Barth syndrome is a rare X-linked inborn error of metabolism characterised by cardiomyopathy, neutropenia, skeletal myopathy, chronic fatigue, exercise intolerance and growth delay. Some patients can also be prone to episodic diarrhoea and to hypoglycaemia particularly after a long fast. Lactic acidosis and excessive excretion of organic acids in particular 3-methylglutaconic acid (3-MGC) may also be present. Patients often have distinctive facial features, such as prominent cheeks.

Those affected by Barth Syndrome are at risk of life-threatening complications secondary to cardiac dysfunction, arrhythmias, and life threatening bacterial infections due to neutropenia and neutrophil dysfunction.

Even though most features of Barth syndrome are present at birth or infancy, affected individuals may not experience health concerns or receive a diagnosis until later in life. Clinical presentation is highly variable, and some patients will have all features but others just one or a few. Severity also varies in each aspect of the condition and within each patient and at different times of life. This makes the disease easy to miss. There may have been a history of stillbirth in males from mothers who then go on to have a child diagnosed with Barth Syndrome.

Barth syndrome has no definitive cure, but early and aggressive intervention may reduce complications, and stop further deterioration or death.

Transmission is X-linked recessive and mostly affects males (in only extremely rare circumstances are females affected). This means a son born to a female carrier has a 50% risk of inheriting the mutation and developing the disease, while a daughter has a 50% risk of being a carrier. All daughters of an affected male will be carriers but none of his sons will be affected.    

Specific signs and symptoms

Cardiac

Dilated cardiomyopathy is often present at birth or within the first few months of life. Up to 70% of patients present with cardiomyopathy by one year of age. Over time the heart muscle becomes weaker and is less able to effectively pump blood. This may lead to heart failure. With appropriate treatment heart failure can be managed and improve. In a small percentage of patients, a heart transplant may be necessary.

Skeletal myopathy

Muscle weakness particularly affects the muscles closest to the centre of the body (proximal muscles) and is often noticeable from birth. The weakness results in low muscle tone (hypotonia), often causing delay in achieving motor skills such as crawling and walking. Affected individuals experience extreme tiredness and fatigue, especially with strenuous physical activity and can have poor stamina and exercise tolerance. This impacts quality of life. Adults with Barth may require wheelchair support and flexible work and support for daily living. 

Neutropenia

The level of white blood cells, which fight infection can be persistently low, vary from low to normal (intermittent) or cycle between episodes of low counts and normal counts. Neutropenia is seen in up to 90% of patients. Neutropenia makes it difficult for the body to fight infection such as bacteria and viruses, so the risk of severe illness is increased. Patients are given a management plan for febrile neutropenia.

Growth and dietary features

Newborns are often smaller than average and feeding and dietary intake can be difficult. Growth continues slowly throughout childhood. Puberty is often delayed (late onset) but once it starts can be rapid. Boys with Barth Syndrome are often taller than their peers after the pubertal growth spurt.  Some require supplemental feeding via nasogastric or gastrostomy tube to support this growth. There is a tendency for food preferences with salty and strong flavours. Poor and variable intake is common and a small number of boys demonstrate nocturnal hypoglycaemia.

Barth syndrome is caused by mutations in the tafazzin (TAZ) gene which is located on the X chromosome. TAZencodes a phospholipid transacylase that promotes cardiolipin acyl chain remodeling. Cardiolipin is a type of fat or lipid in the body and an important component of the inner mitochondrial membrane. Deficiency of tafazzin activity affects remodelling with different types of cardiolipin being produced. In Barth syndrome there are increased levels of monolysocardiolipin (MLCL) and lower cardiolipin (L4-CL) levels.

Urine organic acids: Testing for 3 -methylglutaconic acid (3-MGC) was used as the major biochemical test for the disease until recent years. However, this test is now considered unreliable, as it can sometimes be normal.

Cardiolipin analysis: Analysis of the ratio of monolysocardiolipin (MLCL)/cardiolipin (CL) is the diagnostic test of choice. Cardiolipin analysis on dried blood spots is available in the UK at the Neurometabolic Unit, Institute of Neurology, Queen Square. The test is free to UK NHS patients suspected of having a diagnosis of Barth syndrome. Please see details via the link below:

Bloodspot_cardiolipin_testing_information_September_2023.pdf (uclh.nhs.uk)

Cardiolipin analysis on other tissues is possible but will incur a charge. Please contact the Neurometabolic Unit to discuss.

Description of an intermediate form of Barth syndrome: Cardiolipin testing discriminates extremely well between normal boys and those with Barth Syndrome. The Barth Syndrome Service have identified males from three separate families who have higher cardiolipin levels than most boys or men with the disease. In several cases this caused the diagnosis to be missed on initial biochemical testing. Males with this form of the disease on average appear to be more mildly affected than the average person with Barth syndrome.

Post-mortem testing: If a patient is suspected to have died as a result of Barth syndrome, cardiolipin analysis can be performed in cultured fibroblasts (skin cells). Please discuss with the Neurometabolic unit.

Genetic testing by TAZ Gene Sequencing: Further information on genetic testing in Bristol and the proforma required is given here.

Who to test

It has been estimated that between 3-5% of all young males with dilated cardiomyopathy have Barth Syndrome as the cause of their heart failure. This percentage may be even higher in those who are in heart failure at birth or develop it within the first year of life. We therefore recommend routine cardiolipin testing in all young males with dilated cardiomyopathy. Cardiolipin testing should also be considered in male babies/boys with left ventricular noncompaction (LVNC), unexplained neutropenia (especially with poor growth, developmental delay or weak muscles and easy fatigability) and in families with a male pattern of hypertrophic cardiomyopathy where no genetic cause can be found and other features suggestive of Barth syndrome are present.