Barth syndrome is a rare genetic disorder that primarily affects the heart, muscles, and immune system. It occurs almost exclusively in males and is estimated to affect 1 in 300,000 to 400,000 individuals worldwide, with just over 150 cases described in the medical literature. Symptoms typically appear in infancy or early childhood, most often as heart problems or recurrent infections.
What Causes Barth Syndrome
Barth syndrome is caused by mutations in a gene called TAZ, located on the X chromosome. This gene provides instructions for making a protein called tafazzin, which plays a critical role inside mitochondria, the structures in cells that produce energy. More than 160 different TAZ mutations have been identified, all of which result in tafazzin proteins with little or no function.
Tafazzin’s job is to help build and maintain a specialized fat molecule called cardiolipin, which sits in the inner membrane of mitochondria. Cardiolipin is essential for mitochondria to hold their shape, produce energy efficiently, and transport proteins. Without functional tafazzin, cardiolipin levels drop, its chemical composition becomes abnormal, and the internal folds of mitochondria (where energy production happens) become distorted. In animal models, mitochondria in heart cells take on an abnormal “onion-shaped” appearance, and their ability to generate energy is significantly impaired.
Because the TAZ gene sits on the X chromosome, Barth syndrome follows an X-linked recessive inheritance pattern. Males have only one X chromosome, so a single mutated copy of the gene is enough to cause the condition. Females have two X chromosomes, so they can carry a mutation on one copy without developing symptoms, though they can pass it to their sons. In rare cases, females with a mutation can show mild features of the condition.
Heart Problems Are Often the First Sign
Cardiomyopathy, a weakening or enlargement of the heart muscle, is the most common and often most serious feature of Barth syndrome. It almost always appears before age 5. The most frequent type is dilated cardiomyopathy, where the heart chambers stretch and weaken, reducing the heart’s ability to pump blood effectively. Some boys present with heart failure symptoms in infancy.
About half of patients also have a structural heart feature called left ventricular non-compaction, where the muscle of the left ventricle has a spongy, heavily textured appearance instead of being smooth and compact. This can occur alongside dilated cardiomyopathy or, in some cases, be the only initial finding. Heart rhythm abnormalities (arrhythmias) are another recognized feature. Some infants also develop a thickening of the heart lining known as endocardial fibroelastosis.
Weakened Immune Defense
Most boys with Barth syndrome have neutropenia, a condition in which the body produces too few neutrophils, the white blood cells that serve as a first line of defense against bacterial infections. In a study of 88 patients, 84% had at least one abnormally low neutrophil count, and 44% met criteria for severe chronic neutropenia, meaning their counts were persistently and dangerously low.
This immune vulnerability leads to frequent bacterial infections. In registry data from 68 patients, 69% had documented bacterial infections. Common problems include ear infections (32%), sinusitis (18%), and urinary tract infections (11%). More serious infections have included pneumonia, blood infections (septicemia), bone infections, cellulitis, and soft tissue abscesses. Many boys also experience painful, recurring mouth ulcers and gum inflammation, particularly when their neutrophil counts dip lowest. Neutrophil levels can fluctuate unpredictably, which means infection risk varies over time.
Muscle Weakness and Growth Delays
Because mitochondria power every cell in the body, the energy deficit in Barth syndrome extends well beyond the heart. Boys with the condition typically have skeletal muscle weakness (myopathy) that affects exercise tolerance, stamina, and physical development. Activities that other children handle easily, like climbing stairs or keeping up on a playground, can be significantly more tiring.
Growth delay and short stature are also characteristic. Many boys fall well below average height and weight for their age, particularly in early childhood. Some degree of motor delay is common, and cognitive differences have been described in some patients, though the severity varies widely from person to person. The overall picture of Barth syndrome is highly variable: some boys have severe heart failure in infancy, while others have milder symptoms that take longer to recognize.
How Barth Syndrome Is Diagnosed
Diagnosis relies on a combination of clinical features, biochemical testing, and genetic confirmation. The hallmark lab finding is an abnormal ratio of two forms of cardiolipin in the blood. Using a blood spot screening method, researchers found that all males with Barth syndrome had a ratio above 0.40, while all unaffected individuals had a ratio below 0.23, giving the test 100% sensitivity and specificity at a cutoff of 0.30.
Urine testing can also provide clues. Boys with Barth syndrome excrete elevated levels of a compound called 3-methylglutaconic acid, typically at five to 20 times normal levels. However, this marker is not unique to Barth syndrome and can be elevated in other mitochondrial conditions. The definitive diagnosis comes from genetic testing that identifies a mutation in the TAZ gene. For males, finding a single pathogenic mutation confirms the diagnosis. For female carriers, testing identifies a mutation on one of their two X chromosomes.
Managing the Condition
There is no cure for Barth syndrome, but management focuses on treating each of its major features. Heart failure is managed with standard cardiac therapies aimed at supporting the heart’s pumping ability, reducing fluid overload, and controlling arrhythmias. Some patients with severe heart failure have required heart transplantation. Regular cardiac monitoring, including echocardiograms, is a lifelong part of care.
For neutropenia, a medication called G-CSF (granulocyte colony-stimulating factor) can be used to stimulate the bone marrow to produce more neutrophils, reducing infection risk. Before G-CSF became part of routine management, serious and sometimes life-threatening infections were a major cause of illness in these boys.
Physical therapy and occupational therapy help address muscle weakness and motor delays. Nutritional support may be needed in early childhood, particularly if feeding difficulties or low blood sugar (hypoglycemia) are present at birth or during infancy.
The First Approved Treatment
In a significant milestone, the FDA granted accelerated approval to the first drug specifically targeting Barth syndrome. The medication, developed by Stealth Biotherapeutics, works by binding to the inner part of the mitochondria and improving mitochondrial structure and function. Approval was based on demonstrated improvements in knee extension strength, a measure the FDA considers reasonably likely to predict real-world benefits like easier standing and longer walking distances. The drug is given as a daily injection under the skin, and the most common side effects in clinical trials were mild to moderate injection site reactions. As a condition of the accelerated approval, the manufacturer must conduct a confirmatory trial to verify that the strength improvements translate into meaningful gains in daily life.