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Barth Syndrome

What is Barth Syndrome?

Barth syndrome is a rare, genetic, neuromuscular and metabolic disorder occurring primarily in males. The disorder affects multiple systems of the body including the immune system, heart, and skeletal muscles. Barth syndrome can also affect growth and usually becomes apparent during infancy or early childhood. The age of onset, associated symptoms, disease course and overall severity varies considerably among affected individuals. Barth syndrome is inherited as an X-linked recessive trait and occurs because of alterations (mutations) to a specific gene.



  • 3-methylglutaconic aciduria type 2
  • Barth Syndrome
  • cardioskeletal myopathy with neutropenia and abnormal mitochondria
  • Endocardial fibroelastosis type 2
  • X-linked cardioskeletal myopathy and neutropenia

Barth syndrome is a rare, genetic, neuromuscular and metabolic disorder occurring primarily in males. The disorder affects multiple systems of the body including the immune system, heart, and skeletal muscles. Barth syndrome can also affect growth and usually becomes apparent during infancy or early childhood. The age of onset, associated symptoms, disease course and overall severity varies considerably among affected individuals. Barth syndrome is inherited as an X-linked recessive trait and occurs because of alterations (mutations) to a specific gene.

Rareshare would like to acknowledge Dr. Colin Phoon, Division of Pediatric Cardiology, Department of Pediatrics, New York University School of Medicine, New York for reviewing this content.

The prevalence of Barth syndrome is estimated to occur in 1 in 300,000 to 400,000 births worldwide. Researchers believe that the disorder is underdiagnosed and that the true incidence and prevalence rates are unknown. Barth syndrome affects all racial and ethnic groups.

Name Abbreviation
3-methylglutaconic aciduria type 2 3-methylglutaconic aciduria type 2
Barth Syndrome BTHS
cardioskeletal myopathy with neutropenia and abnormal mitochondria BTHS
Endocardial fibroelastosis type 2 EFE2
X-linked cardioskeletal myopathy and neutropenia X-linked cardioskeletal myopathy and neutropenia

Barth syndrome is caused by mutations in the TAZ gene. This gene provides instructions for making a protein named tafazzin, which is active in structures called mitochondria (the energy-producing centers of cells). This protein is involved in altering a fat called cardiolipin, which plays critical roles in the mitochondrial inner membrane and is key in maintaining mitochondrial shape, energy production, and protein transport within cells. A mutation in the TAZ gene results in tafazzin proteins with little or no function.1 This impairs normal mitochondrial shape and function. Tissues with high energy demands, such as the heart and skeletal muscles, are most susceptible to cell death due to the reduced energy production. Additionally, abnormally shaped mitochondria are found in affected white blood cells, which could affect their ability to grow and mature, leading to neutropenia.2

The mutation in the TAZ gene that causes Barth syndrome is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is enough to cause the condition. The altered gene is passed on from a mother to her son. Women with an altered TAZ gene do not show any symptoms of the disorder, most likely due to their second X-chromosome (with an unaltered TAZ gene) compensating for the altered gene on the other X chromosome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons since they pass on their Y chromosome and not their X chromosome to their sons.

Syptoms of Barth syndrome may be evident at birth, infancy, or early childhood. In rare situations, the disorder may not be diagnosed until adulthood. The specific symptoms that develop and the overall severity of the disorder can vary greatly among individuals with Barth syndrome. All of the symptoms potentially associated with the disorder will not develop in everyone who has the disorder.

Symptoms include weakened heart muscle (cardiomyopathy) that can occur along with the abnormal thickening of the muscular lining of the heart chamber (endocardial fibroelastosis). Endocardial fibroelastosis occurs due to an increase in the amount of supporting connective tissue and elastic fibers in the muscular lining. Another heart condition called left ventricular noncompaction can also occur. This condition is characterized by the presence of muscle tissue that extends in the lower left chamber of the heart (left ventricle).

Heart abnormalities are often present at birth, or appear during the first months of life. These heart abnormalities weaken the heart’s pumping action, reducing the volume of blood circulating to the lungs and the rest of the body, potentially resulting in heart failure. The specific symptoms of this depends on age and other factors. In young children, heart issues may manifest as fatigue and shortness of breath with exertion.2 The risk of irregular heartbeats (arrhythmias), stroke, and sudden death is increased in children with Barth syndrome.

Other symptoms of Barth syndrome include abnormally diminished muscle tone (hypotonia), and muscle weakness (skeletal myopathy), that leads to delays in the development of motor skills and can contribute to exercise intolerance. Weakness of facial muscles may lead to unusual facial expressions. Some infants may have difficulties feeding. Individuals with Barth syndrome may fail to grow and gain weight at the expected rate (failure to thrive). Most children experience growth delays and are below-average in height and weight.

Some children experience mild learning disabilities and in many cases, may be prone to recurrent bacterial infections due to low levels of circulating neutrophils in the blood (neutropenia). Neutrophils are a type of white blood cell and help the body to fight off bacterial infection. There is a risk of developing widespread bacterial infection (sepsis).  

In addition, affected individuals have abnormally increased levels of 3-methylglutaconic acid in their urine and blood.

Barth syndrome may be diagnosed during infancy or early childhood based upon a thorough clinical evaluation, identification of characteristic physical findings, complete patient and family history, and a variety of tests. A diagnosis of Barth syndrome should be considered for any male infant or child with dilated weakened heart muscles (cardiomyopathy) of unknown cause, low levels of circulating neutrophils, elevated levels of 3-methylglutaconic acid, abnormal mitochondria within heart muscle, and/or muscle abnormalities of unknown cause that occur in association with delayed growth.

Diagnostic tests include newborn screening. In addition, for infants and children with signs of weakened heart muscles (cardiomyopathy), metabolic screening tests should be conducted, including studies to measure levels of 3-methylglutaconic acid and other organic acids in the urine and blood. High levels of this acid can be a diagnostic sign of Barth syndrome. It is also important to measure the concentration of neutrophils in the blood, usually low in affected individuals. Prenatal and postnatal testing for the presence of the TAZ gene is available at certain genetic laboratories.

The treatment for Barth syndrome is directed toward the specific symptoms that are apparent. Many infants and children require therapy with the standard medications used to treat heart failure. Aspirin may be considered for the prevention of stroke. Some are gradually removed from cardiac therapy later during their childhood due to improvement of heart functioning. Sometimes, severe heart failure does not respond to treatment (intractable) and may require a heart transplant.

For affected individuals with confirmed neutropenia, complications due to bacterial infection are often preventable by ongoing monitoring and early therapy of suspected infections with antibiotics. Some individuals may receive preventive (prophylactic) treatment with antibiotics. A drug known as granulocyte-colony stimulating factor (G-CSF) may be prescribed. This drug stimulates the bone marrow to produce neutrophils. G-CSF may be given on a regular basis or only during times of high risk (e.g. during surgery or infection).

In boys who cannot take in adequate nutrition by mouth, a nasogastric or gastronomy tube, may be required. Educational support, particularly for children experience significant fatigue, and physical therapy can also be beneficial.

Prognosis of Barth syndrome has improved with early detection and improvements in treatment and management. Although some affected children die of heart failure or infection in infancy/early childhood, other individuals are already surviving into their 40s and are expected to live beyond this age.

As long as the affected individual is monitored and taking proper medications, the prospects of living normally is improved. Fatigue can be a major symptom at certain ages with scheduling in rest time being helpful. Prevent infection by using antibacterial hand sanitizer when needed, avoid sharing drinks and food with others, and pay attention to oral hygiene and tooth brushing. Clean and disinfect cuts and scrapes quickly. The use of uncooked corn starch given just before bedtime has been recommended as a way to avoid muscle protein loss overnight in children.

Barth Syndrome. National Organization for Rare Disorders (NORD) website. Available at:

Barth Syndrome. Barth Syndrome Trust website. Available at:

Barth Syndrome, Familial. Online Mendelian Inheritance in Man (OMIM) website.  

Barth Syndrome. Genetic Home Reference website.

Clarke SLN, Bowron A, Gonzalez IL, et al. Barth Syndrome. Orphanet Journal of Rare Diseases. 2013;8:23. Available at:

Ferreira C, Thompson R, Vernon H. Barth Syndrome. Gene Reviews website.  

Jefferies JL. Barth Syndrome. Am J Med Genet C Semin Med Genet. 2013;163(3):198-205.

Reynolds S. Successful management of Barth syndrome: a systematic review highlighting the importance of a flexible and multidisciplinary approach. J Multidiscip Healthc. 2015;8:345-358.

Steward C. Barth Syndrome. Orphanet website. Available at: 


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Healx Pushing New Drug Development Model in Rare Diseases with Barth Syndrome Foundation 03/01/2019
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Physician-scientist at New York University School of Medicine and attending pediatric cardiologist at Hassenfeld Children's Hospital at NYU Langone.  Primary rare disease interest: Barth...

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