What Is Barth Syndrome?

Barth Syndrome is a rare, genetically inherited condition that almost always affects children assigned male at birth (AMAB). It is a multi-system disorder that usually presents in infancy but does have wide variation in symptom presentation and severity. It requires lifelong patient monitoring and management by a multi-disciplinary team. 

Overview

Barth Syndrome was originally differently labelled and thought to be solely a cardiac (heart) condition. However, in 1983, a Dutch paediatric neurologist, Dr. Peter Barth, noted that multiple children AMAB in a Dutch family were reported to have enlarged and weakened hearts (cardiomyopathy), low numbers of infection fighting cells (neutropaenia) and fatigue/weakness of muscles (skeletal myopathy). He then fully and comprehensively described the condition as the multi-system disorder we now know as Barth Syndrome, specifically calling it a triad of cardiomyopathy, skeletal myopathy and neutropaenia.¹

Causes of barth syndrome

Barth Syndrome is a rare genetic disorder of lipid (fat) metabolism that primarily affects children AMAB and in 1996, mutations in the TAZ gene (also known as tafazzin gene) were found to be the cause of the syndrome. This gene mutation means there is a decreased production of cardiolipin, a chemical substance that the body uses to make fat. This fat is used by the inner cell membranes of tiny structures in each body cell (called mitochondria) to make energy so the body can function.²

Barth Syndrome is an X-linked disorder and is genetically inherited. Genetically inherited material is carried by chromosomes. We have 23 pairs of chromosomes, each pair is made up of one chromosome from each parent. Each of these chromosomes is made up of thousands of genes. The first 22 pairs of chromosomes are the same size and contain the same number of genes but the 23rd pair are called ‘sex chromosomes’. In people assigned female at birth (AFAB), they have two ‘X’ chromosomes which are equally matched but in people AMAB, they have one ‘X’ chromosome and one ‘Y’ chromosome that contains only a few of the genes held on the X chromosome plus a few unique to the Y chromosome. Barth Syndrome is a sex-linked recessive condition meaning, the abnormal TAZ gene, is located on the X chromosome of the 23rd pair(sex chromosomes). As those AFAB receive 2 copies of this X gene, they will almost always inherit a normal chromosome from the other parent. However, in those AMAB, they inherit an ‘X’ gene from their mother and a ‘Y’ gene from their father. This means that there isn't a backup copy for the faulty gene and therefore all babies AMAB with the faulty gene will express the condition.³ 

Therefore if someone is a carrier of the faulty TAZ gene, there is a chance they will pass it on to their children. Due to the genetic inheritance discussed above, Barth Syndrome is usually transmitted mother to a child AMAB. A mother who is a carrier of the gene will show no sign of the condition.⁴ There is a 50% chance that a child AMAB, born to a female carrier, will have Barth Syndrome whereas a child AFAB, born to a female carrier, has a 50% chance of being a carrier themselves. All children AFAB born to a father with Bart Syndrome will be carriers, however no children AMAB will be affected. 

It is important to note that there is a relatively high incidence of new mutations in this syndrome and there are several case reports of children AFAB having the condition.⁵

Signs and symptoms of barth syndrome

Barth Syndrome is usually diagnosed at birth or in infancy but the age of onset can vary greatly. It has variable symptoms between individuals and all the symptoms may not appear together or be present, making this syndrome difficult to recognise. 

However, there are certain symptoms in this syndrome that are present in most patients, to varying degrees and these are listed below. The diagnosis of Barth Syndrome should be considered in anyone presenting with any of these characteristics, a history of AMAB deaths in the family or foetal losses. As stated above, there is a relatively high new mutation incidence so lack of family history should not be a bar to diagnosis.⁶

• Cardiomyopathy (enlarged and weakened heart) - If present, these are almost always discovered before the age of 5 and sometimes in ante-natal scans
• Low muscle mass and muscle weakness - This means they take longer to develop gross motor skills and infant milestones such as sitting, crawling and walking
• Growth delay (delayed growth at first and then accelerated growth in mid to late puberty)
• Exercise intolerance due to heart problems and weak muscles
• Neutropaenia (low white blood cells which are used to fight infection) - This can be long term, intermittent or not present. This means patients with Barth Syndrome have increased occurrence of mouth ulcers, pneumonia or blood infections
• Feeding Problems - some children AMAB are slow to transition to solid food, have some oral (mouth) muscle weakness, poor chewing skills and extended meal times. Some cases will need a tube put into the nose or directly into the stomach for feeding
• 3 methylglutaconic aciduria (MGA) - an increase in body acid that can be detected for diagnosis

In addition some patients have distinctive facial features in childhood that become less noticeable with age. These include a round face with prominent chin, full cheeks, broad forehead, large ears and deep set eyes.  

It has also been noted that many people diagnosed with Barth Syndrome have a learning disability. They often have average reading and vocabulary but have difficulties with mathematics. They can have delay in forming first words, reading maps, recognising shapes, and finding objects in pictures.  

Barth Syndrome patients are at risk of life threatening complications mainly due to cardiac (heart) abnormalities and heart rate changes and to life threatening infections due to reduced infection fighting cells.⁷ 

Management and treatment for barth syndrome

There is no cure for Barth Syndrome. The condition is managed using a multi-disciplinary team who include paediatric cardiologists (children’s heart doctors), blood specialists (haematologists), physiotherapists, occupational therapists and other allied healthcare professionals. 

Annual cardiology reviews are needed, involving a recording of the heart rhythm and a scan of the working heart (echocardiogram). One of the main reasons for reduced life expectancy in Barth Syndrome is heart issues and with the more frequent complication of heart failure,  standard heart medication can be used initially. If the case is severe, a transplant may be needed. 

If the patient has reduced infection fighting cells (neutropenia) they need to be monitored closely for the signs of infection and early intervention with antibiotics is recommended. 

Normal muscle mass is needed to give a reserve during times of fasting. In Barth Syndrome,  patients have reduced muscle mass and so their tolerance of fasting is much reduced. Even overnight fasting can reduce muscle mass further and cause hypoglycaemia. Some patients try to prevent this by eating cornstarch (in a yoghurt) before bed to alleviate these problems. It is important that signs of hypoglycaemia are taken seriously. Also, because of the way Barth Syndrome cells make energy, depletion of certain proteins can occur and supplements are often needed.

Almost all patients will suffer with muscle weakness and general fatigue so the early use of physiotherapy is recommended to increase muscle tone and help children with diverse physical activity. In addition educational support workers, occupational therapists, speech and language therapists, and psychologists can be involved. 

FAQs

How is barth syndrome diagnosed?

It is diagnosed based on detailed physical analysis of the child and thus identifying any of the characteristic findings. The doctor will test the blood and urine for increased levels of MGA in the blood and urine. However, this test may come back as normal as mild increases in the blood of MGA may not be detected in laboratory testing.

Therefore the two diagnostic tests for Barth Syndrome are now thought to be cardiolipin testing or genetic testing. If physical examination reveals a possible Barth Syndrome case, cardiolipin testing is performed on a blood sample and it can take 1 to 2 weeks to receive a result. This is much cheaper than genetic testing so only if the cardiolipin level is raised would you follow up with targeted genetic testing for the TAZ gene. Genetic testing can be performed on blood, saliva, or cheek swab samples and can take 3 to 6 weeks to perform.⁸ 

How can I prevent barth syndrome?

Barth Syndrome is a genetically inherited condition and is not affected or caused by anything done by the parent during preconception, conception, or pregnancy periods. If you have Barth Syndrome in the family and you wish to start a family, you can obtain genetic testing via your doctor. This can advise as to whether you carry the gene and the likelihood of transmission to a baby.  

Who is at risk of barth syndrome?

Barth Syndrome is a rare, genetically inherited condition and the inheritance pattern is detailed above. A person has an increased risk of being a carrier for this condition if they have a family history of people AMAB foetal loss/miscarriage. It is known that heart problems can be proven in Barth Syndrome foetuses as early as 18 weeks gestation.⁸ 

We know that there is however a relatively high incidence of new mutations in this syndrome and that there is no increased occurrence in certain racial or geographical groups.⁹

How common is barth syndrome?

It is not known exactly how many babies are born worldwide with Barth Syndrome. The  United States Barth Syndrome Foundation reports an estimate of 1 in 300,000–400,000 live births. There is increasing data to suggest that Barth Syndrome may be underdiagnosed with a possible prevalence as high as 1 in 140,000 live births.¹⁰ 

Can people AFAB have barth syndrome?

A person AFAB can be a Barth Syndrome carrier and this can be through her mother if she herself is a carrier or through her father if he actually has Barth Syndrome. In addition a new genetic mutation can occur, which has not been passed on from either her mother or father. 

It is highly unlikely that a person AFAB will actually have Barth Syndrome because, as stated earlier, she has to receive a faulty gene from both parents to display the syndrome. However, there are case reports of patients AFAB having the condition, the first of which was reported in 2012. However, the genetic analysis of this child showed that she had large anomalies on the X chromosomes meaning the recessive TAZ gene was unopposed by a normal X gene.¹¹

When should I see a doctor?

You should see a doctor if you have any health concerns for yourself or your child. In addition if you are concerned that you may be carrying a gene for Barth Syndrome or any other genetic condition, then you should seek genetic counseling and testing via your doctor. 

Summary

Barth Syndrome is a rare genetic disease that should be considered when a patient presents with heart conditions, low infection fighting cells, and low muscle tone and mass. It is a multi-system disease and shows huge variability of symptoms and severity between affected individuals. It is diagnosed with testing of the blood and genetic testing to look for a specific mutation in a gene. It has no cure but it can be managed with a multi-disciplinary team who manage the physical heart and blood issues, as well as allied healthcare professionals who can help with mobility, physical development, speech development and choosing the correct learning environment for the child. Early identification of Barth Syndrome in a child allows for family screening and genetic counselling. It also allows the child to be appropriately managed and extends life expectancy.