Introduction

Barth Syndrome is an extremely rare mitochondrial condition that may be misdiagnosed or misunderstood. It is a genetic condition caused by the inheritance of an X-linked recessive gene. Symptoms present in the first years of life, with greater prevalent in infants assigned male at birth; with those assigned female at birth more likely to be carriers. Symptoms of Barth syndrome include facial features, cardiomyopathy (disorder of the heart muscle), metabolic issues, delayed puberty and growth, and musculoskeletal weakness.^1,2,3

Awareness of Barth syndrome is crucial to enhance further research and understanding, of those affected by it. This article will look at the known causes and symptoms of Barth syndrome.

What is barth syndrome?

Barth syndrome (BTHS) is an X-linked recessive inherited condition that disproportionately affects people assigned to males at birth.^7,8 It is a life-threatening condition with no cure.^1,7 It is caused by mutations of the TAZ gene, resulting in the deficiency of cardiolipin phospholipids. These are central to the role of mitochondria- the part of the cell that generates energy through respiration. Cardiolipin deficiency therefore leads to mitochondrial dysfunction.¹

The most recognisable symptoms are cardiomyopathy (weakness of the heart muscle), neutropenia (low white blood cells), skeletal myopathy (muscle weakness) and growth delay.¹ The condition has also been linked to miscarriage and stillbirth. Heart failure is the most common cause of premature death deaths within the first 6 months of life.¹ This ultra-rare syndrome was first reported in 1983 by Dr Peter Bath, yet very few children have been diagnosed.⁵ This is due to the rarity of this life-threatening condition, but this condition may also be underdiagnosed or misdiagnosed. It is so rare that the estimated prevalence is 1 in 454,000 people in the UK.^7,8

Causes of barth syndrome

90% of Barth syndrome cases are caused by point substitution mutations (where one nucleotide is substituted during DNA replication).³ Mutations in the TAZ gene, which codes for the protein tafazzin, located on the X chromosome.^1,11,³ This protein is an enzyme called a transacylase and is essential for the normal functioning of cardiolipin. In Barth Syndrome, the enzyme fails to transfer fatty acids, leading to the incomplete maturity of the phospholipid cardiolipin, making it unstable.  Cardiolipin is found in the membranes of mitochondria, where it is vital for its structure and function, so a defect in this component results in damage to mitochondria.² L For example, Genetic studies of two patients with Barth Syndrome showed the alteration of mitochondrial electron transfer chains (one of the necessary processes of aerobic respiration), resulting in a defective mitochondrial membrane. The low levels of stable cardiolipin produce symptoms in areas of the body where mitochondria are in greater demand, such as the heart.³

Genetics plays a crucial role in identifying Barth syndrome and affects the patients and families involved. Mutation analysis of the cardiolipin transacylase tafazzin (TAZ) confirms the diagnosis. Genetic studies of two patients showed mitochondrial electron transfer chains (one of the necessary processes of aerobic respiration) were altered, resulting in a defective mitochondrial membrane.⁹ 

Risk factors of barth syndrome

The two main risk factors of Barth Syndrome are family history and biological sex:

Barth syndrome (BTHS) is an X-linked recessive inherited condition, meaning the gene mutation sits on the X chromosome, and therefore disproportionately affects people assigned male at birth, who only have one X chromosome.^7,8 The affected individual will only pass on the mutation to daughters. Pregnant people who are carriers of the mutated TAZ gene are at 50% risk of passing the gene to their children. Offspring that are assigned female at birth are usually unaffected but are carriers.³

family history plays an important role in evaluating the risk of affecting future generations. For this reason, genetic counselling is recommended if an individual or couple with a family history are planning a pregnancy so that the risk of genetic transmission can be evaluated.³

If there is a family history of x-linked disorders, and the child assigned male at birth develops dilated cardiomyopathy (read on to find out), Barth syndrome may be suspected.

Symptoms of barth syndrome

Cardiovascular symptoms

The most common cardiac complication of Barth syndrome is Dilated Cardiomyopathy (DCM) where the left ventricle becomes a pumping chamber and is enlarged, causing the muscle to become thin as it is stretched.¹⁴ Cardiac complications such as heart failure are the leading cause of death in affected patients within 6 months of life.¹

Barth syndrome patients are at an increased risk of ventricular arrhythmia (irregular heartbeat resulting from the ventricles of the heart);  which causes the heart to beat too fast.^1,3 This may lead to sudden cardiac death.³ Prognosis of most patients improves after 5 years of age in infancy, when heart function may improve.

Barth syndrome is also associated with foetal cardiomyopathy (weakness of the heart muscle before birth). This may be identified at the specialist Barth Syndrome clinic based at Bristol Royal Hospital.^7,8,1 This has been identified as a cause of, stillbirth, miscarriage and late spontaneous abortion. Infants assigned male at birth with unexplained severe infantile dilated cardiomyopathy should be suspected of Barth syndrome.² 70% of Barth syndrome patients show cardiomyopathy before 6 months of age.^6.,7 dilated cardiomyopathy is highly unlikely after the age of 5 years³ 63% of Barth syndrome patients also displayed left ventricular hypertrabeculation (LVHT) l, where the muscular wall of the heart appears spongy and may present with cardiac abnormalities such as arrhythmia (irregular heartbeat).^2,3

Facial symptoms Facial features that may indicate Barth Syndrome include: 

• Prominent, large and low-set ears 
• Ong and broad forehead
• Eep-set eyes
• Round face 
• Prominent pointed chin 
• Enlarged cheekbones 

Barth syndrome may also cause clubfoot, or talipes equinovarus, feet that turn downwards and inwards myopathy (feet turned). Gynoid fat distribution is usually identified post-post-puberty puberty.³

• Other symptoms 
• Neutropenia: blood tests may indicate a large number of a type of white blood cells called neutrophils in the blood). This puts the individual at greater risk of recurrent infection due to a compromised immune system.^7,8

Hypoglycemia: low blood sugar levels are common³ m³

• Fatigue: this may be due to the low levels of mature cardiolipin causing mitochondrial defects in the muscle³
• Weight loss: common in 50-70% of individuals due to having a diet with limited variety and poor consumption. Individuals with Barth Syndrome often prefer spicy, fried, cheesy and salty foods, rather than fruits and vegetables.³
• Growth delay: due to delayed puberty onset.³ A delayed growth spurt may occur after 18 years old, and eventually become normal in height
• Muscle weakness id
• Delayed motor development of the proximal muscles (muscles closest to the centre of your body).⁴

Summary

Barth syndrome is an extremely rare X-linked recessive genetic disorder mostly affecting infants assigned male The condition arises from a mutation of the TAZ gene, which causes a reduction in the number of phospholipids called cardiolipins in the mitochondria of cells, causing them to be dysfunctional. This leads to cardiac complications such as dilated cardiomyopathy, facial dysmorphism, muscle weakness, neutropenia, fatigue and growth delay. Early diagnosis for Barth syndrome is essential and reduces the likelihood of misdiagnosis. Treatment is symptomatic, but there is no cure. There are opportunities for ongoing research to help advance treatments.^7,8