Barth Syndrome

Barth syndrome is a rare genetic disorder that mainly affects boys. It can cause serious health issues that usually start in infancy or early childhood. These problems include:

• Heart conditions
• Immune system issues
• Muscle weakness
• Growth delays

Barth syndrome happens because of changes in a gene called TAZ (or TAFAZZIN). This gene helps support tiny structures in your child’s cells called mitochondria. Mitochondria take the food your child eats and turn it into energy that their body can use.

When the TAZ gene doesn’t work the way it should, a type of fat called cardiolipin doesn’t form correctly. This makes it harder for your child’s mitochondria to do their job, leading to the signs and symptoms of the condition.

In the past, many children with Barth syndrome didn’t live past early childhood because of heart failure or infections. Today, due to earlier diagnosis and improved treatments, many people with Barth syndrome live into adulthood. Still, the condition is serious and lifelong. Symptoms can change or become life-threatening very quickly.

What are the symptoms of Barth syndrome?

Barth syndrome symptoms can vary, but they commonly include heart problems, neutropenia, low muscle mass and growth delay.

Heart problems

Your baby may be born with structural heart defects, including:

• Enlarged and weakened heart muscle (dilated cardiomyopathy)
• Thickened heart muscle (hypertrophic cardiomyopathy)
• Elastic fibers in their heart muscle (endocardial fibroelastosis)
• Spongy, thickened lower left heart chamber (left ventricular non-compaction)

As your child gets older, they may develop an irregular heartbeat (arrhythmia). Eventually, these problems can lead to heart failure.

Neutropenia

Neutropenia means your child has low levels of a type of white blood cell called neutrophils. Neutrophils are cells that help your body fight infections. So, this condition makes it harder for your child’s body to fight off bacteria and viruses. This increases their risk of developing infections, and it can lead to sepsis. Types of neutropenia include:

• Cyclic: Cyclic neutropenia means neutrophil levels cycle in regular intervals between normal and low.
• Intermittent: Intermittent neutropenia means there’s no predictable pattern. Neutrophil levels can vary from normal to low.
• Chronic: Chronic neutropenia means the condition is always present. Neutrophil levels are consistently low.

Low muscle mass

Barth syndrome can cause muscle weakness (skeletal myopathy) and low muscle tone (hypotonia). Both conditions can lead to extreme fatigue. This can cause delays in motor skill development, like learning how to crawl and walk.

Low muscle mass also affects your child’s ability to go very long between meals. Because your child doesn’t have enough energy stored up, they’re always at risk of low blood sugar (hypoglycemia).

Growth delay

Most babies with Barth syndrome are smaller than average at birth. Your child may remain shorter and weigh less than average throughout childhood. But they should grow quickly during puberty. It may take longer than usual, but your child should reach an average to above-average height and weight.

Other signs and symptoms

Other signs and symptoms of Barth syndrome may include:

• Feeding problems, like trouble sucking or swallowing, picky eating or frequent vomiting
• Unusually high levels of organic acids in your child’s blood and pee (3-methylglutaconic aciduria)
• Bone abnormalities, like curvature of your child’s spine (scoliosis)
• Learning disabilities, especially in math and visual-spatial skills, like reading a map or solving a puzzle

What are the facial features of a person with Barth syndrome?

Barth syndrome features may include:

• Round face
• Pointed chin
• Full cheeks
• Large ears
• Deep-set eyes

These distinct facial features may become less noticeable as your child gets older.

What is the cause of Barth syndrome?

Genetic changes (variants) in the TAZ gene cause Barth syndrome. This gene makes a protein called tafazzin. Tafazzin helps the energy-producing part of cells (mitochondria) work properly. It also alters a fat called cardiolipin. Cardiolipin helps support the mitochondria’s shape, energy production and protein movement.

When the TAZ gene doesn’t work correctly, tafazzin is missing or weak. This means cardiolipin can’t be made into its healthy form. Instead, a different fat called monolysocardiolipin (MLCL) builds up. Without plenty of healthy cardiolipin, mitochondria can’t make enough energy and don’t function properly.

Because of this, tissues in your child’s body that need a lot of energy die. Body parts with the highest energy demand include your child’s heart, muscles and certain white blood cells. This leads to the features seen in Barth syndrome.

How is Barth syndrome inherited?

Barth syndrome is passed down in an X-linked recessive pattern. That means it mostly affects boys, because they have only one X chromosome. A mother who carries the gene variant has a 50% chance of passing it on. Males may develop Barth syndrome, and females may become carriers.

How doctors diagnose Barth syndrome

Diagnosis usually happens during infancy or early childhood. Your child's healthcare provider will perform a physical exam to look for common signs of the condition. These may include heart problems, immune system issues, weak muscles and unique facial features. Because Barth syndrome is inherited in an X-linked pattern, your child’s provider will also ask about their biological family history.

Tests that are used

There are two main lab tests that can help confirm a Barth syndrome diagnosis:

• Genetic testing: This test checks your child’s DNA for variations in the TAZ gene.
• MLCL/CL ratio test: This test measures the ratio of monolysocardiolipin (MLCL) to cardiolipin (CL) in your child’s blood and tissues. People with Barth syndrome have too much MLCL and not enough CL.

Your child’s provider may want to use other tests, including:

• Urine test
• Complete blood count
• Echocardiogram (ultrasound of the heart)
• Heart monitor (a sticker placed on your child’s chest that records their heart rhythm for short periods of time)
• Growth tracking

How is Barth syndrome treated?

There’s no cure for Barth syndrome. Treatment focuses on managing symptoms, monitoring heart function and preventing complications. This may include:

• Routine cardiac observation: This includes echocardiograms and heart monitors to check for fast heart rhythms.
• Heart medications: Medications like beta-blockers and ACE inhibitors may help your child’s heart work better if there’s evidence it’s not working properly.
• Aspirin: Aspirin may help lower the risk of blood clots if there’s evidence that your child’s heart isn’t working properly.
• Antibiotics: Antibiotics may help fight or prevent infections.
• G-CSF: G-CSF is a medicine that may help your child’s body make more white blood cells.
• Cornstarch: If you give your child cornstarch before bedtime, it may help prevent muscle loss overnight.
• Physical and occupational therapy: These therapies may help build strength, improve movement and support development.
• Feeding tube: A feeding tube or other forms of feeding support may help your child gain weight.

Researchers are also testing new Barth syndrome treatment options. While not yet approved, these options show promise as future therapies. They include:

• SS-31: SS-31 is a drug that attaches to cardiolipin. It helps mitochondria keep their shape and work more efficiently. This may improve heart and muscle function.
• MA-5: MA-5 is a drug that reduces stress in cells and helps mitochondria make more energy. In lab studies, it improved heart health and muscle strength.
• Gene therapy: Scientists are testing ways to repair or replace the TAZ gene. A version of the gene called TAFAZZIN-Antp may enter cells better and help prevent heart damage.

What is the life expectancy of someone with Barth syndrome?

Some people with Barth syndrome live into their 30s, while others live into their 60s. The highest chance of early death is in the first few years of life.

Survival depends on three main factors:

• Neutrophil levels: Infants with a very low neutrophil count at diagnosis (fewer than 500 cells per microliter) have a one-year survival rate of 25%. Infants with a neutrophil count of more than 500 cells per microliter at diagnosis have a one-year survival rate of 68%.
• Birth year: Infants born before 2000 have a five-year survival rate of 22%. Infants born in or after 2000 have a five-year survival rate of 70%. This increase is likely due to improved heart treatments.
• Heart-related complications: Some people with Barth syndrome who develop heart failure at an early age may need a heart transplant based on the severity of the disease.