Barth Syndrome

Barth syndrome is a rare inherited disease of the mitochondria, the small structures inside cells that turn food into usable energy. It is caused by changes in the TAFAZZIN gene on the X chromosome, so it affects almost only boys and men. The gene's protein, tafazzin, finishes the building of cardiolipin, a fat molecule that the energy machinery of the mitochondria depends on. The main features are a weak or abnormally formed heart muscle, low counts of the infection-fighting white blood cells called neutrophils, muscle weakness and tiredness, and slow growth.

This page covers what goes wrong inside the cell, who is affected, how the disease shows itself, how it is diagnosed, what registry studies report about survival, the treatments used in care, and the published trial results for elamipretide, a medicine that binds cardiolipin. The heart pattern most closely tied to Barth syndrome has its own page: Left Ventricular Non-Compaction Cardiomyopathy. Low white blood cell counts in general are covered on the Leukopenia page.

Table of Contents

  1. What Barth Syndrome Is
  2. The TAFAZZIN Gene and Cardiolipin
  3. Who Is Affected
  4. The Heart: Cardiomyopathy and Non-Compaction
  5. Neutropenia, Monocytes and Infection
  6. Muscle Weakness, Fatigue, Growth and Feeding
  7. How Barth Syndrome Is Diagnosed
  8. Survival and Outcomes in Registry Studies
  9. Treatments Used in Care
  10. Elamipretide: Trial Results and the US Label
  11. What Is Not Known
  12. Key Research Papers
  13. Connections
  14. Featured Videos

What Barth Syndrome Is

Barth syndrome was first described in 1983. For years it was regarded as a heart disease, but a 2013 review by a clinical and laboratory team based in Bristol, United Kingdom, describes it as a multi-system disorder that may first be seen by many different specialists or by family doctors (PMID 23398819). A 2013 review in a genetics journal lists the usual picture: cardiomyopathy (disease of the heart muscle), skeletal myopathy (weakness of the muscles that move the body), growth delay, neutropenia (a low count of neutrophils), and raised levels of 3-methylglutaconic acid in the urine. The same review stresses that the picture varies a great deal, and that some patients show only some of these findings (PMID 23843353).

A 2026 analysis of the largest patient database describes Barth syndrome as ultra-rare and life-limiting, with cardiomyopathy, muscle disease, neutropenia, gastrointestinal problems and fatigue as its main features (PMID 42070974).

The 2013 British review gives the full range of features that have been reported, in varying combinations:

The TAFAZZIN Gene and Cardiolipin

The gene behind Barth syndrome sits at position Xq28 on the X chromosome. The gene is named TAFAZZIN; older papers call it TAZ, and it is also known as G4.5. The changes that cause the disease remove the function of its protein, tafazzin (PMID 23843353).

Tafazzin works on cardiolipin, one of the main fat molecules of the inner membrane of the mitochondria (PMID 23398819). Cardiolipin is first made in an unfinished form and then remodelled. Tafazzin carries out part of that remodelling. Monolysocardiolipin is the half-finished intermediate in this process (PMID 37549445). When tafazzin fails, cells show less cardiolipin and more monolysocardiolipin (PMID 19454236). A 2025 review describes the result as defects in mature cardiolipin and in how it is built into the inner mitochondrial membrane (PMID 40816230).

The inner membrane is where the respiratory chain sits: the chain of protein complexes that uses oxygen to make the cell's energy currency. A 2012 case report states that the loss of cardiolipin in this membrane results in respiratory chain dysfunction. In the patient it describes, skin cells grown in the laboratory showed reduced activity of complexes I, III and IV of that chain (PMID 22410210).

Who Is Affected

Barth syndrome is X-linked recessive (PMID 23843353). A boy has one X chromosome, so one faulty copy of the gene is enough to cause the disease. A girl has two X chromosomes, and the working copy on her second X normally covers for the faulty one. A woman who carries one faulty copy can pass it to her sons. Gene testing allows carrier detection in female relatives and testing before birth (PMID 23398819). The US prescribing information for elamipretide describes the disease as not likely to affect females.

A 2012 report described the first girl with Barth syndrome confirmed by gene analysis. She had a large deletion in one copy of the gene, and a rearrangement of her other X chromosome that removed the region holding the second copy. She had severe heart failure from one month of age, progressive muscle weakness and cyclic neutropenia, and died of septic shock at 3 years. The authors state that no specific symptom has been identified in female carriers (PMID 22410210).

The disease is rare. A French national study estimated an incidence of 1.5 cases per million births (95% confidence interval 0.2 to 2.3) (PMID 23656970). The 2013 British review counted fewer than 200 living males known worldwide at that time and added that evidence was accumulating that the disorder is substantially under-diagnosed. The same review notes that Barth syndrome was described in 2010 as an unrecognised cause of death before birth, and lists recurrent miscarriage and stillbirth of male babies among the situations in which it comes into question (PMID 23398819). The 2026 database analysis covered 502 people, which its authors describe as more than 80% of the known global population (PMID 42070974).

The Heart: Cardiomyopathy and Non-Compaction

Left ventricular non-compaction and dilated cardiomyopathy are the most common heart patterns reported in Barth syndrome. Both can lead to heart failure and to dangerous rhythms that start in the lower chambers of the heart (PMID 23843353). In left ventricular non-compaction, the inner wall of the main pumping chamber stays spongy, with deep grooves, instead of becoming a smooth, solid muscle wall. The general condition is described on the left ventricular non-compaction page; the broader family of heart muscle diseases is covered on the Cardiomyopathy page.

The heart problems usually start very early. In the French national study, 14 of 22 patients first came to medical attention with cardiomyopathy, and cardiomyopathy was found in 20 during follow-up. The left ventricle pumped very poorly during the first year of life, and its function tended to return toward normal over time (PMID 23656970). In a 2025 study of 21 boys followed from birth to 48 months at a specialist Barth clinic in the United States, cardiomyopathy was the most common first sign (10 patients), 18 developed reduced heart function, and 25% needed a heart transplant (PMID 41177130).

A minority of patients have hidden or absent cardiomyopathy (PMID 23398819), so a normal heart scan at one point in time does not exclude the disease.

Heart function can also change in later childhood and adulthood. A US study followed 44 children, teenagers and adults (median age 7 years at entry) with heart ultrasound and electrocardiograms at seven time points between 2002 and 2018. Transplant-free survival was 74.4% at 15 years from the first evaluation, and over those 15 years 25% progressed to cardiac death or transplant. The 9 patients who died or received a transplant showed a worsening, enlarging left ventricle and a falling ejection fraction (the share of blood pumped out with each beat); reduced function of the right ventricle also predicted this outcome (PMID 35238957).

Neutropenia, Monocytes and Infection

Neutrophils are the white blood cells that respond first to bacteria. A 2019 review of 88 patients found at least one neutrophil count below 1.5 × 109/L in 74 (84%), and 44% had severe chronic neutropenia, with several counts below 0.5 × 109/L. The pattern differed from person to person: intermittent and unpredictable in some, chronic and severe in others, and in others cyclical, rising and falling with mathematically regular timing. Monocytes, another kind of white blood cell, were raised above 1.0 × 109/L at least once in 64 of 85 patients (75%) (PMID 30451719). The 2013 British review notes that some children with Barth syndrome have never been neutropenic (PMID 23398819).

Low neutrophil counts leave patients open to life-threatening bacterial infections, and sepsis is a significant cause of illness and death (PMID 23843353). In the French national study, 2 of the 11 deaths were due to sepsis, and severe neutropenia at diagnosis (below 0.5 × 109/L) was one of two factors linked to survival (PMID 23656970). In the 2025 study of infants and toddlers, 19 of 21 had neutropenia, with variable severity and infection risk (PMID 41177130).

The 2019 review states that Barth syndrome belongs on the list of possible causes in any male with neutropenia who also has any of the characteristic features of the syndrome (PMID 30451719).

Muscle Weakness, Fatigue, Growth and Feeding

Muscle weakness and tiredness are the most common long-term complaints. In the 2026 database analysis, clinical problems increased with age, and musculoskeletal problems and fatigue were the most frequent, reported in 66% (PMID 42070974).

The 2025 study of 21 boys from birth to 48 months gives the clearest picture of early life. Failure to thrive was the first sign in 6. Feeding difficulties affected 16, and 7 needed a gastrostomy tube (a feeding tube placed through the wall of the abdomen into the stomach). Growth delay was common, although weight for height was often preserved. Gross motor development, especially standing and walking, was delayed, and the deficits on standard motor testing grew over time. Parent-reported quality of life was substantially impaired, most of all for fatigue and general functioning. Pain was rarely reported (PMID 41177130).

The 2019 neutropenia review describes the growth pattern as constitutional growth delay, alongside motor delay, weakness of the muscles close to the trunk and feeding problems (PMID 30451719). The French national study found plasma levels of the amino acid arginine reduced or in the low-normal range (PMID 23656970).

How Barth Syndrome Is Diagnosed

Diagnosis is often late. A 2025 review of published case reports, registry data and US insurance claims found that most affected people were not diagnosed until after cardiomyopathy had developed or until a family member had been diagnosed, even when they already had symptoms (PMID 41268908).

Urine 3-methylglutaconic acid

A raised level of 3-methylglutaconic acid in the urine is one of the classic findings (PMID 23843353), but it is not reliable on its own. The French national study found it to be inconstant and moderate (PMID 23656970), and the 2013 British review notes that some patients lack the increase altogether (PMID 23398819).

The monolysocardiolipin to cardiolipin ratio

Because the disease leaves too much monolysocardiolipin and too little finished cardiolipin, the ratio between the two is a direct marker. A 2008 study measured this ratio in dried blood spots, the same kind of blood spot collected for newborn screening. All 31 patients had ratios above 0.40, and all 215 control samples were below 0.23. With a cut-off of 0.30, a blinded test of 206 samples (199 controls and 7 patients) showed 100% sensitivity and 100% specificity. The blood spots could be stored for more than a year without changing the result, and three newborn screening cards taken 3.6 to 5.8 years earlier were correctly identified as positive (PMID 18070816).

A 2009 study set up the same measurement in cultured skin cells, white blood cells and muscle. When the authors re-tested 121 stored muscle samples from patients with suspected mitochondrial muscle disease, they found one patient with Barth-type cardiolipin changes, and gene analysis then confirmed a TAFAZZIN mutation (PMID 19454236). The 2012 case of the girl with Barth syndrome was also first picked up by an abnormal blood-spot ratio (PMID 22410210).

A 2023 study states that the ratio is always abnormal in Barth syndrome, but that neither the ratio nor urine 3-methylglutaconic acid has been shown to rise and fall with a patient's clinical state over time. The same study found the blood markers FGF21 and GDF15 raised in 16 patients and linked to measures of liver, blood cell and heart involvement, and proposes them for monitoring (PMID 37549445).

Gene testing

Sequencing of the TAFAZZIN gene confirms the diagnosis, detects female carriers and allows testing before birth. Cardiolipin testing and gene sequencing can both be done on fresh or stored tissue, blood, or newborn blood spots, so a diagnosis can also be made after the fact (PMID 23398819). In the 2025 infant study, the average age at diagnosis was 5.5 months, significantly earlier than in older cohorts; the authors credit wider genetic testing (PMID 41177130).

Conditions that are considered alongside Barth syndrome include metabolic and viral cardiomyopathies, other mitochondrial diseases, the many other causes of neutropenia, and recurrent loss of male pregnancies (PMID 23398819).

Survival and Outcomes in Registry Studies

All the survival figures below come from observational studies. They describe what happened to groups of patients; they do not prove what caused better or worse outcomes.

The French national cohort (2013)

Researchers reviewed the records of every known patient in France: 22 patients from 16 families. The median age at first presentation was 3.1 weeks. Eleven patients died, at a median age of 5.1 months; 9 deaths were related to cardiomyopathy and 2 to sepsis. The 5-year survival rate was 51%, and no deaths occurred in patients aged 3 years or older. Survival was 70% for patients born after 2000 and 20% for those born before 2000 (PMID 23656970).

The international database of 502 people (2026)

The largest analysis so far used a patient organization's intake database of 502 people and a patient-entered registry of 162 people with up to 11 years of follow-up. Deaths fell mostly on young children: transplant-free survival for those under age 5 was 59%. The risk of death levelled off between ages 5 and 25 and then rose again. Heart transplantation (hazard ratio 0.316, 95% confidence interval 0.162 to 0.619) and living in a developed country (hazard ratio 0.109, 95% confidence interval 0.018 to 0.659) were associated with a lower risk of death; a hazard ratio below 1 means a lower risk. Heart causes led the causes of death: cardiomyopathy or heart failure in 51.3%, mostly in children under 5, and arrhythmia or cardiac arrest in 15%. The authors note that although deaths and hospital stays levelled off between ages 5 and 25, the overall burden of the disease kept growing throughout life (PMID 42070974).

Other studies

The US heart study of 44 patients reported 74.4% transplant-free survival at 15 years from the first evaluation (PMID 35238957). In the 2025 infant study, one of the 21 boys died, of cardiopulmonary arrest (PMID 41177130). A 2025 review reports that more than 15% of living people known to have Barth syndrome have needed a heart transplant (PMID 41268908). The 2013 British review states that multidisciplinary teams and clinics allow many more people with Barth syndrome to live into adulthood (PMID 23398819).

Treatments Used in Care

The 2013 British review lists the main parts of care: medical treatment of the cardiomyopathy, heart transplantation (in 14% of patients at that time), preventive antibiotics, and granulocyte colony-stimulating factor (G-CSF), a growth factor that stimulates the bone marrow to make neutrophils (PMID 23398819).

Heart failure care and transplant

The general approach to heart failure is described on the Heart Failure page. A 2013 review notes that newer treatments for end-stage heart muscle failure offer a chance to change the course of the disease (PMID 23843353). The French authors concluded that modern heart failure management and prevention of infection in infancy may improve survival without the need for a transplant (PMID 23656970). In the 2026 database analysis, heart transplantation was associated with a lower risk of death (PMID 42070974).

Granulocyte colony-stimulating factor and antibiotics

In the 2019 review of 88 patients, 39 (44%) received granulocyte colony-stimulating factor, and 21 of 26 neutropenic patients also received preventive antibiotics. Before treatment, bone marrow samples mainly showed reduced maturation of the neutrophil line; this returned to normal on granulocyte colony-stimulating factor in 7 of the 13 patients examined. The review reports consistent clinical improvement, with fewer signs and symptoms of infection, on preventive granulocyte colony-stimulating factor with or without antibiotics. Infections still occurred: one adult died with several infections related to implanted medical devices and a feeding-tube site after 15.5 years on granulocyte colony-stimulating factor, and one child needed a gastrostomy tube removed because of repeated skin infections of the abdominal wall (PMID 30451719).

Nutrition and Early Intervention

Feeding support, including gastrostomy tubes, is common in young children with Barth syndrome (PMID 41177130). The infant study's authors call for proactive heart surveillance, nutritional support and early therapeutic interventions in this age group (PMID 41177130).

Elamipretide: Trial Results and the US Label

Elamipretide is a small peptide made of four amino acids that interacts with cardiolipin in the inner membrane of the mitochondria (PMID 33077895). The US prescribing information calls it a mitochondrial cardiolipin binder and states that it improves the shape and function of mitochondria. Laboratory and early clinical studies reported that it stabilizes cardiolipin and improves mitochondrial energy production (PMID 40816230).

The TAZPOWER trial

The TAZPOWER trial began with a randomized, double-blind, placebo-controlled crossover phase. Twelve patients received 40 mg of elamipretide per day or a placebo for 12 weeks, then had a 4-week break, then switched to the other arm for 12 weeks. The two main measures were the six-minute walk test (how far a person walks in six minutes) and a Barth syndrome symptom questionnaire. Neither main measure improved in this randomized phase (PMID 33077895). The US prescribing information gives the patients' ages as 12 to 35 years, and states that elamipretide was not superior to placebo on these measures.

Ten patients then continued on open-label elamipretide (everyone knew they were taking the drug, and there was no placebo group). At 36 weeks, the eight patients who reached that point walked 95.9 metres further in six minutes (p = 0.024), with gains in thigh muscle (knee extensor) strength, in the patients' own overall rating of their symptoms, and in some heart measures (PMID 33077895).

The extension ran to 168 weeks. Eight of the ten patients reached the week-168 visit. Six-minute walk distance improved at every time point, by a cumulative 96.1 metres at week 168 (P = .003). Fatigue scores stayed better than baseline. Three-dimensional ultrasound measures of left ventricle volume showed significant trends toward improvement, and the monolysocardiolipin to cardiolipin ratio improved. Injection-site reactions were the most common side effect (PMID 38602181).

Comparison with untreated patients

Because the extension had no control group, a 2022 study compared the 8 treated patients with 19 untreated patients from earlier records, matched by a statistical method (propensity scores). It was retrospective, not randomized. The treated group walked further, by a least-squares mean difference of 79.7 metres at week 64 (P = 0.0004) and 91.0 metres at week 76 (P = 0.0005), and was stronger by 40.8 newtons at 64 weeks (P = 0.0002) and 56.7 newtons at 76 weeks (P = 0.0005). Left ventricle stroke volume rose in the treated patients and fell in the untreated ones (PMID 36056411).

Several authors of the TAZPOWER papers were employees of the drug's manufacturer or received research funding from it, as the papers' conflict-of-interest statements disclose (PMID 33077895, 38602181, 36056411).

Approval and the US label

In September 2025, elamipretide received accelerated approval in the United States, the first treatment approved specifically for Barth syndrome (PMID 41335372). A 2026 commentary dates the approval to 19 September 2025 and notes that a confirmatory trial is required as a condition of accelerated approval (PMID 41260682). A case report written in August 2025, shortly before the approval, still stated that no FDA-approved therapies existed (PMID 40816230).

The US prescribing information on DailyMed (version published 11 November 2026) states:

Case reports in young children

Two case reports describe elamipretide given outside the approved weight range. In one, Barth syndrome was identified before birth with severe left ventricular non-compaction; elamipretide was started shortly after birth for heart failure, and the report describes significant, sustained improvement that moved the baby to inactive status on the heart transplant list (PMID 40816230). In the other, a 5-year-old boy in France with advanced heart failure (ejection fraction 20%), on a gastrostomy tube and listed for transplant, received elamipretide under a compassionate-use program; the report gave 10 mg per day alongside full standard heart failure treatment. Over six months his ejection fraction rose to 50%, leaking of the mitral valve fell from moderate-to-severe to mild, his heart failure class improved from IV to I, he returned to full-time school, and he was temporarily removed from the transplant list. One short episode of abdominal pain with a moderate rise in pancreatic enzymes resolved without stopping treatment (PMID 42415111). Single case reports cannot show that the drug caused the improvement, because heart function in Barth syndrome can also change on its own (PMID 23656970).

What Is Not Known

Key Research Papers

  1. Fu K, Huang Y, Bowen V, McCurdy K, Tan RB, Phoon CKL, et al. Survival and Clinical Progression in Barth Syndrome: Insights From the Barth Syndrome Foundation's Database of 502 Affected Individuals. J Inherit Metab Dis. 2026;49(3):e70189. PubMed PMID: 42070974
  2. Vishwanath S, Brockmeyer A, Hornby B, Thompson WR, Vernon HJ. Barth syndrome: Natural history in infants and young children. Mol Genet Metab. 2025;146(4):109270. PubMed PMID: 41177130
  3. Jacob N, Schecter D, Marshall M, Bansal N, Lamour J, Vernon H, et al. Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report. Mol Genet Metab. 2025;146(1-2):109220. PubMed PMID: 40816230
  4. Reid Thompson W, Hornby B, Manuel R, Bradley E, Laux J, Carr J, et al. A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism. Genet Med. 2021;23(3):471-478. PubMed PMID: 33077895
  5. Thompson WR, Manuel R, Abbruscato A, Carr J, Campbell J, Hornby B, et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genet Med. 2024;26(7):101138. PubMed PMID: 38602181
  6. Hornby B, Thompson WR, Almuqbil M, Manuel R, Abbruscato A, Carr J, et al. Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome. Orphanet J Rare Dis. 2022;17(1):336. PubMed PMID: 36056411
  7. Shirley M. Elamipretide: First Approval. Drugs. 2026;86(3):377-383. PubMed PMID: 41335372
  8. Zhao C, Zhuang X, Gao J. Elamipretide: The first cardiolipin-directed mitochondrial therapeutic for Barth syndrome approved under accelerated approval. Drug Discov Ther. 2026;19(6):435-436. PubMed PMID: 41260682
  9. Amedro P, Andrianoely M, Gohier P, Leroux J, Aladjidi N, Lagorce S, et al. Elamipretide in pediatric Barth syndrome: from heart failure to school return. Orphanet J Rare Dis. 2026;21(1):340. PubMed PMID: 42415111
  10. Rigaud C, Lebre AS, Touraine R, Beaupain B, Ottolenghi C, Chabli A, et al. Natural history of Barth syndrome: a national cohort study of 22 patients. Orphanet J Rare Dis. 2013;8:70. PubMed PMID: 23656970
  11. Chowdhury S, Jackson L, Byrne BJ, Bryant RM, Cade WT, Churchill TL, et al. Longitudinal Observational Study of Cardiac Outcome Risk Factor Prediction in Children, Adolescents, and Adults with Barth Syndrome. Pediatr Cardiol. 2022;43(6):1251-1263. PubMed PMID: 35238957
  12. Clarke SL, Bowron A, Gonzalez IL, Groves SJ, Newbury-Ecob R, Clayton N, et al. Barth syndrome. Orphanet J Rare Dis. 2013;8:23. PubMed PMID: 23398819
  13. Jefferies JL. Barth syndrome. Am J Med Genet C Semin Med Genet. 2013;163C(3):198-205. PubMed PMID: 23843353
  14. Steward CG, Groves SJ, Taylor CT, Maisenbacher MK, Versluys B, Newbury-Ecob RA, et al. Neutropenia in Barth syndrome: characteristics, risks, and management. Curr Opin Hematol. 2019;26(1):6-15. PubMed PMID: 30451719
  15. Kulik W, van Lenthe H, Stet FS, Houtkooper RH, Kemp H, Stone JE, et al. Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome. Clin Chem. 2008;54(2):371-8. PubMed PMID: 18070816
  16. Houtkooper RH, Rodenburg RJ, Thiels C, van Lenthe H, Stet F, Poll-The BT, et al. Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high-performance liquid chromatography-mass spectrometry as a diagnostic test for Barth syndrome. Anal Biochem. 2009;387(2):230-7. PubMed PMID: 19454236
  17. Liu O, Chinni BK, Manlhiot C, Vernon HJ. FGF21 and GDF15 are elevated in Barth Syndrome and are correlated to important clinical measures. Mol Genet Metab. 2023;140(3):107676. PubMed PMID: 37549445
  18. Cosson L, Toutain A, Simard G, Kulik W, Matyas G, Guichet A, et al. Barth syndrome in a female patient. Mol Genet Metab. 2012;106(1):115-20. PubMed PMID: 22410210
  19. Marjoram L, Huang Y, Koenig MK, Cohen BH, Anderson E. Real-world disease burden and health care resource utilization for patients with Barth syndrome. J Med Econ. 2025;28(1):2010-2026. PubMed PMID: 41268908

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