NORD gratefully acknowledges Merlene Peter, MMSc, NORD Editorial Intern from the Emory University Genetic Counseling Training Program and Cecelia A. Bellcross, PhD, MS, CGC, Associate Professor, Director, Genetic Counseling Training Program, Emory University School of Medicine, for assistance in the preparation of this report.
Barth syndrome is a genetic condition that mainly affects males. Some of the symptoms of the condition include enlarged heart, low blood cell count, weakness of muscles, and fatigue. Additionally, there can be increased levels of chemicals like 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood. Barth syndrome is caused by changes (mutations) in the TAZ gene and has an X-linked inheritance pattern.
In 1983, multiple boys from a Dutch family were reported with enlarged and weakened heart (dilated cardiomyopathy), low white blood cells (neutropenia) and fatigue and weakness of muscles (hypotonia). This condition was named Barth syndrome after Dr. Peter Barth and is also called X-linked endocardial fibroelastosis because of the shiny white appearance of the inner membrane of the heart muscle. In 1996, mutations in the TAZ gene were found to be the cause of Barth syndrome.
Barth syndrome is mainly found in early infancy or childhood. However, in some patients, symptoms appear in adulthood. Symptoms can present differently and can vary from one person to another.
Males with Barth syndrome could have various heart problems like dilated cardiomyopathy, hypertrophic cardiomyopathy, endocardial fibroelastosis and left ventricular non-compaction. Dilated cardiomyopathy is when the left ventricle muscle becomes enlarged and weak which decreases the heart’s ability to pump blood. In some people with Barth syndrome, the heart muscles become very thick making it difficult to pump blood (hypertrophic cardiomyopathy). Sometimes, this thickening may be due to the build-up of connective tissues and elastin fibres (endocardial fibroelastosis). In other patients, the left ventricles do not develop properly (left ventricular noncompaction) so instead of the muscle being smooth, it becomes thick and spongy making it difficult to pump blood. These heart findings are almost always present before the age of 5. Sometimes the heart problems can be seen on an ultrasound exam in the last trimester in pregnancy. In addition to structural differences to the heart, in some adolescents and young adults, there could be an irregular heartbeat identified (arrhythmia). The heart problems might lead to decrease in blood circulation from in the body and to the lungs (heart failure). Symptoms of heart failure may include shortness of breath, tiredness and nausea, but the symptoms depend on the child and other factors.
People with Barth syndrome have a low level of white blood cells (neutropenia). The white blood cells in our body help us fight infections. Due to neutropenia, people have mouth ulcers, pneumonia or blood infections. Males with Barth syndrome have weak muscles (hypotonia) especially in the hands and feet. Due to the hypotonia, children take longer to develop gross motor skills like crawling, sitting or walking. Due to the heart issues and weak muscles, these boys do not tolerate exercise well. Males with the condition have growth delay during childhood, but there is a significant growth spurt in puberty. Other symptoms include curvature of the spine (scoliosis) and delayed bone age.
Males with Barth syndrome have distinct facial features. They have a round face with prominent chin and full cheeks. The ears are large, and they have deep set eyes. The facial features become less noticeable with age. The striking feature in adolescence and adulthood is the fat distribution in the hips, thighs and chest.
People diagnosed with the condition have some form of learning disability. They have age appropriate reading skills and vocabulary. However, they may need extra help with mathematics. Their first words or forming sentences can be delayed in comparison to other people. They have delay in developing skills like reading a map, recognizing shapes and finding objects in a picture. The boys have feeding difficulties. The Barth syndrome registry data suggest that a third of males with this condition would need a tube put through the nose or directly to the stomach for feeding. Boys with this condition are picky eaters. Salty, cheesy and spicy food are some of the foods they prefer.
In addition to the cardiomyopathy, neutropenia and growth delay, people with this condition have increased levels of biochemical markers. Increased levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid in the urine or blood is the common marker used to reach a diagnosis. However, there have been no symptoms associated with the increased levels of these chemicals.
Barth syndrome is caused by mutations in the TAZ gene. The TAZ gene produces a protein called tafazzin. Tafazzin helps in altering a fat called cardiolipin. Cardiolipin is present in the inner membrane of structures called mitochondria. Mitochondria are structures in the cell which helps in making energy. Loss of tafazzin protein mainly affects energy requiring organs like heart and skeletal muscles. However, more research is required to understand how the loss of tafazzin leads to cardiomyopathy and neutropenia.
Barth syndrome is inherited in an X-linked manner. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have an abnormal gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the abnormal gene. No females who are carriers for Barth syndrome have reported any symptoms.
Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains an abnormal gene, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Barth syndrome affects all ethnic groups. The incidence of Barth syndrome is estimated to be 1 in 300,000 to 1 in 400,00 in United States. As of 2013, there have been 151 patients reported in the medical literature.
Barth syndrome is usually diagnosed during infancy or early childhood, but has been diagnosed later in some patients. Diagnosis is based upon clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and a variety of specialized tests.
Consider Barth syndrome if someone has:
Multiple pregnancy losses involving a male fetus have been observed in some families with Barth syndrome.
Molecular genetic testing for mutations in the TAZ gene confirms the diagnosis of Barth syndrome. The TAZ gene testing can be done individually or as a part of a multigene panel.
Clinical testing and workup
As a part of routine follow up, growth and height of the children are monitored regularly. Annual cardiac follow up using ECG, echocardiogram and Holter monitor is considered.
The treatment of Barth syndrome is for specific symptoms. Such treatments may need the efforts of a team of medical professionals, such as pediatricians; physicians who specialize in childhood heart disease (pediatric cardiologists); specialists in the study of the blood and blood-forming tissues (hematologists); specialists in the treatment of bacterial infections, physical therapists; occupational therapists; and/or other health care professionals.
Heart failure and/or bacterial infections are the threats to a patient with Barth syndrome. This is one of the main reasons for a reduced life expectancy. Standard heart failure medications like beta blockers, ACE inhibitors and digoxin are used. This helps in improving the heart function and reduces symptoms of heart failure. Aspirin is used for reducing clot formation. Heart transplant is considered when there is severe heart failure. The heart functioning tends to improve after infancy, so heart transplant should be carefully considered.
For affected people with confirmed neutropenia, complications due to bacterial infection can be prevented by monitoring and starting early therapy of suspected infections with antibiotics. For example, antibiotics may be provided as a preventive (prophylactic) therapy during neutropenia to prevent the onset of infection. Giving uncooked cornstarch before bedtime is recommended to prevent muscle loss. Early intervention like physical therapy is recommended for increasing muscle tone and helps children to attain various developmental milestones.
Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
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