RARE DISEASE
Barth syndrome
Barth syndrome
Barth syndrome
Synonyms: 3-methylglutaconic aciduria type 2, BTHS, Cardioskeletal myopathy with neutropenia and abnormal mitochondria, Cardioskeletal myopathy-neutropenia syndrome, MGA2, X-linked cardioskeletal myopathy and neutropenia
Synonyms: 3-methylglutaconic aciduria type 2, BTHS, Cardioskeletal myopathy with neutropenia and abnormal mitochondria, Cardioskeletal myopathy-neutropenia syndrome, MGA2, X-linked cardioskeletal myopathy and neutropenia
Synonyms: 3-methylglutaconic aciduria type 2, BTHS, Cardioskeletal myopathy with neutropenia and abnormal mitochondria, Cardioskeletal myopathy-neutropenia syndrome, MGA2, X-linked cardioskeletal myopathy and neutropenia
Drug discovery
3
drugs
With orphan designations
Overview
Barth syndrome is an X-linked mitochondrial disorder caused by TAZ gene mutations disrupting cardiolipin metabolism, leading to cardiomyopathy, skeletal myopathy, chronic neutropenia, growth delays, and fatigue [1][6][17]. Diagnosis involves genetic testing, echocardiography, and elevated 3-methylglutaconic acid levels [1][6][12].
Burden
Mortality peaks before age 5 (85% of deaths), often from heart failure or sepsis; survivors typically live into their 40s [2][12][19].
High healthcare utilization: Patients see 3–4 specialists/year, with 30% requiring cardiac transplantation [4][12][17].
Chronic fatigue affects 61% of patients, with 47% reporting moderate-to-severe impacts on daily function [4][12].
Therapies
Cardiac management: Beta-blockers, ACE inhibitors, and cardiac transplantation for end-stage cardiomyopathy [1][6][17].
Supportive care: Granulocyte colony-stimulating factor (G-CSF) for neutropenia, prophylactic antibiotics, and tailored physical/nutritional therapy [6][12][17].
Investigational therapies: Elamipretide (cardiolipin stabilizer) and bezafibrate (PPAR agonist) in clinical trials targeting mitochondrial dysfunction [3][13][18].
Categories: rare cardiac diseases, rare genetic diseases, rare immunological diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
188 drug discovery papers about Barth syndrome, with 5 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
188 drug discovery papers about Barth syndrome, with 5 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2026-08-10 | Barth Syndrome and Referral to Heart Transplantation: Single-Center Experience and Literature Review.
Barth syndrome is an X-linked mitochondrial disorder caused by pathogenic variants in the TAZ gene, resulting in impaired cardiolipin remodeling and mitochondrial dysfunction. Cardiomyopathy is the most prominent manifestation, often presenting in early infancy and potentially progressing to advanced heart failure requiring heart transplantation. Due to phenotypic overlapping with other cardiac diseases, diagnosis is frequently delayed. The aim of this study was to describe our experience with pediatric patients with Barth syndrome referred to heart transplantation and their clinical outcomes at the largest heart transplantation center in Latin America. We retrospectively reviewed pediatric patients with Barth syndrome referred for heart transplantation evaluation at the Heart Institute (InCor), University of São Paulo Medical School, between 1992 and 2025. Clinical characteristics, heart failure severity, transplant evaluation, treatment response, listing status, and outcomes were described. We retrospectively reviewed three pediatric patients with genetically confirmed Barth syndrome referred to our center for heart transplantation evaluation. Despite severe early cardiac involvement, they exhibited markedly different heart failure trajectories. Barth syndrome cardiomyopathy follows a highly heterogeneous clinical course. Although some patients demonstrate significant recovery with optimized heart failure therapy, others progress to end-stage heart failure requiring transplantation. Our experience reinforces that early referral to pediatric heart transplant centers and individualized transplant listing based on longitudinal clinical evolution, rather than left ventricular ejection fraction alone, may optimize patient outcomes. Early referral to pediatric heart transplant centers and individualized transplant listing based on longitudinal clinical evolution may optimize outcomes in Barth syndrome.
2025-06-25 | Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome.
Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN, which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. Here we explored the possibility of using stem-cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem (iPS) cells from healthy individuals and from patients with BTHS and differentiated them into cardiomyocytes. The iPS-cell-differentiated cardiomyocytes (CMs) derived from patients with BTHS exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT and cTnI, and smaller cell size than normal iPS-cell-derived CMs. Multielectrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired and mitophagy was decreased in BTHS CMs compared with normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.
2024-11-13 | Rescue of mitochondrial dysfunction through alteration of extracellular matrix composition in barth syndrome cardiac fibroblasts.
Fibroblast-ECM (dys)regulation is associated with a plethora of diseases. The ECM acts as a reservoir of inflammatory factors and cytokines that mediate molecular mechanisms within cardiac cell populations. The role of ECM-mitochondria crosstalk in the development and progression of cardiac disorders remains uncertain. We evaluated the influence of ECM produced by stromal cells from patients with the mitochondrial cardiomyopathy (Barth syndrome, BTHS) and unaffected healthy controls on cardiac fibroblast (CF) metabolic function. To do this, cell-derived matrices CDMs were generated from BTHS and healthy human pluripotent stem cell-derived CFs (hPSC-CF) and used as cell culture substrates. BTHS CDMs negatively impacted the mitochondrial function of healthy hPSC-CFs while healthy CDMs improved mitochondrial function in BTHS hPSC-CFs. Mass spectrometry comparisons identified 5 matrisome proteins differentially expressed in BTHS compared to healthy CDM. Our results highlight a key role for the ECM in disease through its impact on mitochondrial function.
2022-07-13 | Tafazzin deficiency in mouse mesenchymal stem cells promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.
Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutation in the TAFAZZIN gene. Tafazzin (Taz) deficiency in BTHS patients results in an increased risk of infections. Mesenchymal stem cells (MSCs) are well known for their immune-inhibitory function. We examined how Taz-deficiency in murine MSCs impact their ability to modulate the function of lipopolysaccharide (LPS)-activated wild type (WT) B lymphocytes. MSCs from tafazzin knockdown (TazKD) mice exhibited a reduction in mitochondrial cardiolipin compared to wild type (WT) MSCs. However, mitochondrial bioenergetics and membrane potential were unaltered. In contrast, TazKD MSCs exhibited increased reactive oxygen species generation and increased glycolysis. The increased glycolysis was associated with an elevated proliferation, phosphatidylinositol-3-kinase expression and expression of the immunosuppressive markers indoleamine-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4, interleukin-10, and cluster of differentiation 59 compared to controls. Inhibition of glycolysis with 2-deoxyglucose attenuated the TazKD-mediated increased expression of cytotoxic T-lymphocyte-associated protein 4 and interleukin-10. When co-cultured with LPS-activated WT B cells, TazKD MSCs inhibited B cell proliferation and growth rate and reduced B cell secretion of immunoglobulin M compared to controls. In addition, co-culture of LPS-activated WT B cells with TazKD MSCs promoted B cell differentiation toward interleukin-10 secreting plasma cells and B regulatory cells compared to controls. The results indicate that Taz deficiency in MSCs promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.
2017-09-22 | MODELING THE DILATED CARDIOMYOPATHY WITH ATAXIA SYNDROME (DCMA), A PEDIATRIC MITOCHONDRIAL CARDIOMYOPATHY, USING CARDIOMYOCYTES DERIVED FROM INDUCED PLURIPOTENT STEM CELLS
Cardiomyopathy is a predominant and lethal feature of many inborn metabolic disorders but results from derangements in cellular energetics rather than ischemic myocardial injury. This fundamental difference is likely why standard heart failure medications appear to be ineffective. This problem is exemplified by the dilated cardiomyopathy with ataxia syndrome (DCMA). DCMA is related to Barth syndrome with abnormal cardiolipin and mitochondria causing heart failure, conduction defects and other systemic features. Isolated cases of DCMA have been identified worldwide but the largest known group of patients is found in the Hutterites of southern Alberta. No effective therapy exists and in our cohort there is 39% mortality in early childhood related to cardiac dysfunction despite recommended optimal medical therapy. The lack of useful drugs for mitochondrial cardiomyopathies means that there are few therapies available outside of mechanical circulatory support or heart transplantation. Since the rarity and heterogeneity of the pediatric cardiomyopathies preclude randomized drug trials, the use of patient cells and in vitro drug modeling represents the best possible option to identify effective therapeutics. Here, we describe the creation and characterization of cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) (as an in vitro model of DCMA) from 4 children with DCMA and varying severity of cardiac dysfunction. Purified peripheral blood mononuclear cells derived from 4 DCMA patients (Table 1) were reprogrammed into induced pluripotent stem cells (iPSCs) using Sendai virus and the 4 Yamanaka factors, and characterized using standard pluripotency tests. Our iPSCs expressed markers of pluripotency including SSEA4 and OCT4. The DCMA-derived iPSCs were sequenced to detect the DCMA related mutation in their genomic DNA. Results showed that the iPSCs carried the DNAJC19 mutation (rs137854888) responsible for the abnormal splicing causing the disease phenotype. These iPSCs were successfully differentiated into beating cardiomyocytes using a modified protocol and lactate as a sole carbon source to enrich purified iPSC-CMs. The resulting iPSC-CMs expressed the cardiac-specific markers TNNT2 and NKX2.5. We describe the development of iPSC-CMs for DCMA which represent a novel in vitro model for mitochondrial cardiomyopathy and provide a platform to study the efficacy of potential therapeutics and genome editing approaches.
small molecules
2026-09-26 | Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
Inherited mitochondrial cardiomyopathies arise from pathogenic variants affecting oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin remodeling, protein import, cofactor metabolism, and mitochondrial dynamics or proteostasis. These disorders may be cardiac-predominant or part of multisystem disease. Their overlapping cardiac phenotypes suggest convergence on interacting pathways of energetic stress, cristae disruption, calcium imbalance, and redox injury, but do not establish a universal requirement for defective mitophagy. Mitochondrial quality control encompasses protein surveillance, membrane remodeling, dynamics, biogenesis, and organelle disposal; mitophagy is one component. We critically examine the hypothesis that inadequate clearance of damaged mitochondria contributes to progression in a subset of genotypes and disease stages. Disease-specific studies provide support in selected Barth syndrome models, whereas findings in frataxin deficiency vary with model and assay. We distinguish mitochondrial delivery to lysosomes, dynamic turnover measurements, and changes in pathway markers, and identify indirect evidence from acquired heart disease and fatty acid oxidation deficiency. Therapeutic evidence is separated into cellular, animal, and human studies and approved indications. Elamipretide has accelerated approval for muscle-strength improvement in patients with Barth syndrome weighing at least 30 kg; cardiac disease modification remains unconfirmed. Gene replacement has reached early clinical testing, including adeno-associated virus-mediated frataxin gene delivery (AAV-FXN), whereas mitochondrial genome editing and selective mitophagy modulation remain investigational. We propose testable predictions addressing progression, selective rescue, and treatment timing, together with outcomes that would challenge the hypothesis. This framework supports genotype- and stage-specific investigation without assuming that enhanced mitophagy will benefit every mitochondrial cardiomyopathy.
2026-07-13 | Compensatory Metabolic Responses of Peroxisomes in Barth Syndrome Cardiomyopathy
Mitochondrial function relies on the unique phospholipid cardiolipin, which is enriched in the inner mitochondrial membrane (IMM) and plays a central role in maintaining cristae architecture, stabilizing respiratory chain supercomplexes, and supporting efficient oxidative phosphorylation. Disruption of cardiolipin remodelling compromises mitochondrial structure and bioenergetic capacity and is associated with altered redox balance and stress signaling pathways, placing cells under chronic energetic and oxidative stress. These mitochondrial defects are a defining feature of Barth syndrome (BTHS), a rare X-linked disorder caused by mutations in the TAFAZZIN gene. In tissues with high energetic demand, particularly the heart, impaired mitochondrial function contributes to progressive cardiomyopathy alongside systemic manifestations such as skeletal myopathy and neutropenia. Although mitochondrial dysfunction represents the primary molecular defect in Barth syndrome (BTHS), its effects extend beyond mitochondrial function. Chronic mitochondrial stress engages adaptive signaling pathways, including the integrated stress response (ISR), which coordinates transcriptional programs that regulate redox, metabolism, and protein homeostasis. Activation of ISR-associated transcription factors such as ATF4 and CHOP reflects an attempt to mitigate oxidative and metabolic stress; however, sustained activation may also increase vulnerability under prolonged stress conditions. How cells tolerate ongoing mitochondrial dysfunction in BTHS, and which additional organelles contribute to this adaptive balance, remain incompletely understood. Peroxisomes are metabolically active organelles with established roles in lipid metabolism and redox regulation and maintain close physical and functional interactions with both mitochondria and the endoplasmic reticulum (ER). Through β-oxidation of specific lipid species, hydrogen peroxide (H\(^2\)O\(^2\)) detoxification via catalase, and the initiation of plasmalogen biosynthesis, peroxisomes are positioned to influence cellular stress responses. In the context of BTHS, in which mitochondrial bioenergetics and lipid remodelling are altered, peroxisomal pathways may undergo compensatory adjustments to maintain redox and metabolic homeostasis. This thesis investigates the contribution of peroxisomal metabolism to the cellular response to mitochondrial dysfunction in BTHS, with a focus on catalase-mediated ROS buffering and plasmalogen biosynthesis via glyceronephosphate O-acyltransferase (GNPAT). Using Tafazzin-deficient mouse embryonic fibroblasts (MEFs) following targeted knockdown of catalase and GNPAT, the functional roles of these pathways were examined in relation to oxidative stress handling, ISR signaling, and stress susceptibility. Molecular, biochemical, imaging-based, and ultrastructural analyses were integrated to assess changes in redox balance, stress-responsive gene expression, and organelle organization. The findings demonstrate that peroxisomal pathways are actively engaged in response to mitochondrial dysfunction in Tafazzin deficiency. Peroxisomal catalase contributes to H\(^2\)O\(^2\) buffering, while plasmalogen biosynthesis modulates membrane-dependent stress signaling rather than functioning as a direct antioxidant pathway. Importantly, these peroxisomal responses shape redox homeostasis and stress-signal thresholds, determining whether mitochondrial dysfunction remains within an adaptive range or progresses toward heightened stress vulnerability. Together, these results expand the pathophysiological framework of BTHS beyond isolated mitochondrial dysfunction and identify peroxisome-mitochondria crosstalk as a key component of cellular stress adaptation and a potential target for strategies to enhance resilience in mitochondrial cardiomyopathy.
2026-07-08 | Elamipretide in pediatric Barth syndrome: from heart failure to school return.
Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder characterized by cardiomyopathy, neutropenia, and skeletal myopathy. Elamipretide is a mitochondria-targeting peptide that stabilizes cardiolipin and improves mitochondrial function. While use of this treatment in infants with BTHS has been reported in the United States, no cases have been described outside the US or in older children. We report the first case of a preschool-aged child with genetically confirmed BTHS and advanced heart failure, who was treated with elamipretide under a compassionate use program approved by the French Drug Administration (ANSM). At treatment initiation, this 5-year-old patient presented with severe left ventricular dysfunction (LVEF = 20%) and moderate-to-severe mitral regurgitation. He was dependent on gastrostomy feeding and had been listed for heart transplantation. Subcutaneous elamipretide (10 mg/day) was initiated alongside maximal conventional heart failure therapy. Over six months, LVEF improved to 50%, mitral regurgitation decreased to mild, Ross class improved from IV to I, and substantial gains were observed in functional capacity, nutritional status, and health-related quality of life (HRQoL). The patient returned to full-time school and remained temporarily suspended from the transplant list. Treatment was generally well tolerated. One transient, non-serious episode of abdominal pain with moderate pancreatic enzyme elevation occurred, which resolved without treatment discontinuation. This case suggests that elamipretide may improve cardiac function, exercise tolerance, nutrition, and HRQoL in preschool-aged pediatric BTHS patients, potentially delaying the need for transplantation. Broader pediatric evaluation is warranted. Further strategies, such as youth-tailored hybrid cardiac rehabilitation programs, could complement pharmacological therapy and further optimize outcomes in this population.
2026-06-30 | Peroxisomal catalase and plasmalogen biosynthesis protect from oxidative stress in Barth syndrome cardiomyopathy.
Barth Syndrome (BTHS) is an inherited mitochondrial cardiomyopathy caused by variants in the gene encoding TAFAZZIN (Taz), a transacylase catalyzing the synthesis of the essential mitochondrial phospholipid cardiolipin (CL). Although defects in Taz deteriorate mitochondrial respiration, Ca2+-uptake, and redox regulation in cardiac myocytes, we previously observed an unexpected lack of oxidative cardiac damage, despite the development of cardiomyopathy in a BTHS mouse model with Taz-knockdown (KD). Furthermore, we revealed that the integrated stress response (ISR) governs metabolic rewiring in Taz-KD hearts to compensate for deficient mitochondrial FAO and to support GSH production. Here, we interrogated whether adaptive mechanisms in peroxisomes, which are closely associated with mitochondria and harbor antioxidative enzymes, can also compensate for the mitochondrial defects. We identified alterations in the peroxisomal biogenesis factors PEX14 and PEX19, indicating changes in the peroxisomal proteome in Taz-KD vs. WT hearts. While the enzymes of peroxisomal FAO were unchanged, levels of Lon Protease 2 (LONP2) and catalase were elevated in Taz-KD hearts. Inhibition or siRNA-mediated knockdown of catalase increased reactive oxygen species (ROS) and blunted the protection of mouse embryonic fibroblasts (MEF) with Taz-knockout (KO), but not in WT, from ROS-induced activation of the apoptotic caspase 3. Furthermore, we observed that the increase in plasmalogen synthesis in cardiac Taz-KD peroxisomes contributes to the activation of the ISR, since siRNA-mediated knockdown of the key enzyme GNPAT blunted the ISR and thereby increased cellular ROS in Taz-KO, but not WT MEFs. In conclusion, peroxisomes facilitate a counterregulatory response to dysfunctional mitochondria by activating a catalase-driven ROS defense and maintaining ISR-mediated metabolic alterations, both of which compensate for mitochondrial dysfunction and oxidative stress. Therefore, the so far poorly investigated mitochondrial-peroxisome crosstalk may represent a novel therapeutic target in an orphan disease with a poor prognosis.
2026-06-27 | AMCP Market Insights: Managed care considerations in Barth syndrome.
Barth syndrome is an ultrarare, complex, multisystem, X-linked metabolic and neuromuscular disease, which poses significant and wide-ranging burden to patients and caregivers. Pharmacologic management focuses on treatment of disease manifestations and prevention of secondary complications. Elamipretide, the first treatment indicated specifically for improving muscle strength in Barth syndrome, was approved in 2025 via accelerated approval warranting guidance for payers. To discuss managed care considerations in Barth syndrome including management of elamipretide, AMCP Market Insights virtually convened an expert panel of managed care stakeholders in March 2026. This article provides a qualitative summary of the panel discussion along with key insights and suggested payer practices meant to support informed coverage decisions and guide future work such as collaboration, research, and advocacy. Key insights highlight that there are unique challenges in generating clinical trial evidence for treatments in ultrarare conditions, which leads to difficulties determining the value of these treatments and differences in whether they are covered among payers. Additionally, there are numerous elements of care to which patients with Barth syndrome and their caregivers need equitable access, which is complicated by involving multiple specialists and fragmentation. Suggested payer practices involve education, care delivery, and coverage and benefit design.
proteins
2025-08-07 | Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
Mitochondrial calcium (Ca2+) uptake and factors that regulate this process have been an area of immense interest given the roles in cellular energetics. Here, we have investigated the ability of the Ca2+ sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca2+ Uniporter (MCU). Our data leveraged recombinantly produced CaM and mitochondria isolated from healthy and MCU impaired/diseased mice (Barth syndrome model). We found CaM enhanced Ca2+ uptake in both the absence and presence of CaMKII inhibition (KN93 as well as AIP). Mitochondria lacking function MCU (Barth syndrome model) validated that MCU was responsible for Ca2+ uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca2+ buffering. Fitting the Ca2+fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca2+ uptake. This CaM enhancement effect persisted in the presence of PTP impairment (cyclosporin), and subtle modification to the CaM protein sequence (D131E) revealed that an intact CaM-C domain Ca2+ binding was required for enhancement of MCU function.
2025-01-01 | Adaptive mechanisms in pancreatic islets counteract mitochondrial dysfunction in Barth syndrome
Aims/hypothesis Barth syndrome is a mitochondrial disorder caused by Tafazzin (TAZ) mutations, which impair cardiolipin remodelling and contribute to systemic metabolic alterations. While islet dysfunction has been implicated in Barth syndrome, its underlying mechanisms remain unknown. We aimed to determine how Tafazzin (Taz) deficiency affects mouse pancreatic islet metabolism and hormone secretion, and whether systemic signals, such as circulating factors, modulate these effects in vivo. In vivo and in vitro models were used to separate direct islet effects from systemic influences of Taz deficiency. Methods We used a mouse model of global Taz knockdown (Taz-KD) and combined in vivo and in vitro approaches to assess pancreatic islet metabolism, morphology and hormone secretion. Islet function was evaluated under basal and glucotoxic conditions. Transcriptomic profiling was performed to identify gene expression changes in isolated islets from Taz-KD mice and following in vitro Taz-KD. Additionally, we examined the role of the circulating factor fibroblast growth factor 21 (FGF-21) in modulating islet function. Results Despite impaired cardiolipin remodelling, pancreatic islets from Taz-KD mice maintained insulin secretion, sup ported by compensatory mechanisms such as increased glucose uptake, expanded mitochondrial volume and increased metabolic parameters. In addition, alpha cell mass and glucagon secretion were significantly increased in Taz-KD islets. These islet-specific adaptations occurred alongside improved whole-body glucose tolerance, elevated circulating FGF-21 levels and enhanced glucose uptake in brown adipose tissue. In contrast, in vitro Taz-KD led to impaired islet function and reduced insulin secretion. Transcriptomic analysis revealed distinct gene expression patterns between in vivo and in vitro Taz-KD models. While in vivo upregulation of genes related to N-acetylglucosamine biosynthesis and O-GlcNAcylation were related to compensatory mechanisms, in vitro Taz-KD affected, among others, the MAPK pathway, contributing to islet dysfunction. Notably, islet incubation with FGF-21 was able to restore insulin secretion after in vitro Taz-KD. Conclusions/interpretation Our findings demonstrate that while Taz and cardiolipin remodelling are essential for beta cell physiology, systemic and islet-specific compensatory mechanisms preserve insulin secretion in vivo in Taz-KD mice, alongside increased glucagon secretion. These adaptations probably contribute to the altered metabolic phenotype observed in Barth syndrome and highlight a potential role for hormones and circulating factors such as FGF-21 in maintaining islet function and glucose homeostasis.
2022-09-08 | Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome.
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. 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). 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. 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. 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.
2021-12-15 | Barth syndrome with severe dilated cardiomyopathy and growth hormone resistance: a case report.
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.
2020-02-06 | Neutropenia in Barth syndrome: characteristics, risks, and management.
Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 μg/kg/day (mean 1.16 μg/kg/day, median 1.16 μg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ± prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.
gene therapies
2026-09-29 | Comparative Efficacy of AAV-Tafazzin and AAV-Δ5 Tafazzin in Restoring Mitochondrial Function in Barth Syndrome Induced Pluripotent Stem Cell Derived Cardiomyocytes
We compared efficacy and efficiency of two AAV-Tafazzin variants AAV-CoTAZ (full length) and AAV-Δ5 (exon 5 removed) in Barth syndrome iPSC cardiomyocytes. We performed AAV transduction in iPSC cardiomyocytes and cultured cells for 7 days followed by an array of mitochondrial functional assays and gene expression analysis. The raw data from MTT, ATP, ROS, TMRE, and OCR assays and the qRT-PCR assay for all healthy and BTHS cell lines. Mitochondrial assays are normalized to 1ug of protein for all assays. We hypothesized that the AAV delivery of tafazzin improves mitochondrial function in BTHS iPSC cardiomyocytes and that Δ5 variant performs superior as it is abundant in heart and skeletal muscle.
2026-09-05 | Barth syndrome manifesting as neonatal left ventricular dysfunction, an uncommon presentation
No abstract available
2025-12-05 | Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth's Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease.
2025-08-01 | Abstract Fri113: Targeting mitochondrial proteostasis in Barth syndrome-related cardiomyopathy
Background: Barth syndrome (BTHS) is a disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) metabolism and leads to cardiac and skeletal myopathy, neutropenia, and 3-methylglutaconic aciduria. Altered CL impairs mitochondrial function, contributing to symptoms of BTHS. Despite extensive research, the molecular mechanisms underlying BTHS remain unclear, and no cure exists. Mitochondrial protein quality control (MPQC) is crucial for maintaining mitochondrial homeostasis, yet its role in BTHS is underexplored. Our preliminary data indicate elevated levels of Caseinolytic peptidase B (CLPB), a mitochondrial chaperonin localized in the intermembrane space (IMS) with disaggregase activity, in BTHS patient-derived cells, and Tafazzin-deficient BTHS mice. Hypothesis: Our data-driven hypothesis proposes that CLPB regulates the quality control of IMS proteins, mitochondrial function, and bioenergetics to support cardiac health. However, this adaptive response becomes maladaptive during BTHS pathology. Aim: We aim to understand CLPB’s function in BTHS and explore its potential as a therapeutic target. Methods: We generated CLPB knockouts in both control and Tafazzin -/- C2C12 cells, as well as a CLPB knockdown mouse model in Tafazzin fl/fl (control) and Tafazzin fl/fl x aMHC-Cre. Using cellular, molecular, and physiological approaches, we evaluated CLPB’s impact on mitochondrial homeostasis and its therapeutic potential in BTHS. Results: CLPB loss improves NADH and calcium retention capacity without affecting mitochondrial respiration rate&membrane potential, ATP, and mtDNA content in Tafazzin -/- -Clpb -/- compared to control, Clpb -/- and Tafazzin -/- C2C12 cells. To explore the underlying mechanisms behind changes in the metabolic state of Tafazzin -/- -Clpb -/- cells, we analyzed transcripts of CL regulators (ALCLAT1 and CLS1), mitochondrial biogenesis (PGC1a, Tfam, and NRF1/2), and mtUPR (ATF4/5, HSP70, CHOP, and SOD2) markers. The Tafazzin -/- -Clpb -/- activate mitochondrial biogenesis and CL synthesis by elevating PGC1a and CLS1 transcripts, while their mtUPR transcript profile is comparable to control cells. Furthermore, echocardiographic analysis shows restoration of ejection fraction in CLPB KD and Tafazzin fl/fl x aMHC-Cre -CLPB KD mice. Conclusion: These findings highlight CLPB’s crucial role in IMS proteins quality control and mitochondrial homeostasis, providing a basis for new therapeutic avenues against mitochondrial dysfunction in BTHS.
2025-07-10 | A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions.
Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodeling are mediated by a coordinated set of enzymes, and disruptions in this pathway are increasingly recognized as causes of inherited mitochondrial diseases. This review provides a comprehensive overview of the genetic disorders associated with defects in cardiolipin metabolism, highlighting genetic and molecular characteristics, clinical manifestations, and available models with which to study these diseases. We examine the roles of key genes involved in cardiolipin biosynthesis (PGS1, CRLS1) and remodeling (TAZ, AGK, among others), and describe how pathogenic variants disrupt mitochondrial function. The prototypical disorder, Barth syndrome, is discussed in depth alongside recently identified conditions linked to defects in related enzymes.
other
2025-02-21 | [Analysis of 21 cases of Barth syndrome in children].
Objective: To investigate the clinical manifestations, treatment, and outcomes of Barth syndrome (BTHS). Methods: A retrospective analysis was conducted on 21 pediatric patients diagnosed with BTHS between January 2010 and December 2023 at Beijing Children's Hospital, Beijing Anzhen Hospital, and Beijing JingDu Children's Hospital. Clinical data including gender, age at onset, initial symptoms, clinical manifestations, personal history, family genetic history, and laboratory tests (neutrophil count, echocardiography, electrocardiogram and genetic testing) were reviewed. Results: All the 21 patients were male, with the age of onset at 4.1 (1.1, 9.3) months. Main clinical manifestations included heart failure (18 cases), neutropenia (16 cases), respiratory symptoms (15 cases), 3-methylpentenediuria (7 cases),develop retardation (8 cases), gastrointestinal symptoms (7 cases), fatigue and anorexia (6 cases), and recurrent infection (2 cases). Electrocardiogram abnormalities included ST changes (18 cases), flattened T wave and low voltage of limb leads (2 cases), and abnormal Q waves in lead Ⅰ and avL (1 case). Echocardiographic features showed increased trabeculation, interventricular septum and left ventricular wall thickening, and left ventricular enlargement with reduced ejection fraction. Genetic testing identified TAZ gene variations in all 21 patients: 11 missense mutations, 2 nonsense mutations, 2 frameshift mutations, 2 whole code mutations, 2 exon deletions, 1 splicing mutation, and 1 synonymous mutation. Fifteen mutations were maternally inherited, 2 were de novo, and 4 lacked verified variant origin.In terms of treatment, all 18 patients with heart failure received routine heart failure treatment, of whom 11 patients also received intravenous immunoglobulin and corticosteroids. After the follow-up of 91.0 (75.5, 109.5) months, 15 of the 18 patients showed restoration of cardiac function after 4.5 (3.0, 9.8) months of treatment, with one case of significant improvement, while 2 cases suddenly died. Conclusions: BTHS predominantly affects males with early onset, mainly characterized by abnormal cardiac structure and function, along with clinical features including fatigue, delayed growth and development, and neutropenia. Early diagnosis and intervention, including heart failure treatment, intravenous immunoglobulin, and corticosteroids, can lead to significant improvement in cardiac function, though sudden death remains a risk.
2021-12-28 | Extended recovery of cardiac function after severe infantile cardiomyopathy presentation of Barth syndrome
Cardiomyopathy is the most common presenting feature of Barth syndrome, often presenting in infancy with severe heart failure and cardiac dysfunction. Historically, affected infants commonly died early after presentation, sometimes before a diagnosis of Barth syndrome was made. With increases in awareness of Barth syndrome and in the care of infants with severe heart failure, survival of children with Barth syndrome and severe heart failure has improved. We describe our experience caring for five unrelated boys with Barth syndrome who presented with severe cardiomyopathy and heart failure prior to age 2 who have had marked improvement with long-term response to medical heart failure therapy.
cell therapies
2026-08-10 | Barth Syndrome and Referral to Heart Transplantation: Single-Center Experience and Literature Review.
Barth syndrome is an X-linked mitochondrial disorder caused by pathogenic variants in the TAZ gene, resulting in impaired cardiolipin remodeling and mitochondrial dysfunction. Cardiomyopathy is the most prominent manifestation, often presenting in early infancy and potentially progressing to advanced heart failure requiring heart transplantation. Due to phenotypic overlapping with other cardiac diseases, diagnosis is frequently delayed. The aim of this study was to describe our experience with pediatric patients with Barth syndrome referred to heart transplantation and their clinical outcomes at the largest heart transplantation center in Latin America. We retrospectively reviewed pediatric patients with Barth syndrome referred for heart transplantation evaluation at the Heart Institute (InCor), University of São Paulo Medical School, between 1992 and 2025. Clinical characteristics, heart failure severity, transplant evaluation, treatment response, listing status, and outcomes were described. We retrospectively reviewed three pediatric patients with genetically confirmed Barth syndrome referred to our center for heart transplantation evaluation. Despite severe early cardiac involvement, they exhibited markedly different heart failure trajectories. Barth syndrome cardiomyopathy follows a highly heterogeneous clinical course. Although some patients demonstrate significant recovery with optimized heart failure therapy, others progress to end-stage heart failure requiring transplantation. Our experience reinforces that early referral to pediatric heart transplant centers and individualized transplant listing based on longitudinal clinical evolution, rather than left ventricular ejection fraction alone, may optimize patient outcomes. Early referral to pediatric heart transplant centers and individualized transplant listing based on longitudinal clinical evolution may optimize outcomes in Barth syndrome.
2025-06-25 | Allogenic mitochondria transfer improves cardiac function in iPS-cell-differentiated cardiomyocytes of a patient with Barth syndrome.
Barth syndrome (BTHS) is an ultrarare, infantile-onset, X-linked recessive mitochondrial disorder that primarily affects males, owing to mutations in TAFAZZIN, which catalyzes the remodeling of cardiolipin, a mitochondrial phospholipid required for oxidative phosphorylation. Mitochondrial transplantation is a novel technique to treat mitochondrial dysfunction by delivering healthy mitochondria to diseased cells or tissues. Here we explored the possibility of using stem-cell-derived cardiomyocytes as a source of mitochondrial transplantation to treat BTHS. We established induced pluripotent stem (iPS) cells from healthy individuals and from patients with BTHS and differentiated them into cardiomyocytes. The iPS-cell-differentiated cardiomyocytes (CMs) derived from patients with BTHS exhibited less expression of cardiomyocytes markers, such as α-SA, cTnT and cTnI, and smaller cell size than normal iPS-cell-derived CMs. Multielectrode array analysis revealed that BTHS CMs exhibited shorter beat period and longer field potential duration than normal CMs. In addition, mitochondrial morphology and function were impaired and mitophagy was decreased in BTHS CMs compared with normal CMs. Transplantation of mitochondria isolated from normal CMs induced mitophagy in BTHS CMs, mitigated mitochondrial dysfunction and promoted mitochondrial biogenesis. Furthermore, mitochondrial transplantation stimulated cardiac maturation and alleviated cardiac arrhythmia of BTHS CMs. These results suggest that normal CMs are useful for allogeneic transplantation in the treatment of mitochondrial diseases, including BTHS.
2024-11-13 | Rescue of mitochondrial dysfunction through alteration of extracellular matrix composition in barth syndrome cardiac fibroblasts.
Fibroblast-ECM (dys)regulation is associated with a plethora of diseases. The ECM acts as a reservoir of inflammatory factors and cytokines that mediate molecular mechanisms within cardiac cell populations. The role of ECM-mitochondria crosstalk in the development and progression of cardiac disorders remains uncertain. We evaluated the influence of ECM produced by stromal cells from patients with the mitochondrial cardiomyopathy (Barth syndrome, BTHS) and unaffected healthy controls on cardiac fibroblast (CF) metabolic function. To do this, cell-derived matrices CDMs were generated from BTHS and healthy human pluripotent stem cell-derived CFs (hPSC-CF) and used as cell culture substrates. BTHS CDMs negatively impacted the mitochondrial function of healthy hPSC-CFs while healthy CDMs improved mitochondrial function in BTHS hPSC-CFs. Mass spectrometry comparisons identified 5 matrisome proteins differentially expressed in BTHS compared to healthy CDM. Our results highlight a key role for the ECM in disease through its impact on mitochondrial function.
2022-07-13 | Tafazzin deficiency in mouse mesenchymal stem cells promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.
Barth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutation in the TAFAZZIN gene. Tafazzin (Taz) deficiency in BTHS patients results in an increased risk of infections. Mesenchymal stem cells (MSCs) are well known for their immune-inhibitory function. We examined how Taz-deficiency in murine MSCs impact their ability to modulate the function of lipopolysaccharide (LPS)-activated wild type (WT) B lymphocytes. MSCs from tafazzin knockdown (TazKD) mice exhibited a reduction in mitochondrial cardiolipin compared to wild type (WT) MSCs. However, mitochondrial bioenergetics and membrane potential were unaltered. In contrast, TazKD MSCs exhibited increased reactive oxygen species generation and increased glycolysis. The increased glycolysis was associated with an elevated proliferation, phosphatidylinositol-3-kinase expression and expression of the immunosuppressive markers indoleamine-2,3-dioxygenase, cytotoxic T-lymphocyte-associated protein 4, interleukin-10, and cluster of differentiation 59 compared to controls. Inhibition of glycolysis with 2-deoxyglucose attenuated the TazKD-mediated increased expression of cytotoxic T-lymphocyte-associated protein 4 and interleukin-10. When co-cultured with LPS-activated WT B cells, TazKD MSCs inhibited B cell proliferation and growth rate and reduced B cell secretion of immunoglobulin M compared to controls. In addition, co-culture of LPS-activated WT B cells with TazKD MSCs promoted B cell differentiation toward interleukin-10 secreting plasma cells and B regulatory cells compared to controls. The results indicate that Taz deficiency in MSCs promote reprogramming of activated B lymphocytes toward immunosuppressive phenotypes.
2017-09-22 | MODELING THE DILATED CARDIOMYOPATHY WITH ATAXIA SYNDROME (DCMA), A PEDIATRIC MITOCHONDRIAL CARDIOMYOPATHY, USING CARDIOMYOCYTES DERIVED FROM INDUCED PLURIPOTENT STEM CELLS
Cardiomyopathy is a predominant and lethal feature of many inborn metabolic disorders but results from derangements in cellular energetics rather than ischemic myocardial injury. This fundamental difference is likely why standard heart failure medications appear to be ineffective. This problem is exemplified by the dilated cardiomyopathy with ataxia syndrome (DCMA). DCMA is related to Barth syndrome with abnormal cardiolipin and mitochondria causing heart failure, conduction defects and other systemic features. Isolated cases of DCMA have been identified worldwide but the largest known group of patients is found in the Hutterites of southern Alberta. No effective therapy exists and in our cohort there is 39% mortality in early childhood related to cardiac dysfunction despite recommended optimal medical therapy. The lack of useful drugs for mitochondrial cardiomyopathies means that there are few therapies available outside of mechanical circulatory support or heart transplantation. Since the rarity and heterogeneity of the pediatric cardiomyopathies preclude randomized drug trials, the use of patient cells and in vitro drug modeling represents the best possible option to identify effective therapeutics. Here, we describe the creation and characterization of cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs) (as an in vitro model of DCMA) from 4 children with DCMA and varying severity of cardiac dysfunction. Purified peripheral blood mononuclear cells derived from 4 DCMA patients (Table 1) were reprogrammed into induced pluripotent stem cells (iPSCs) using Sendai virus and the 4 Yamanaka factors, and characterized using standard pluripotency tests. Our iPSCs expressed markers of pluripotency including SSEA4 and OCT4. The DCMA-derived iPSCs were sequenced to detect the DCMA related mutation in their genomic DNA. Results showed that the iPSCs carried the DNAJC19 mutation (rs137854888) responsible for the abnormal splicing causing the disease phenotype. These iPSCs were successfully differentiated into beating cardiomyocytes using a modified protocol and lactate as a sole carbon source to enrich purified iPSC-CMs. The resulting iPSC-CMs expressed the cardiac-specific markers TNNT2 and NKX2.5. We describe the development of iPSC-CMs for DCMA which represent a novel in vitro model for mitochondrial cardiomyopathy and provide a platform to study the efficacy of potential therapeutics and genome editing approaches.
small molecules
2026-09-26 | Mitochondrial Quality Control in Inherited Mitochondrial Cardiomyopathy: Convergent Pathobiology and a Testable Therapeutic Framework.
Inherited mitochondrial cardiomyopathies arise from pathogenic variants affecting oxidative phosphorylation, mitochondrial DNA maintenance, cardiolipin remodeling, protein import, cofactor metabolism, and mitochondrial dynamics or proteostasis. These disorders may be cardiac-predominant or part of multisystem disease. Their overlapping cardiac phenotypes suggest convergence on interacting pathways of energetic stress, cristae disruption, calcium imbalance, and redox injury, but do not establish a universal requirement for defective mitophagy. Mitochondrial quality control encompasses protein surveillance, membrane remodeling, dynamics, biogenesis, and organelle disposal; mitophagy is one component. We critically examine the hypothesis that inadequate clearance of damaged mitochondria contributes to progression in a subset of genotypes and disease stages. Disease-specific studies provide support in selected Barth syndrome models, whereas findings in frataxin deficiency vary with model and assay. We distinguish mitochondrial delivery to lysosomes, dynamic turnover measurements, and changes in pathway markers, and identify indirect evidence from acquired heart disease and fatty acid oxidation deficiency. Therapeutic evidence is separated into cellular, animal, and human studies and approved indications. Elamipretide has accelerated approval for muscle-strength improvement in patients with Barth syndrome weighing at least 30 kg; cardiac disease modification remains unconfirmed. Gene replacement has reached early clinical testing, including adeno-associated virus-mediated frataxin gene delivery (AAV-FXN), whereas mitochondrial genome editing and selective mitophagy modulation remain investigational. We propose testable predictions addressing progression, selective rescue, and treatment timing, together with outcomes that would challenge the hypothesis. This framework supports genotype- and stage-specific investigation without assuming that enhanced mitophagy will benefit every mitochondrial cardiomyopathy.
2026-07-13 | Compensatory Metabolic Responses of Peroxisomes in Barth Syndrome Cardiomyopathy
Mitochondrial function relies on the unique phospholipid cardiolipin, which is enriched in the inner mitochondrial membrane (IMM) and plays a central role in maintaining cristae architecture, stabilizing respiratory chain supercomplexes, and supporting efficient oxidative phosphorylation. Disruption of cardiolipin remodelling compromises mitochondrial structure and bioenergetic capacity and is associated with altered redox balance and stress signaling pathways, placing cells under chronic energetic and oxidative stress. These mitochondrial defects are a defining feature of Barth syndrome (BTHS), a rare X-linked disorder caused by mutations in the TAFAZZIN gene. In tissues with high energetic demand, particularly the heart, impaired mitochondrial function contributes to progressive cardiomyopathy alongside systemic manifestations such as skeletal myopathy and neutropenia. Although mitochondrial dysfunction represents the primary molecular defect in Barth syndrome (BTHS), its effects extend beyond mitochondrial function. Chronic mitochondrial stress engages adaptive signaling pathways, including the integrated stress response (ISR), which coordinates transcriptional programs that regulate redox, metabolism, and protein homeostasis. Activation of ISR-associated transcription factors such as ATF4 and CHOP reflects an attempt to mitigate oxidative and metabolic stress; however, sustained activation may also increase vulnerability under prolonged stress conditions. How cells tolerate ongoing mitochondrial dysfunction in BTHS, and which additional organelles contribute to this adaptive balance, remain incompletely understood. Peroxisomes are metabolically active organelles with established roles in lipid metabolism and redox regulation and maintain close physical and functional interactions with both mitochondria and the endoplasmic reticulum (ER). Through β-oxidation of specific lipid species, hydrogen peroxide (H\(^2\)O\(^2\)) detoxification via catalase, and the initiation of plasmalogen biosynthesis, peroxisomes are positioned to influence cellular stress responses. In the context of BTHS, in which mitochondrial bioenergetics and lipid remodelling are altered, peroxisomal pathways may undergo compensatory adjustments to maintain redox and metabolic homeostasis. This thesis investigates the contribution of peroxisomal metabolism to the cellular response to mitochondrial dysfunction in BTHS, with a focus on catalase-mediated ROS buffering and plasmalogen biosynthesis via glyceronephosphate O-acyltransferase (GNPAT). Using Tafazzin-deficient mouse embryonic fibroblasts (MEFs) following targeted knockdown of catalase and GNPAT, the functional roles of these pathways were examined in relation to oxidative stress handling, ISR signaling, and stress susceptibility. Molecular, biochemical, imaging-based, and ultrastructural analyses were integrated to assess changes in redox balance, stress-responsive gene expression, and organelle organization. The findings demonstrate that peroxisomal pathways are actively engaged in response to mitochondrial dysfunction in Tafazzin deficiency. Peroxisomal catalase contributes to H\(^2\)O\(^2\) buffering, while plasmalogen biosynthesis modulates membrane-dependent stress signaling rather than functioning as a direct antioxidant pathway. Importantly, these peroxisomal responses shape redox homeostasis and stress-signal thresholds, determining whether mitochondrial dysfunction remains within an adaptive range or progresses toward heightened stress vulnerability. Together, these results expand the pathophysiological framework of BTHS beyond isolated mitochondrial dysfunction and identify peroxisome-mitochondria crosstalk as a key component of cellular stress adaptation and a potential target for strategies to enhance resilience in mitochondrial cardiomyopathy.
2026-07-08 | Elamipretide in pediatric Barth syndrome: from heart failure to school return.
Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder characterized by cardiomyopathy, neutropenia, and skeletal myopathy. Elamipretide is a mitochondria-targeting peptide that stabilizes cardiolipin and improves mitochondrial function. While use of this treatment in infants with BTHS has been reported in the United States, no cases have been described outside the US or in older children. We report the first case of a preschool-aged child with genetically confirmed BTHS and advanced heart failure, who was treated with elamipretide under a compassionate use program approved by the French Drug Administration (ANSM). At treatment initiation, this 5-year-old patient presented with severe left ventricular dysfunction (LVEF = 20%) and moderate-to-severe mitral regurgitation. He was dependent on gastrostomy feeding and had been listed for heart transplantation. Subcutaneous elamipretide (10 mg/day) was initiated alongside maximal conventional heart failure therapy. Over six months, LVEF improved to 50%, mitral regurgitation decreased to mild, Ross class improved from IV to I, and substantial gains were observed in functional capacity, nutritional status, and health-related quality of life (HRQoL). The patient returned to full-time school and remained temporarily suspended from the transplant list. Treatment was generally well tolerated. One transient, non-serious episode of abdominal pain with moderate pancreatic enzyme elevation occurred, which resolved without treatment discontinuation. This case suggests that elamipretide may improve cardiac function, exercise tolerance, nutrition, and HRQoL in preschool-aged pediatric BTHS patients, potentially delaying the need for transplantation. Broader pediatric evaluation is warranted. Further strategies, such as youth-tailored hybrid cardiac rehabilitation programs, could complement pharmacological therapy and further optimize outcomes in this population.
2026-06-30 | Peroxisomal catalase and plasmalogen biosynthesis protect from oxidative stress in Barth syndrome cardiomyopathy.
Barth Syndrome (BTHS) is an inherited mitochondrial cardiomyopathy caused by variants in the gene encoding TAFAZZIN (Taz), a transacylase catalyzing the synthesis of the essential mitochondrial phospholipid cardiolipin (CL). Although defects in Taz deteriorate mitochondrial respiration, Ca2+-uptake, and redox regulation in cardiac myocytes, we previously observed an unexpected lack of oxidative cardiac damage, despite the development of cardiomyopathy in a BTHS mouse model with Taz-knockdown (KD). Furthermore, we revealed that the integrated stress response (ISR) governs metabolic rewiring in Taz-KD hearts to compensate for deficient mitochondrial FAO and to support GSH production. Here, we interrogated whether adaptive mechanisms in peroxisomes, which are closely associated with mitochondria and harbor antioxidative enzymes, can also compensate for the mitochondrial defects. We identified alterations in the peroxisomal biogenesis factors PEX14 and PEX19, indicating changes in the peroxisomal proteome in Taz-KD vs. WT hearts. While the enzymes of peroxisomal FAO were unchanged, levels of Lon Protease 2 (LONP2) and catalase were elevated in Taz-KD hearts. Inhibition or siRNA-mediated knockdown of catalase increased reactive oxygen species (ROS) and blunted the protection of mouse embryonic fibroblasts (MEF) with Taz-knockout (KO), but not in WT, from ROS-induced activation of the apoptotic caspase 3. Furthermore, we observed that the increase in plasmalogen synthesis in cardiac Taz-KD peroxisomes contributes to the activation of the ISR, since siRNA-mediated knockdown of the key enzyme GNPAT blunted the ISR and thereby increased cellular ROS in Taz-KO, but not WT MEFs. In conclusion, peroxisomes facilitate a counterregulatory response to dysfunctional mitochondria by activating a catalase-driven ROS defense and maintaining ISR-mediated metabolic alterations, both of which compensate for mitochondrial dysfunction and oxidative stress. Therefore, the so far poorly investigated mitochondrial-peroxisome crosstalk may represent a novel therapeutic target in an orphan disease with a poor prognosis.
2026-06-27 | AMCP Market Insights: Managed care considerations in Barth syndrome.
Barth syndrome is an ultrarare, complex, multisystem, X-linked metabolic and neuromuscular disease, which poses significant and wide-ranging burden to patients and caregivers. Pharmacologic management focuses on treatment of disease manifestations and prevention of secondary complications. Elamipretide, the first treatment indicated specifically for improving muscle strength in Barth syndrome, was approved in 2025 via accelerated approval warranting guidance for payers. To discuss managed care considerations in Barth syndrome including management of elamipretide, AMCP Market Insights virtually convened an expert panel of managed care stakeholders in March 2026. This article provides a qualitative summary of the panel discussion along with key insights and suggested payer practices meant to support informed coverage decisions and guide future work such as collaboration, research, and advocacy. Key insights highlight that there are unique challenges in generating clinical trial evidence for treatments in ultrarare conditions, which leads to difficulties determining the value of these treatments and differences in whether they are covered among payers. Additionally, there are numerous elements of care to which patients with Barth syndrome and their caregivers need equitable access, which is complicated by involving multiple specialists and fragmentation. Suggested payer practices involve education, care delivery, and coverage and benefit design.
proteins
2025-08-07 | Calmodulin enhancement of mitochondrial calcium uniporter function in isolated mitochondria.
Mitochondrial calcium (Ca2+) uptake and factors that regulate this process have been an area of immense interest given the roles in cellular energetics. Here, we have investigated the ability of the Ca2+ sensing protein Calmodulin (CaM) to modify the function of the Mitochondrial Ca2+ Uniporter (MCU). Our data leveraged recombinantly produced CaM and mitochondria isolated from healthy and MCU impaired/diseased mice (Barth syndrome model). We found CaM enhanced Ca2+ uptake in both the absence and presence of CaMKII inhibition (KN93 as well as AIP). Mitochondria lacking function MCU (Barth syndrome model) validated that MCU was responsible for Ca2+ uptake in our experiments. Control experiments demonstrate that the observed CaM enhancement does not arise from CaM Ca2+ buffering. Fitting the Ca2+fluorescence data supported a monophasic decay process where the presence of CaM yielded enhanced kinetic rates of Ca2+ uptake. This CaM enhancement effect persisted in the presence of PTP impairment (cyclosporin), and subtle modification to the CaM protein sequence (D131E) revealed that an intact CaM-C domain Ca2+ binding was required for enhancement of MCU function.
2025-01-01 | Adaptive mechanisms in pancreatic islets counteract mitochondrial dysfunction in Barth syndrome
Aims/hypothesis Barth syndrome is a mitochondrial disorder caused by Tafazzin (TAZ) mutations, which impair cardiolipin remodelling and contribute to systemic metabolic alterations. While islet dysfunction has been implicated in Barth syndrome, its underlying mechanisms remain unknown. We aimed to determine how Tafazzin (Taz) deficiency affects mouse pancreatic islet metabolism and hormone secretion, and whether systemic signals, such as circulating factors, modulate these effects in vivo. In vivo and in vitro models were used to separate direct islet effects from systemic influences of Taz deficiency. Methods We used a mouse model of global Taz knockdown (Taz-KD) and combined in vivo and in vitro approaches to assess pancreatic islet metabolism, morphology and hormone secretion. Islet function was evaluated under basal and glucotoxic conditions. Transcriptomic profiling was performed to identify gene expression changes in isolated islets from Taz-KD mice and following in vitro Taz-KD. Additionally, we examined the role of the circulating factor fibroblast growth factor 21 (FGF-21) in modulating islet function. Results Despite impaired cardiolipin remodelling, pancreatic islets from Taz-KD mice maintained insulin secretion, sup ported by compensatory mechanisms such as increased glucose uptake, expanded mitochondrial volume and increased metabolic parameters. In addition, alpha cell mass and glucagon secretion were significantly increased in Taz-KD islets. These islet-specific adaptations occurred alongside improved whole-body glucose tolerance, elevated circulating FGF-21 levels and enhanced glucose uptake in brown adipose tissue. In contrast, in vitro Taz-KD led to impaired islet function and reduced insulin secretion. Transcriptomic analysis revealed distinct gene expression patterns between in vivo and in vitro Taz-KD models. While in vivo upregulation of genes related to N-acetylglucosamine biosynthesis and O-GlcNAcylation were related to compensatory mechanisms, in vitro Taz-KD affected, among others, the MAPK pathway, contributing to islet dysfunction. Notably, islet incubation with FGF-21 was able to restore insulin secretion after in vitro Taz-KD. Conclusions/interpretation Our findings demonstrate that while Taz and cardiolipin remodelling are essential for beta cell physiology, systemic and islet-specific compensatory mechanisms preserve insulin secretion in vivo in Taz-KD mice, alongside increased glucagon secretion. These adaptations probably contribute to the altered metabolic phenotype observed in Barth syndrome and highlight a potential role for hormones and circulating factors such as FGF-21 in maintaining islet function and glucose homeostasis.
2022-09-08 | Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome.
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. 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). 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. 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. 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.
2021-12-15 | Barth syndrome with severe dilated cardiomyopathy and growth hormone resistance: a case report.
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.
2020-02-06 | Neutropenia in Barth syndrome: characteristics, risks, and management.
Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 × 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 × 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 × 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 μg/kg/day (mean 1.16 μg/kg/day, median 1.16 μg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF ± prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF ± antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices.
gene therapies
2026-09-29 | Comparative Efficacy of AAV-Tafazzin and AAV-Δ5 Tafazzin in Restoring Mitochondrial Function in Barth Syndrome Induced Pluripotent Stem Cell Derived Cardiomyocytes
We compared efficacy and efficiency of two AAV-Tafazzin variants AAV-CoTAZ (full length) and AAV-Δ5 (exon 5 removed) in Barth syndrome iPSC cardiomyocytes. We performed AAV transduction in iPSC cardiomyocytes and cultured cells for 7 days followed by an array of mitochondrial functional assays and gene expression analysis. The raw data from MTT, ATP, ROS, TMRE, and OCR assays and the qRT-PCR assay for all healthy and BTHS cell lines. Mitochondrial assays are normalized to 1ug of protein for all assays. We hypothesized that the AAV delivery of tafazzin improves mitochondrial function in BTHS iPSC cardiomyocytes and that Δ5 variant performs superior as it is abundant in heart and skeletal muscle.
2026-09-05 | Barth syndrome manifesting as neonatal left ventricular dysfunction, an uncommon presentation
No abstract available
2025-12-05 | Defective vascular smooth muscle cell tafazzin impairs mitochondrial function and promotes atherosclerosis in preclinical models.
Atherosclerotic lesions show significant mitochondrial dysfunction but the underlying mechanisms and consequences remain unknown. Cardiolipin is a phospholipid found exclusively in the mitochondrial inner membrane, the site of oxidative phosphorylation. Tafazzin is a trans-acylase that acylates immature monolysocardiolipin to mature cardiolipin. Tafazzin mutations can result in Barth's Syndrome, which is characterised by dilated cardiomyopathy, skeletal myopathy and impaired growth. However, a role for tafazzin in atherosclerosis development has not been previously identified. Here we show that tafazzin expression is decreased in atherosclerotic lesions and specifically in plaque vascular smooth muscle cells (VSMCs). MicroRNA 125a-5p expression is increased in plaques, downregulates tafazzin expression and is induced by oxidised low-density lipoprotein in a NFκB-dependent manner. Silencing tafazzin or overexpression of mutant tafazzin decreases VSMC cardiolipin content and mitochondrial respiration, and promotes apoptosis and atherosclerosis. In contrast tafazzin overexpression increases respiration, protects against apoptosis and increases features of plaque stability. Tafazzin therefore has important effects on VSMC mitochondrial function and atherosclerosis, and is a potential therapeutic target in atherosclerotic disease.
2025-08-01 | Abstract Fri113: Targeting mitochondrial proteostasis in Barth syndrome-related cardiomyopathy
Background: Barth syndrome (BTHS) is a disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) metabolism and leads to cardiac and skeletal myopathy, neutropenia, and 3-methylglutaconic aciduria. Altered CL impairs mitochondrial function, contributing to symptoms of BTHS. Despite extensive research, the molecular mechanisms underlying BTHS remain unclear, and no cure exists. Mitochondrial protein quality control (MPQC) is crucial for maintaining mitochondrial homeostasis, yet its role in BTHS is underexplored. Our preliminary data indicate elevated levels of Caseinolytic peptidase B (CLPB), a mitochondrial chaperonin localized in the intermembrane space (IMS) with disaggregase activity, in BTHS patient-derived cells, and Tafazzin-deficient BTHS mice. Hypothesis: Our data-driven hypothesis proposes that CLPB regulates the quality control of IMS proteins, mitochondrial function, and bioenergetics to support cardiac health. However, this adaptive response becomes maladaptive during BTHS pathology. Aim: We aim to understand CLPB’s function in BTHS and explore its potential as a therapeutic target. Methods: We generated CLPB knockouts in both control and Tafazzin -/- C2C12 cells, as well as a CLPB knockdown mouse model in Tafazzin fl/fl (control) and Tafazzin fl/fl x aMHC-Cre. Using cellular, molecular, and physiological approaches, we evaluated CLPB’s impact on mitochondrial homeostasis and its therapeutic potential in BTHS. Results: CLPB loss improves NADH and calcium retention capacity without affecting mitochondrial respiration rate&membrane potential, ATP, and mtDNA content in Tafazzin -/- -Clpb -/- compared to control, Clpb -/- and Tafazzin -/- C2C12 cells. To explore the underlying mechanisms behind changes in the metabolic state of Tafazzin -/- -Clpb -/- cells, we analyzed transcripts of CL regulators (ALCLAT1 and CLS1), mitochondrial biogenesis (PGC1a, Tfam, and NRF1/2), and mtUPR (ATF4/5, HSP70, CHOP, and SOD2) markers. The Tafazzin -/- -Clpb -/- activate mitochondrial biogenesis and CL synthesis by elevating PGC1a and CLS1 transcripts, while their mtUPR transcript profile is comparable to control cells. Furthermore, echocardiographic analysis shows restoration of ejection fraction in CLPB KD and Tafazzin fl/fl x aMHC-Cre -CLPB KD mice. Conclusion: These findings highlight CLPB’s crucial role in IMS proteins quality control and mitochondrial homeostasis, providing a basis for new therapeutic avenues against mitochondrial dysfunction in BTHS.
2025-07-10 | A review of disorders of cardiolipin metabolism: Pathophysiology, clinical presentation and future directions.
Cardiolipin is a mitochondria-specific phospholipid essential for maintaining mitochondrial membrane architecture, supporting respiratory chain function, and regulating apoptotic signaling. Its biosynthesis and remodeling are mediated by a coordinated set of enzymes, and disruptions in this pathway are increasingly recognized as causes of inherited mitochondrial diseases. This review provides a comprehensive overview of the genetic disorders associated with defects in cardiolipin metabolism, highlighting genetic and molecular characteristics, clinical manifestations, and available models with which to study these diseases. We examine the roles of key genes involved in cardiolipin biosynthesis (PGS1, CRLS1) and remodeling (TAZ, AGK, among others), and describe how pathogenic variants disrupt mitochondrial function. The prototypical disorder, Barth syndrome, is discussed in depth alongside recently identified conditions linked to defects in related enzymes.
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2025-02-21 | [Analysis of 21 cases of Barth syndrome in children].
Objective: To investigate the clinical manifestations, treatment, and outcomes of Barth syndrome (BTHS). Methods: A retrospective analysis was conducted on 21 pediatric patients diagnosed with BTHS between January 2010 and December 2023 at Beijing Children's Hospital, Beijing Anzhen Hospital, and Beijing JingDu Children's Hospital. Clinical data including gender, age at onset, initial symptoms, clinical manifestations, personal history, family genetic history, and laboratory tests (neutrophil count, echocardiography, electrocardiogram and genetic testing) were reviewed. Results: All the 21 patients were male, with the age of onset at 4.1 (1.1, 9.3) months. Main clinical manifestations included heart failure (18 cases), neutropenia (16 cases), respiratory symptoms (15 cases), 3-methylpentenediuria (7 cases),develop retardation (8 cases), gastrointestinal symptoms (7 cases), fatigue and anorexia (6 cases), and recurrent infection (2 cases). Electrocardiogram abnormalities included ST changes (18 cases), flattened T wave and low voltage of limb leads (2 cases), and abnormal Q waves in lead Ⅰ and avL (1 case). Echocardiographic features showed increased trabeculation, interventricular septum and left ventricular wall thickening, and left ventricular enlargement with reduced ejection fraction. Genetic testing identified TAZ gene variations in all 21 patients: 11 missense mutations, 2 nonsense mutations, 2 frameshift mutations, 2 whole code mutations, 2 exon deletions, 1 splicing mutation, and 1 synonymous mutation. Fifteen mutations were maternally inherited, 2 were de novo, and 4 lacked verified variant origin.In terms of treatment, all 18 patients with heart failure received routine heart failure treatment, of whom 11 patients also received intravenous immunoglobulin and corticosteroids. After the follow-up of 91.0 (75.5, 109.5) months, 15 of the 18 patients showed restoration of cardiac function after 4.5 (3.0, 9.8) months of treatment, with one case of significant improvement, while 2 cases suddenly died. Conclusions: BTHS predominantly affects males with early onset, mainly characterized by abnormal cardiac structure and function, along with clinical features including fatigue, delayed growth and development, and neutropenia. Early diagnosis and intervention, including heart failure treatment, intravenous immunoglobulin, and corticosteroids, can lead to significant improvement in cardiac function, though sudden death remains a risk.
2021-12-28 | Extended recovery of cardiac function after severe infantile cardiomyopathy presentation of Barth syndrome
Cardiomyopathy is the most common presenting feature of Barth syndrome, often presenting in infancy with severe heart failure and cardiac dysfunction. Historically, affected infants commonly died early after presentation, sometimes before a diagnosis of Barth syndrome was made. With increases in awareness of Barth syndrome and in the care of infants with severe heart failure, survival of children with Barth syndrome and severe heart failure has improved. We describe our experience caring for five unrelated boys with Barth syndrome who presented with severe cardiomyopathy and heart failure prior to age 2 who have had marked improvement with long-term response to medical heart failure therapy.
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Drug Discovery Landscape
3 orphan drug designations for Barth syndrome, including 1 approved therapy.
3 orphan drug designations for Barth syndrome, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Elamipretide | peptides | EMA | Atnahs Pharma Netherlands B. V. | |
elamipretide [Forzinity] | peptides | FDA | Approved | Stealth Biotherapeutics, Inc. |
bezafibrate | small molecules | FDA | Barth Sydrome Foundation, Inc. |
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