Overview

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.