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
183 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:
183 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:
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.
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.
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.
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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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 | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Elamipretide | peptides | EMA | 2021-05-20 | — | Atnahs Pharma Netherlands B. V. |
elamipretide [Forzinity] | peptides | FDA | 2018-03-22 | 2025-09-19 | Stealth Biotherapeutics, Inc. |
bezafibrate | small molecules | FDA | 2013-07-24 | — | Barth Sydrome Foundation, Inc. |
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