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
179 drug discovery papers related to Barth syndrome, with 5 first-in-class and 6 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
179 drug discovery papers related to Barth syndrome, with 5 first-in-class and 6 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-06-27 | 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.
2026-06-27 | Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
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.
2026-06-27 | 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.
2026-06-27 | Clinical development in primary mitochondrial diseases at a translational inflection point: Lessons, mechanisms, and emerging therapeutic strategies.
Clinical development for primary mitochondrial diseases (PMDs) has spanned more than two decades, yet therapeutic success remains limited. In this Review, we provide a comprehensive, pharmacology-focused analysis of the PMD clinical trial landscape and identify key mechanistic and translational determinants underlying recent progress. A systematic survey of ClinicalTrials.gov covering January 2010 to April 2026 identified 159 registered studies across PMD subtypes after deduplication, including 110 interventional trials. Progress has been constrained by marked genetic and phenotypic heterogeneity, small and geographically dispersed patient populations, and the lack of validated pharmacodynamic and disease-specific endpoints. Consequently, several well-designed late-stage trials have yielded negative or inconclusive outcomes, and regulatory approvals have historically been scarce. Recent advances, however, indicate a shift in trajectory. Four therapies have achieved regulatory authorization, including idebenone for Leber hereditary optic neuropathy, taurine for MELAS, and recent FDA approvals of doxecitine and doxribtimine (Kygevvi) for thymidine kinase 2 deficiency and elamipretide (FORZINITY) for Barth syndrome. These successes share a convergent translational framework integrating mechanism-based pharmacology, genotype-driven patient selection, and biologically aligned endpoints. Clinical activity has also accelerated, with approximately half of PMD interventional trials initiated since 2020 and 50 studies currently active or recruiting. Emerging strategies include NAD⁺ augmentation, soluble guanylate cyclase stimulation, mTOR modulation, gene therapies, and heteroplasmy-targeting approaches. Collectively, these advances mark an emerging inflection point and suggest a path toward greater regulatory success in the coming decade.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles 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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