What is Barth Syndrome?

Barth syndrome is a rare genetic condition that progressively affects the normal development of an individual’s muscles, heart, and immune cells from infancy (among other symptoms). Barth Syndrome mostly affects males, and it is estimated to occur in 1.5 individuals per 1 million births.¹ However, this is probably an underestimate, as the number of diagnoses continues to rise every year due to an increased awareness and understanding of the syndrome.² The syndrome was first described in the 1980s, but before the year 2000, the prognosis of individuals afflicted with it was poor, with only 22% of male patients surviving past 5 years old. For sufferers born after 2000, the prognosis is much more promising, with a 70% rate of survival past 5 years old.³ This is attributed to better medical treatment and management of the syndrome. It is important to raise awareness of Barth Syndrome to allow prompt, accurate diagnosis and effective treatment regimes to begin as soon as possible for those affected by it.

What Causes Barth Syndrome?

The Molecular Cause of Barth Syndrome

The molecular cause of Barth Syndrome is well-understood and has been definitively traced to changes (also known as mutations) in a specific gene called the TAZ gene, found on the X chromosome. In healthy people, the TAZ gene is involved in the production of a phospholipid (a fatty-acid building-block molecule) called cardiolipin, which is essential for the normal functioning of mitochondria (often nicknamed the “powerhouses of the cell” due to their ability to generate energy). In people with Barth syndrome, the mutated TAZ gene means that mitochondria are unable to generate energy properly. The resulting energy deficiency affects the development of cells and tissues across the body as an infant, particularly in the heart and skeletal muscles.⁴

How is Barth Syndrome Inherited?

In Barth Syndrome, the mutated TAZ gene that gets passed down from the parent to their child is located on the X chromosome. Hence, this condition is known as an “X-linked syndrome”. In human biology, females have 2 X chromosomes, whilst males have an X and a Y chromosome, and each parent passes on one of these chromosomes to their offspring. 

Understanding the nuances of genetic inheritance is beyond the scope of this article, but the important takeaways regarding Barth syndrome are as follows:

• Male and female children can both inherit the mutated TAZ gene, but the males will always have Barth syndrome whereas the females are usually completely unaffected. This is because males only have one copy of the X chromosome; if this copy is mutated, they will surely develop the disease. 
• A mother with the mutated TAZ gene has a 50% chance of passing this gene onto her children (of either sex).
• An affected father will always pass on the mutated TAZ gene to his daughter(s), but never to his son(s).
• If family history of Barth syndrome is already known, genetic counselling before pregnancy can predict the statistical likelihood of passing on the mutated TAZ gene.
• During pregnancy, the mutated TAZ gene can be tested for and identified with genetic testing.³

What are the Symptoms of Barth Syndrome?

The main clinical symptoms that define Barth syndrome are:

• Cardiomyopathy - poor development of the heart tissue
• Skeletal myopathy - poor development of muscles
• Neutropenia - abnormally low levels of a type of immune cell in the blood called neutrophils⁵ 

There are additional clinical symptoms that are often seen in individuals with Barth syndrome, including:

• Delayed growth (followed by a dramatic “catch-up” growth spurt at around 18 years old)
• Organic acids in urine, particularly “3-MGCA”
• Arrhythmia – irregular heartbeat
• Mild intellectual and cognitive impairment
• Facial appearance – tall forehead; round face; full cheeks; pointed chin; large prominent ears; and deep-set eyes (“cherubic” appearance)⁶
• Clubfoot – where the feet point downward and inward
• Increased gynoid fat levels post-puberty – gynoid fat is located around hips, breasts, and thighs;
• Reduced bone density
• Refusal to eat food and being a “fussy eater”⁵

Symptoms of Barth syndrome may be apparent at birth, but may also become more noticeable in the coming months and years as the patient grows up. There is a large degree of variability of the symptoms across Barth syndrome sufferers, and even within a single individual, their symptoms may change throughout their life (in terms of severity and presentation).⁵ 

Cardiomyopathy

Cardiomyopathy is found in 90% of individuals with Barth syndrome,⁷ and is frequently seen in patients under the age of 5. It often takes the form of “dilated cardiomyopathy” (DCM), where the tissue of the left ventricle (lower-left chamber) of the heart is abnormally thick and less able to pump blood.⁸ The tissue of the left ventricle can also develop a spongy texture (“left ventricular noncompaction” (LVNC)) instead of being firm and smooth, which also impacts its ability to function properly.⁶ Numerous other cardiomyopathies that have been associated with Barth syndrome, and they can all seriously affect an individual’s health, and may lead to sudden cardiac death. Secondary cardiac complications that can occur in Barth syndrome patients, due to a dysfunctional heart, include  blood clot formation and increased risk of stroke.³

Skeletal Myopathy

Skeletal myopathy is found in most individuals with Barth syndrome.⁹ Weak skeletal muscles can impact an individual’s quality of life in several ways:

• Difficulty in walking
• Poor grip strength
• Exaggerated spinal curve
• Being underweight
• Exercise intolerance
• Fatigue⁶ 

Around 2/3 of children with Barth syndrome have difficulty sitting up and walking.¹⁰ Stunted growth as an infant and into childhood is commonly seen in Barth syndrome patients, although some patients can recover from this in their teenage years and adulthood. Skeletal myopathy from Barth syndrome causes difficulty socialising and increased experiences of loneliness, particularly in children and young adults.¹¹ 

Neutropenia

Neutropenia is the condition in which a patient has an abnormally low number of immune cells, called neutrophils, circulating in the blood. Neutropenia is a main symptom of Barth syndrome, and it is found in roughly 70% of patients.³ Neutrophils are crucial in the healthy body’s first line of defence against invading germs like viruses and bacteria.¹² Whilst severe neutropenia in Barth syndrome can lead to life-threatening illnesses, more commonly the neutropenia is manageable and at most causes persistent but mild infections, particularly mouth ulcers.⁹

How is Barth Syndrome Diagnosed?

Barth syndrome is usually diagnosed early into a child’s life based on clinical presentation of symptoms, especially skeletal myopathy and cardiomyopathy, which are easy to detect. However, it can be diagnosed this way at any age – especially as awareness of the syndrome increases both in the medical world and in the public. 

A doctor may also test for levels of organic acids in the patient’s urine, as this is a strong indicator of Barth syndrome. 

However, because the physical symptoms described above and the presence of organic acids in urine can commonly occur in other growth-deficiency syndromes, the most accurate method of diagnosis is with a genetic test (from a blood sample) looking for the mutated TAZ gene. This test is widely accessible and commonly performed in a laboratory, and the results are usually available within a number of weeks.⁵

Medical professionals may also perform an extensive check of an individual’s family genetic history for a more accurate diagnosis, as well as to provide the statistical chances of passing on the syndrome to offspring. This examination of a family’s genetic history is called genetic counselling.

Prognosis And Life Expectancy Of Individuals With Barth Syndrome

The prognosis (the expected outcome to a person’s health) of Barth syndrome patients is significantly better these days compared to before the year 2000. This is due to advancements in diagnosis and more advanced treatment plans.¹³ These days, 70% of diagnosed patients survive past 5 years old.³ Life expectancy of Barth syndrome patients is increasing, and the oldest reported patients with Barth syndrome are currently in their 50s, with numerous others in their 30s-40s.⁶

Treatment and Management of Barth Syndrome

As the life expectancy of individuals with Barth syndrome increases, it is ever more important for medical treatment to be effective and sustainable across several decades of a person’s life. Symptoms of Barth syndrome change from childhood into adulthood, with adults most commonly reporting exhaustion, muscle weakness, and a fast heartbeat. Unfortunately, these symptoms often get worse over the years, and can negatively impact a person’s social life and emotional wellbeing.¹³ Multi-faceted treatment plans, that consider the individual’s life holistically, are essential to ensure the best possible quality of life. Medical professionals work with the patient to create a tailor-made treatment plan.

Currently, the primary medical treatments for the main symptoms of Barth syndrome are as follows:

• For skeletal myopathy: Regular physiotherapy to reach “developmental milestones”.
• For cardiomyopathy: Careful fluid intake to avoid too much or too little water. Standard heart failure medication such as ACE inhibitors and beta blockers will help to improve heart function. Heart transplantation in especially severe cases is becoming increasingly more feasible.
• For neutropenia: Regular administration of G-CSF, which is a hormone that stimulates the body to produce more immune cells. This is administered at least twice a week until normal immune cell levels are reached. Specific antibiotics may be needed to prevent bacterial infections due to the weakened immune system.³

Summary

Barth syndrome is a rare genetic disorder that primarily affects males, and disrupts the normal development of skeletal muscles, the heart, and immune cells from infancy. Historically, Barth syndrome has had a poor survival rate, with patients not surviving past the age of 5, but since the year 2000, the prognosis and life expectancy for people affected by Barth syndrome have significantly improved. This is due to an increased scientific understanding of the syndrome, along with improvements in medical treatment. These days the oldest-known people with Barth syndrome are living fulfilling lives into their late 50s, and are expected to survive many years more. Swift, accurate diagnosis through genetic testing is crucial to creating comprehensive lifelong treatment regimes, as well as to helping individuals thoroughly understand their disorder and how it impacts the lives of their families and children.