Course:MEDG550/Student Activities/Barth Syndrome

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Barth Syndrome

Overview

Barth syndrome is a rare genetic condition that mainly affects males (referring to someone who was assigned male at birth). Symptoms include heart problems, low blood cell count, muscle weakness, and extreme tiredness. The condition was discovered in 1983 by Dr. Peter Barth[1]. Barth syndrome is caused by genetic changes (also known as “genetic variants”) in the TAFAZZIN gene[2].

Signs and Symptoms

Many different parts of the body can be affected in Barth syndrome. This includes the heart, immune system, muscles, bones, and face. Males with Barth syndrome can have a range of symptoms, with some people more affected than others. Because of this big range, Barth syndrome is hard to recognize and diagnose[1].

Heart

Heart problems leading to heart failure (when the heart cannot pump blood to the body) are common in young males with Barth syndrome. In most cases, males with Barth syndrome will begin to have heart problems in their first year of life. Some will develop heart problems later on, but even then, symptoms usually begin before the age of 5[3].

This photo shows the difference between a normal heart and a heart with dilated cardiomyopathy.

These heart problems can include:

  • Dilated cardiomyopathy (dilated = swollen, cardio = heart, myopathy = muscle weakness) this is the most common heart problem in males with Barth syndrome[2]. Dilated cardiomyopathy is a condition where the heart muscles are weakened and thin. With this muscle thinning, the heart appears bigger than it should. When the muscles become weak, the heart is not able to pump blood as easily throughout the rest of the body. Dilated cardiomyopathy is what’s known as progressive, which means that it continues to worsen over time[4].
  • Endocardial fibroelastosis (endo = inner, cardial = heart, fibro = related to fiber, elastosis = breakdown of elasticity) – this condition is caused by thickening of the inner layer of the heart due to buildup of fibrous and elastic material[5]. Sometimes males with Barth syndrome who have dilated cardiomyopathy (see above) will also have endocardial fibroelastosis.
  • Left ventricular non-compaction (ventricular = refers to lower heart chambers) – this condition is caused by the heart muscle being abnormally thick and spongey, making it more challenging to pump blood[6].
  • Hypertrophic cardiomyopathy (hypertrophic = overgrown, cardio = heart, myopathy = muscle weakness) – Hypertrophic cardiomyopathy is like the opposite of dilated cardiomyopathy. In this condition, the heart muscle is abnormally thick. In Barth syndrome, it is less common than dilated cardiomyopathy[2].
  • Arrhythmias – these are changes in the heartbeat rhythm, which can cause fainting or life-threatening symptoms. They are less common in males with Barth syndrome compared to the physical differences in the heart (the ones above) but can still occur[7].

Immune System

Some males with Barth syndrome have an immune deficiency that’s known as “neutropenia". This means that they have fewer white blood cells than expected. White blood cells are an important part of our immune system. When someone has neutropenia, their body has a harder time fighting infections. Males with Barth syndrome are more likely to experience mouth sores, pneumonia, and extreme reactions to infections (also called “sepsis”)[2].

This photo shows some examples of males with Barth syndrome who have the unique facial features of the condition.

Muscular and Skeletal

Most males with Barth syndrome will experience muscle weakness, also called “hypotonia”[2]. This can result in early motor delays, meaning that children with Barth syndrome may not move like other children their age.

Barth syndrome also impacts growth. About half of males with the condition will experience a growth delay before puberty, so they will be shorter and smaller than other friends their age. This growth delay is usually followed by a catch-up phase, where after puberty, they will have a growth spurt[8].

Facial Features

In early childhood, males with Barth syndrome have unique facial features. This includes round faces, full cheeks, pointed chins, large ears, and deep-set eyes[2].

Other Symptoms

Some other symptoms of Barth syndrome include extreme tiredness, feeding and digestive problems, and differences in the chemical levels in urine[1].

Prognosis

Heart problems and low blood cell count are the main causes of death in males with Barth syndrome[9]. Depending on the severity of these issues, males with Barth syndrome may die in early childhood. However, with better detection and treatment of these conditions, the survival of males with Barth syndrome has increased. Some males live into their late 50s and 60s with the diagnosis[2][10].

Prevalence

Barth syndrome is a rare condition that almost only affects males. Because of how rare it is, it’s hard to give an accurate estimation of how many people are affected. One study found that it affects around 1 in a million males. However, to date, only about 230-250 cases around the world have been identified, which is much less than we would expect[9]. This means that the condition is likely underdiagnosed.

Genetics

Why is Barth syndrome a genetic condition?

Every cell in our body contains DNA. DNA is important because it acts like a recipe book with all of the instructions our body needs to grow and develop. These instructions are called “genes”. Like in a book, we can have spelling changes in our genes (for example, a typo or a missing paragraph), which can affect the instructions and impact our health. These spelling changes are called “genetic variants”. In Barth syndrome, the genetic variants that cause the condition are found in the TAFAZZIN gene (previously known as TAZ)[1].

How do genetic variants in TAFAZZIN cause Barth syndrome?

TAFAZZIN helps to make cardiolipin (cardio = heart, lipin = refers to type of fat). Cardiolipin is important in our bones and muscles. In Barth syndrome, genetic variants in TAFAZZIN cause less cardiolipin to be made, which affects bones and muscles, including the heart[1].

Why are males affected by Barth syndrome?

In order to fit all the DNA into our cells, it organizes itself into structures known as “chromosomes”. Humans typically have 46 chromosomes, including two sex chromosomes which determine your sex assigned at birth.

  • Males have one X chromosome and one Y chromosome.
  • Females have two X chromosomes.

Males are mainly affected by Barth syndrome because the TAFAZZIN gene is present on the X chromosome[3]. Since males only have one copy of the X chromosome, they only have one copy of the TAFAZZIN gene. If there is a genetic variant in TAFAZZIN, they do not have a backup copy.

Because females have two X chromosomes, they have two copies of the TAFAZZIN gene (one on each chromosome). This means that they can have a genetic variant in one of their TAFAZZIN genes, and still not have any symptoms of Barth syndrome, since they have a backup. These females can be considered “carriers” of Barth syndrome. Carriers of the condition do not have Barth syndrome, but they are able to pass it on to their children. The only way to detect if they are carriers is by genetic testing[11].

There are very rare cases where females are affected by Barth syndrome. In these cases, it’s because their second X chromosome has another genetic difference that makes it unable to act as a backup[2].

This photo shows the two different ways that Barth syndrome gets passed down, either from a mom who is a carrier (left), or a dad who has Barth syndrome (right).

How is Barth syndrome passed down?

Because the TAFAZZIN gene is found on the X chromosome, it gets passed down in an X-linked inheritance pattern.

If a female carrier of the condition is pregnant with a female fetus, there is:

  • A 50% chance that the daughter will be a carrier.
  • A 50% chance that the daughter will be unaffected (not a carrier and no symptoms).

If a female carrier of the condition is pregnant with a male fetus, there is:

  • A 50% chance that the son will have Barth syndrome.
  • A 50% chance that the son will be unaffected (not a carrier and no symptoms).

If a male with Barth syndrome has children:

  • All of his daughters will be carriers, since he will pass on his affected X chromosome.
  • All of his sons will be unaffected, since he does not pass on his X chromosome to his sons (he only passes on his Y chromosome).

Diagnosis[2]

There are two types of tests that can diagnose Barth syndrome:

  1. The first type is a monolysocardiolipin : cardiolipin ratio, also called a “ML:CL ratio”. Because males with Barth syndrome have less cardiolipin, this test is able to diagnose the condition.
  2. Genetic testing of the TAFAZZIN gene will also diagnose the condition, or detect carrier females, since they do not have symptoms.

Sometimes, other lab testing might be done to support the diagnosis. This can include:

  • Cholesterol levels
  • White blood cell levels
  • Urine tests

Management and Treatment[2]

Currently, there is no cure for Barth syndrome. Treatment instead focuses on managing the symptoms, which can be different for each person. This is why it's important for individuals with Barth syndrome and their families to speak with their doctors to make sure they have the best care.

Some treatments and supports may include:

  • Heart medication
  • Devices for heart monitoring
  • Heart transplant
  • Monitoring fluid levels
  • Medications, like antibiotics, to avoid infection
  • Physical therapy
  • Feeding therapy
  • Support from a psychologist
  • Developmental assessments

Patient Resources

Websites

Barth Syndrome Foundation[12]

This is an American organization that works to raise awareness about Barth syndrome and provide information, support, and resources to families.

Remember the Girls[13]

This organization provides resources and support to female carriers of X-linked conditions, including Barth syndrome.

National Organization for Rare Diseases[14]

This organization provides information and resources for rare diseases, including Barth syndrome.

Genetic Counselling

Genetic counsellors are healthcare providers that can play a role in individuals and their family’s journey with Barth syndrome. They are able to provide information on the condition, the genetics, and how it may impact other family members. They may also discuss genetic testing options.

More information on what genetic counsellors do: Canadian Association of Genetic Counsellors

References

  1. ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 Clarke, S. L., Bowron, A., Gonzalez, I. L., Groves, S. J., Newbury-Ecob, R., Clayton, N., Martin, R. P., Tsai-Goodman, B., Garratt, V., Ashworth, M., Bowen, V. M., McCurdy, K. R., Damin, M. K., Spencer, C. T., Toth, M. J., Kelley, R. I., & Steward, C. G. (2013). Barth syndrome. Orphanet Journal of Rare Diseases, 8, 23. https://doi.org/10.1186/1750-1172-8-23
  2. ↑ Jump up to: 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 Ferreira C, Pierre G, Thompson R, et al. Barth Syndrome. 2014 Oct 9 [Updated 2020 Jul 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK247162/
  3. ↑ Jump up to: 3.0 3.1 Roberts, A. E., Nixon, C., Steward, C. G., Gauvreau, K., Maisenbacher, M., Fletcher, M., Geva, J., Byrne, B. J., & Spencer, C. T. (2012). The Barth Syndrome Registry: Distinguishing disease characteristics and growth data from a longitudinal study. American Journal of Medical Genetics Part A, 158A(11), 2726–2732. https://doi.org/10.1002/ajmg.a.35609
  4. ↑ Mahmaljy H, Yelamanchili VS, Singhal M. Dilated Cardiomyopathy. [Updated 2023 Apr 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441911/
  5. ↑ Sana MK, Mahajan K. Endocardial Fibroelastosis. [Updated 2023 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559128/
  6. ↑ Singh DP, Horenstein MS, Rout P, et al. Left Ventricular Noncompaction Cardiomyopathy. [Updated 2024 Feb 12]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537025/
  7. ↑ Kang, S.-L., Forsey, J., Dudley, D., Steward, C. G., & Tsai-Goodman, B. (2016). Clinical Characteristics and Outcomes of Cardiomyopathy in Barth Syndrome: The UK Experience. Pediatric Cardiology, 37(1), 167–176. https://doi.org/10.1007/s00246-015-1260-z
  8. ↑ Spencer, C. T., Bryant, R. M., Day, J., Gonzalez, I. L., Colan, S. D., Thompson, W. R., Berthy, J., Redfearn, S. P., & Byrne, B. J. (2006). Cardiac and Clinical Phenotype in Barth Syndrome. Pediatrics, 118(2), e337–e346. https://doi.org/10.1542/peds.2005-2667
  9. ↑ Jump up to: 9.0 9.1 Miller, P. C., Ren, M., Schlame, M., Toth, M. J., & Phoon, C. K. L. (2020). A Bayesian Analysis to Determine the Prevalence of Barth Syndrome in the Pediatric Population. The Journal of Pediatrics, 217, 139–144. https://doi.org/10.1016/j.jpeds.2019.09.074
  10. ↑ Mazar, I., Stokes, J., Ollis, S., Love, E., Espensen, A., Barth, P. G., Powers, J. H., & Shields, A. L. (2019). Understanding the life experience of Barth syndrome from the perspective of adults: A qualitative one-on-one interview study. Orphanet Journal of Rare Diseases, 14, 243. https://doi.org/10.1186/s13023-019-1200-8
  11. ↑ Vernon, H. J., Sandlers, Y., McClellan, R., & Kelley, R. I. (2014). Clinical laboratory studies in Barth Syndrome. Molecular Genetics and Metabolism, 112(2), 143–147. https://doi.org/10.1016/j.ymgme.2014.03.007
  12. ↑ Home: Barth Syndrome Foundation. (n.d.). Retrieved January 31, 2025, from https://www.barthsyndrome.org/
  13. ↑ Home To Females Impacted By X-Linked Conditions. (2024, November 18). Remember The Girls. https://rememberthegirls.org/
  14. ↑ Barth Syndrome—Symptoms, Causes, Treatment | NORD. (n.d.). Retrieved January 31, 2025, from https://rarediseases.org/rare-diseases/barth-syndrome/
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