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Barth Syndrome

Barth syndrome is a rare condition that causes several problems in males, including enlarged heart and cardiac disease, weakened immune system from neutropenia (low quantity of white blood cells), muscle weakness, fatigue, delayed growth and high levels of a chemical called 3-methylglutaconic acid in the urine. Barth syndrome is caused by variants in the TAZ gene on the X chromosome. TAZ is important in the maturation of a mitochondrial membrane molecule (cardiolipin), so immature cardiolipin builds up instead and the function of the mitochondria becomes impaired1. The mitochondria is a part of cells in the body that generates energy, so improper function of the mitochondria can cause many issues.

The severity of disease and features experienced by males with Barth syndrome is variable, with the most common symptom being heart disease (present in >90% of male patients, usually within the first year of life)1. The specific type of heart disease varies and can include a combination of structural changes to the heart and arrhythmias (electrical instability). Barth syndrome has poor phenotype-genotype correlation, meaning that the specific genetic mutation that an individual has does not consistently predict the severity of disease that they will experience. This also means that members of the same family who have the same exact TAZ gene mutation might be impacted by the disease in significantly different ways.

Barth syndrome was first described in 1983, making it a relatively new disease to be understood1. The number of patients and families diagnosed with the disease remains low, however there is some evidence that it is an under-diagnosed condition. In many families, Barth syndrome has been recognized as the cause for recurrent fetal loss of male fetuses (miscarriages and stillbirths), indicating that sometimes these TAZ mutations cause such severe disease that a fetus is unable to survive long enough to be born1.

 

Females with Barth Syndrome

Female carriers of Barth syndrome, i.e. females who have a variant in the TAZ gene on one of their two X chromosomes (heterozygotes), are almost always asymptomatic carriers. Females with Barth syndrome are thought to be particularly protected from developing any features of disease because of skewed X-inactivation favoring the normal allele. See below for explanation:

X-inactivation occurs in all cells of a female fetus early in development, where each cell inactivates one of their two X chromosomes, leaving only one active. Because this is a random process, this usually results in balanced (~50:50) expression of each X chromosome across the cells in the body. In female carriers of Barth syndrome, the early cells that inactivate the normal X chromosome are left with no functioning TAZ gene, so they are less likely to survive compared to the cells that inactivated the mutant X chromosome (and thus still have an active normal copy of the TAZ gene). Because of this, as their cells continue to multiply, females with Barth syndrome end up with skewage of their X chromosome expression favoring the normal copy. This protects female carriers from the effects of the disease, as a majority of their cells will have normal TAZ gene expression.

One study looking at 16 female carriers of Barth syndrome found that 6 of them had extremely skewed X-inactivation (>95:5 normal:mutant) and 5 had skewed inactivation (80:20 normal:mutant), compared to normally balanced expression in the the vast majority of female controls (females without any TAZ mutations)2. This study supports the theory that females are often especially protected from Barth syndrome by skewed X-inactivation favoring the normal X chromosome. Of note, no symptoms were reported in any of the carrier females in that study, including those without skewed X-inactivation. So, having roughly half of cells express the normal TAZ copy is probably enough to prevent symptoms in Barth syndrome. And, another study looking at 8 female carriers similarly reported no symptoms or chemical imbalance indicative of the disease in any of the patients3.

Two females have been reported to have symptoms of Barth syndrome, however these patients were rare exceptions. One female patient with severe dilated heart disease diagnosed at one month of age had genetic defects involving the TAZ gene on both of her X chromosomes, so she did not have any healthy copy of the TAZ gene to express4. The other patient had left ventricular noncompaction (another form of heart disease) diagnosed at 3 months of age and hypotonia (weak muscle tone) diagnosed at 9 years of age5. Her symptoms, which were significantly milder than her brother who had the same TAZ mutation, are thought to be due to skewed X inactivation favoring the mutant X chromosome instead of the normal X chromosome. This is the only reported case of this happening, and the reason remains unknown5.

While female carriers of Barth syndrome typically do not experience symptoms of disease, there have been exceptions (outlined above). And, carriers of the condition are often impacted by frequent pregnancy loss, because male fetuses with Barth syndrome sometimes do not survive1. This can come with significant physical and social harm to Barth syndrome carriers, in addition to challenges surrounding family planning, caretaking of affected family members, and stigmas of genetic disease.

This page was last updated in August, 2026. Please note that research into females with this condition is limited and the number of reported cases is small. Decisions regarding your own health should be made in consultation with your medical provider.

  1. Clarke SL, Bowron A, Gonzalez IL, et al. Barth syndrome. Orphanet J Rare Dis. 2013;8:23. doi:10.1186/1750-1172-8-23
  2. Ørstavik KH, Ørstavik RE, Naumova AK, et al. X Chromosome Inactivation in Carriers of Barth Syndrome. Am J Hum Genet. 1998;63(5):1457-1463. doi:10.1086/302095
  3. Vernon HJ, Sandlers Y, McClellan R, Kelley RI. Clinical laboratory studies in Barth Syndrome. Mol Genet Metab. 2014;112(2):143-147. doi:10.1016/j.ymgme.2014.03.007
  4. Cosson L, Toutain A, Simard G, et al. Barth syndrome in a female patient. Mol Genet Metab. 2012;106(1):115-120. doi:10.1016/j.ymgme.2012.01.015
  5. Avdjieva-Tzavella DM, Todorova AP, Kathom H M null, et al. BARTH SYNDROME IN MALE AND FEMALE SIBLINGS CAUSED BY A NOVEL MUTATION IN THE TAZ GENE. Genet Couns. 2016;27(4):495-501.