An Overview of Barth Syndrome

Barth syndrome, also known as 3-Methylglutaconic aciduria type II, is a rare X-linked genetic disorder. It only occurs in males and is present at birth. It affects multiple organ systems but many of the primary symptoms are cardiovascular. The condition was first described by, and named for, a Dutch pediatrician named Peter Barth in 1983.

Symptoms

Barth syndrome is a rare genetic disorder that is present at birth. It is usually diagnosed shortly after an infant is born, if not during prenatal screenings. In some cases, the health problems associated with Barth syndrome only become apparent in childhood or, more rarely, adulthood.

While Barth syndrome can affect multiple organ systems, the condition is usually associated with three key features: weakened heart muscle (cardiomyopathy), low white blood cells (neutropenia), and underdeveloped skeletal muscle which leads to weakness and growth delays.

Cardiomyopathy is a condition where the muscles of the heart become thin and weak, which leads to stretching and enlargement of the organ's chambers (dilated cardiomyopathy). Some patients with Barth syndrome develop cardiomyopathy in part because the muscles of their heart have elastic fibers (endocardial fibroelastosis) that make it harder for the muscle to contract and pump blood. Serious cardiomyopathy may lead to heart failure. In some rare cases, cardiomyopathy present in infants with Barth syndrome has improved as the child gets older—though this is not common.

Neutropenia is an abnormally low number of white blood cells called neutrophils. These cells are an important part of the immune system and the body's ability to fight infection. In people with Barth syndrome, neutropenia can be chronic or may come and go.

Some people with Barth syndrome have normal levels of neutrophils. Having a low number of white blood cells can make a person more likely to get infections, some of which can be very serious. Babies born with severe neutropenia can be at risk for developing sepsis.

Weak or underdeveloped muscles (hypotonia) can lead to stunted growth. Children with Barth syndrome are often small for their age, though many eventually "catch up" to their peers in height and weight after going through puberty. Having weakened muscles means a person with Barth syndrome often has a hard time with exercise and may get tired very quickly.

These primary symptoms, while commonly seen, are not present in every person who has Barth syndrome. There are also other symptoms associated with the condition, many of which will become apparent during childhood. These symptoms can include:

• Heart conditions such as arrhythmias, heart failure, and cardiomyopathy
• Failure to thrive
• Delays in meeting developmental milestones
• Delays in the acquisition of gross motor skills
• Exercise intolerance
• Muscle weakness
• Easily fatigued
• Chronic or recurrent diarrhea
• Feeding problems in infancy, "picky eating" in children
• Nutritional deficiencies
• Trouble paying attention and mild learning disabilities
• Difficulty with tasks that require visual-spatial skills
• Auditory processing difficulty
• Recurrent infections
• Stunted growth and short stature
• Delayed puberty

People with Barth syndrome sometimes have very distinct facial features, including prominent ears, cheekbones, and deep-set eyes.

Causes

Barth syndrome is an X-linked genetic disorder, which means its inheritance pattern is linked to the X chromosome. Sex-linked genetic disorders are inherited through either the X or Y chromosome.

Female fetuses have two X chromosomes, one of which is inactive. Male fetuses only have one X chromosome, which means they are more likely to develop conditions linked to the X chromosome. However, males with the affected gene only pass it on to female offspring who become carriers.

Females with the affected gene may not show symptoms (asymptomatic) or be affected by an X-linked condition like Barth syndrome, but they can pass the condition on to male offspring. This is called an X-linked recessive pattern of inheritance.

In some cases, people who have experienced repeated miscarriage or stillbirth of male fetuses have been found to be asymptomatic carriers of Barth syndrome. With each pregnancy, a female carrier of the gene has a 25 percent chance of giving birth to:

• A non-affected female carrier
• A female who is not a carrier
• A male with Barth syndrome
• A male who does not have Barth syndrome

The specific gene linked to Barth syndrome is called TAZ, which is responsible for programming a protein called tafazzin. The protein helps the mitochondria of the body's cells produce energy through a type of fat called cardiolipin.

When mutations in the TAZ gene occur, it means the cells can't produce enough functional cardiolipin required by mitochondria to meet the energy needs of the body. The muscles of the body, including the heart, demand a great deal of energy in order to function, which is why they are profoundly affected in people with Barth syndrome.

When the defective mitochondria are found in white blood cells it can lead to neutropenia—either because the body can't produce enough of the cells or the cells that are produced are ineffective.

Diagnosis

Barth syndrome is usually diagnosed shortly after a baby is born. Because it's linked to the X chromosome, the condition is almost always exclusively diagnosed in male infants.

Diagnosis is usually made during the course of a thorough newborn evaluation, which can detect cardiovascular conditions, neutropenia, and some of the physical characteristics that are often associated with Barth syndrome. Genetic testing can confirm the presence of mutations in the TAZ gene.

People with Barth syndrome also tend to have high levels of 3-methylglutaconic acid in their urine and blood; a condition called 3-methylglutaconic acid type II. Special tests that measure this substance are also used to make a diagnosis in infants, children, and adults if a doctor suspects they could have Barth syndrome. However, the levels of 3-methylglutaconic acid are not associated with the severity of the condition; some people who have severe symptoms of Barth syndrome have been found to have normal levels of 3-methylglutaconic acid.

While it's recognized that some features, signs, or symptoms may not be present in every case, the official diagnostic criteria for Barth syndrome include:

• Growth delay
• Cardiomyopathy
• Neutropenia
• Elevated levels of 3-methylglutaconic acid (3-methylglutaconic acid type II)

Treatment

There is no cure for Barth syndrome. Treatment is usually approached case by case, though children with the condition usually need to work with a team of medical professionals to ensure all their health needs are addressed.

Specialists in cardiology, hematology, and immunology can help manage some of the potentially serious aspects of the condition. In some cases, the cardiac conditions associated with Barth syndrome don't persist as a child grows up and they may no longer need treatment as they enter adulthood. However, careful monitoring of cardiovascular health is essential, as the potential complications can be fatal.

Complications from low white blood cell counts, such as repeated infections, can be treated with antibiotics (sometimes given prophylactically). Prevention of bacterial infections in those with Barth syndrome is also important, as sepsis has been found to be the second-leading cause of death in infants with the condition.

Occupational and physical therapists can help children who are struggling with motor skills or physical disability due to muscle weakness. Some people with Barth syndrome use mobility aids.

Once children with Barth syndrome start school, they may benefit from special education interventions if they are struggling with learning disabilities. Children may also experience social challenges due to their limited ability to participate in physical activities or, in some cases, food-related social activities.

Support groups and resources for families of children with Barth syndrome can help them work with health, educational, and social support professionals to coordinate care and address their child's unique individual needs at home and at school.

Other treatments to help with a person's specific symptoms throughout childhood and potentially into adulthood are generally supportive. Treatment can help avoid complications but cannot cure the condition.

Barth syndrome generally shortens a person's life expectancy due to immune or cardiac complications in infancy or childhood. However, of those with Barth syndrome who have survived into adulthood, many have lived to reach middle age.

A Word From Verywell

While there is currently no cure for Barth syndrome and it can shorten a person's lifespan, treatment to manage symptoms and prevent infections is available. Many people with Barth syndrome who reach adulthood live well into their middle age. Families of children the syndrome have many resources available to them to help coordinate a child's medical, educational, and social needs to ensure they can participate in as many childhood activities as possible.