Barth syndrome is a rare, X-linked genetic disorder that primarily affects males. It is ultra-rare, affecting an estimated one in every 300,000 to 400,000 live births worldwide. The condition impacts the heart, immune system, and muscles. This disorder is a significant cause of mortality, particularly in infancy, due to its profound effects on the body’s energy production.
Genetic Basis and Inheritance Pattern
Barth syndrome is caused by a pathogenic variant in the TAFAZZIN gene, commonly known as TAZ, which is located on the X chromosome. The TAZ gene provides instructions for making the tafazzin protein, an enzyme that functions within the mitochondria. Mitochondria are the primary energy-producing structures within nearly all human cells.
The tafazzin enzyme is responsible for remodeling cardiolipin, a specialized phospholipid that is found almost exclusively in the inner mitochondrial membrane. Cardiolipin maintains mitochondrial structure and ensures the proper function of the electron transport chain, which generates cellular energy. A mutation in the TAZ gene leads to the production of an abnormal or reduced amount of mature cardiolipin. This lipid abnormality results in dysfunctional mitochondria, which compromises energy generation in organs with high energy demands, such as the heart and skeletal muscles.
Since the TAZ gene is located on the X chromosome, the syndrome follows an X-linked inheritance pattern. Because males have only one X chromosome, they are almost exclusively affected by the disorder if they inherit the mutated gene. Females have two X chromosomes, and if one is affected, they typically remain asymptomatic carriers but can still pass the gene on to their children.
Core Health Complications
The metabolic defect leads to various clinical manifestations. The most concerning feature is cardiomyopathy, which is a disease of the heart muscle. This often presents as dilated cardiomyopathy, where the heart chambers become enlarged and weakened, reducing the heart’s ability to pump blood effectively. In some cases, the condition may also involve hypertrophic cardiomyopathy, which is a thickening of the heart muscle, or endocardial fibroelastosis.
The heart problems can begin prenatally or in the first few months of life and are the leading cause of death in infancy for affected individuals. Individuals with Barth syndrome are also at an increased risk for serious heart rhythm disturbances, or arrhythmias, which can lead to sudden cardiac death.
Another defining characteristic is neutropenia, an abnormally low count of neutrophils (a type of white blood cell). This reduction can be persistent, intermittent, or cyclical, significantly impairing the immune system’s ability to fight bacterial and fungal infections. The resulting susceptibility to infection, which can lead to sepsis, is the second leading cause of infant mortality.
Skeletal myopathy, or muscle weakness, is also common and affects the muscles closest to the center of the body. This muscle weakness often causes hypotonia, or low muscle tone, and can result in delays in achieving motor milestones like crawling and walking. Affected individuals experience fatigue and exercise intolerance, which is thought to be related to the underlying mitochondrial dysfunction.
Growth delay is present in many affected boys. This developmental delay is common during childhood, but a notable growth spurt often occurs during late adolescence, allowing many to achieve a normal adult height.
Diagnostic Procedures and Monitoring
The initial suspicion for Barth syndrome often arises when an infant presents with unexplained cardiomyopathy, muscle weakness, or recurrent infections. A definitive diagnosis involves a combination of genetic and biochemical testing.
Genetic testing is highly specific, confirming the diagnosis by identifying a pathogenic variant in the TAFAZZIN gene. However, the gold standard for biochemical diagnosis is the measurement of specific cardiolipin species. This test analyzes the ratio of monolysocardiolipin (MLCL) to cardiolipin (CL) in blood spots, cultured cells, or tissue samples.
An elevated MLCL/CL ratio, often referred to as the “Barth signature,” is an indicator of the disorder. Biochemical testing is particularly useful for rapid screening and for confirming the functional consequence of an identified TAZ mutation.
Once a diagnosis is established, monitoring is required due to the multisystem nature of the disease. Regular cardiac monitoring uses echocardiograms to track heart function and electrocardiograms to screen for arrhythmias. Complete blood counts are routinely performed to track the absolute neutrophil count and identify episodes of neutropenia.
Management and Therapeutic Approaches
The current treatment approach for Barth syndrome is primarily supportive, focusing on managing symptoms and preventing complications. Cardiac management follows standard guidelines for heart failure, including medications like beta-blockers and angiotensin-converting enzyme (ACE) inhibitors to help the heart work more efficiently. Regular cardiac monitoring is essential; in cases of severe, end-stage heart failure, a heart transplant may be considered.
Neutropenia is addressed by infection prevention protocols and, in cases of severe or persistent low counts, the use of granulocyte colony-stimulating factor (G-CSF). This medication helps stimulate the bone marrow to produce more white blood cells, thereby boosting the immune response.
Nutritional support is part of the management plan, as affected individuals often have high caloric needs and feeding difficulties. Dietary interventions are used to ensure adequate caloric intake, which is for addressing growth delay and supporting the body’s high metabolic demands.
Physical and occupational therapy are implemented to address the skeletal myopathy and muscle weakness. These therapies help improve muscle tone, strength, and motor development, which can reduce the fatigue associated with the condition. Newer therapeutic strategies are under investigation, including the use of mitochondrial-targeted peptides like elamipretide, which aims to improve cardiolipin function and enhance cellular energy production.