantly adapt to the metabolic needs of a cell. This mitochondrial plasticity is critical to T cells, which modulate metabolism depending on antigen-driven signals and environment. We show here that de novo synthesis of the mitochondrial membrane-specific lipid cardiolipin maintains CD8+ T cell function. T cells deficient for the cardiolipin-synthesizing enzyme PTPMT1 had reduced cardiolipin and responded poorly to antigen because basal cardiolipin levels were required for activation. However, neither de novo cardiolipin synthesis, nor its Tafazzin-dependent remodeling, was needed for T cell activation. In contrast, PTPMT1-dependent cardiolipin synthesis was vital when mitochondrial fitness was required, most notably during memory T cell differentiation or nutrient stress. We also found CD8+ T cell defects in a small cohort of patients with Barth syndrome, where TAFAZZIN is mutated, and in a Tafazzin-deficient mouse model. Thus, the dynamic regulation of a single mitochondrial lipid is crucial for CD8+ T cell immunity.

Barth Syndrome with Tafazzin Variants Associated with Left Ventricular Noncompaction Cardiomyopathy Estimating on Layer-Specific Two-Dimensional Speckle Tracking Echocardiography: A Case Report

Barth Syndrome with Tafazzin Variants Associated with Left Ventricular Noncompaction Cardiomyopathy Estimating on Layer-Specific Two-Dimensional Speckle Tracking Echocardiography: A Case Report

Cardiolipin deficiency in Barth syndrome is not associated with increasedsuperoxide/H2 O2 production in heart and skeletal muscle mitochondria.

Barth syndrome (BTHS) is a rare X‐linked genetic disorder caused by mutations in the gene encoding the transacylase tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial oxidants have been implicated in the cardiomyopathy in BTHS. Eleven mitochondrial sites produce superoxide/hydrogen peroxide (H2O2) at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2O2 production from each site and the ex vivo rate of superoxide/H2O2 production in the heart and skeletal muscle mitochondria of the tafazzin knockdown mice (tazkd) from 3 to 12 months of age. Despite reduced oxidative capacity, superoxide/H2O2 production was indistinguishable between tazkd mice and wild‐type littermates. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology.

Abstract 14116: Favorable Outcomes for Heart Transplantation in Barth Syndrome as Demonstrated by Multicenter/multiregistry Analysis

Introduction: Barth Syndrome (BTHS) is a rare (~1/350,000), X-linked mitochondrial disease characterized by cardioskeletal myopathy and neutropenia. Reported outcomes after heart transplant (HT) are limited to case reports. We sought to identify a large cohort of BTHS HT recipients to describe clinical outcomes. Hypothesis: HT in BTHS is associated with non-inferior survival, acute rejection (AR), infection, and vasculopathy (CAV) relative to non-BTHS dilated cardiomyopathy (DCM). Methods: We analyzed data from the Barth Syndrome Registry and Repository (BRR), Pediatric Heart Transplant Society (PHTS), and Scientific Registry of Transplant Recipients (SRTR). To avoid recounting patients occurring in &gt;1 source, we used years of birth, listing, and HT and listing/HT city to link records across registries. BTHS HT recipients were matched 1:4 on age, era, urgency status, and use of ECMO/VAD to male, non-BHTS, DCM HT recipients in PHTS. Survival was analyzed for all BTHS HT recipients. Because BRR and SRTR morbidity data are limited, AR, infection, malignancy, and CAV were analyzed only for those with PHTS data. Results: Forty-seven BTHS patients with 51 listings and 43 HTs (including 2 re-transplants) were identified; 29 BTHS HTs (1 re-transplant) had data in PHTS. Median age at HT was 1.9 yrs (IQR: 0.6-5.8) with 35% &lt;1 years-old at HT. Median follow up was 4.2 yrs (2.1-9.1). Mechanical circulatory support at HT was common (VAD 29%, ECMO 5%). We found no difference in survival between BTHS and non-BTHS HT recipients (HR 0.93, 95% CI 0.40-2.14). Freedom from infection (HR 0.63, 0.33-1.20), bacterial infection (HR 0.76, 0.29-1.99), malignancy (HR 0.22, 0.02-2.02), and CAV (HR 0.55, 0.15-1.97) were also similar between the groups. BTHS HT recipients had greater freedom from AR (HR 0.39, 0.17-0.87). Use of induction therapy (62 vs 74%, p=0.21), steroids at 30 days (76 vs 62%, p=0.17), and dual or triple immunosuppression at 1 year (80 vs 84%, p=0.58) were similar for BTHS and non-BTHS recipients. Conclusions: In this largest cohort yet reported, BTHS HT recipients show equivalent survival and freedom from infection, malignancy, and CAV, with a lower risk of acute rejection. Thus, individuals with BTHS should not be excluded from HT solely based on the diagnosis of BTHS.