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Barth syndrome
This X-linked condition affects males more severely and often presents in infancy or early childhood. It results from genetic changes in the TAZ gene, impacting cellular energy production and overall health.
Overview
Barth syndrome is a rare genetic disorder that mainly affects males, although females can be carriers and may sometimes experience milder symptoms. It is characterised by several key features, including cardiomyopathy (a disease of the heart muscle), muscle weakness, and neutropenia (a lower-than-normal count of neutrophils, a type of white blood cell crucial for fighting infection) [PMID:36523999]. Other common features include delayed growth in height and difficulties with feeding.
First described in 1983, the condition is named after Dr. Peter Barth. Although rare, understanding Barth syndrome is important for early diagnosis and appropriate management to improve outcomes for affected individuals. It typically presents in infancy or early childhood, but presentation can vary.
Symptoms & clinical features
Individuals with Barth syndrome often experience a range of symptoms, with varying severity. The most common and serious symptom is cardiomyopathy, where the heart muscle becomes thin and weakened, affecting its ability to pump blood effectively. This can lead to heart failure and may require significant medical intervention [PMID:17926462].
Skeletal muscle weakness is also a prominent feature, which can contribute to difficulties with movement and fatigue. Many affected children experience delayed motor milestones, such as sitting or walking. Neutropenia increases the risk of recurrent bacterial infections, which can be life-threatening if not managed promptly. Other features can include feeding difficulties in infancy, metabolic issues, an increased risk of blood clots, and growth delay [PMID:36523999].
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Affected organs
The primary organs affected by Barth syndrome are the heart, skeletal muscles, and the immune system (specifically, bone marrow producing white blood cells). The heart muscle's function is compromised, leading to cardiomyopathy. Skeletal muscles throughout the body are weakened, impacting mobility and strength.
The immune system dysfunction manifests as neutropenia, which impairs the body's ability to fight off infections. Other systems that can be affected include the digestive system, leading to feeding issues, and the endocrine system, contributing to growth delay.
Risks & severity
Barth syndrome exhibits a wide range of severity, even within the same family. In some cases, the condition can be life-threatening in infancy due to severe heart failure or overwhelming infections related to neutropenia. However, with improved diagnosis and medical management, individuals often live into adulthood.
Lifetime risks for heart failure and severe infection remain significant, necessitating ongoing medical surveillance. The age of onset is typically in infancy or early childhood, though diagnosis may sometimes occur later if symptoms are milder or non-specific initially. The exact prevalence of Barth syndrome is rare; precise figures are not well established.
Genetic causes
Barth syndrome is caused by pathogenic variants (genetic changes) in the TAZ gene (also known as TAFAZZIN). The TAZ gene provides instructions for making a protein called tafazzin. This protein is essential for the remodelling of cardiolipin, a special type of fat (lipid) found in the inner membrane of mitochondria [PMID:17926462]. Mitochondria are often called the 'powerhouses' of cells because they generate most of the chemical energy needed to power biochemical reactions.
Cardiolipin plays a crucial role in maintaining mitochondrial structure and function, which are vital for energy production. When the TAZ gene has a pathogenic variant, it leads to a shortage of functional tafazzin protein. This disrupts cardiolipin remodelling, impairing mitochondrial function and energy production, particularly in tissues with high energy demands like the heart and skeletal muscles.
- TAFAZZIN tafazzin, phospholipid-lysophospholipid transacylase
Inheritance pattern
Barth syndrome follows an X-linked recessive inheritance pattern. This means the TAZ gene is located on the X chromosome, one of the two sex chromosomes. Males have one X and one Y chromosome, while females have two X chromosomes.
Because males only have one X chromosome, a pathogenic variant on their single X chromosome will usually result in the condition. Females, with two X chromosomes, generally need pathogenic variants on both X chromosomes to develop the condition, which is extremely rare. More commonly, females with one pathogenic variant are carriers; they typically do not show symptoms themselves or have very mild ones, but they can pass the pathogenic variant to their children. Each son of a carrier mother has a 50% chance of inheriting the pathogenic variant and developing Barth syndrome, while each daughter has a 50% chance of being a carrier.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosis of Barth syndrome typically begins with recognising the characteristic clinical features, such as cardiomyopathy, neutropenia, and muscle weakness. Confirmatory diagnosis involves genetic testing to identify pathogenic variants in the TAZ gene [PMID:36523999]. This may be accessed through the NHS Genomic Medicine Service (GMS) after a referral from a specialist clinician.
Genetic testing can involve a single gene test for TAZ or may be part of a larger genetic panel that includes other genes associated with cardiomyopathy or mitochondrial disorders. In the UK, genetic testing for Barth syndrome falls under specific national genomic testing directory R-codes, such as R301 'Cardiomyopathy' or R303 'Congenital heart disease', depending on the primary presentation. Referral to a clinical genetics service is essential for accurate diagnosis and genetic counselling.
Management & lifestyle
While there is currently no cure for Barth syndrome, management focuses on treating the symptoms and preventing complications. This involves a multidisciplinary approach, often coordinated through specialised clinics, and guidance within the NHS.
Treatments may include medications for heart failure, such as ACE inhibitors or beta-blockers, and sometimes even heart transplantation in severe cases. Neutropenia is managed carefully, often with granulocyte colony-stimulating factor (G-CSF) to boost white blood cell counts and reduce infection risk. Nutritional support, physical therapy, and occupational therapy are crucial for addressing muscle weakness and growth delay. Regular monitoring of heart function, blood counts, and growth is essential for comprehensive care.
UK care pathway
In the UK, individuals suspected of having Barth syndrome are typically referred by their paediatrician or cardiologist to a regional clinical genetics service. This service can facilitate genetic testing via the NHS Genomic Medicine Service (GMS), aligning with the National Genomic Test Directory R-codes, such as those for cardiomyopathy.
Genetic counsellors within these services provide vital support, offering information about the condition, its inheritance pattern, and implications for family planning. Care is usually coordinated by a specialist team, often based at a centre with expertise in rare metabolic or mitochondrial disorders, to ensure a cohesive and comprehensive management plan.
Frequently asked questions
How does Barth syndrome affect daily life?
Barth syndrome can significantly impact daily life, particularly due to heart problems, muscle weakness, and a higher risk of infections. Many individuals need ongoing medical care, specific diets, and therapy to manage their symptoms and support their development.
Can females be affected by Barth syndrome?
Barth syndrome is an X-linked condition, meaning it almost exclusively affects males, who inherit the condition from their mother. Females are typically carriers and usually do not show symptoms, though some carriers may experience very mild heart issues or muscle weakness.
What is the life expectancy for someone with Barth syndrome?
Life expectancy for individuals with Barth syndrome has significantly improved with advances in medical care and management. While it can be life-threatening in severe cases, many individuals now live into adulthood with ongoing medical support and management of their symptoms.
Is there a cure for Barth syndrome?
Currently, there is no cure for Barth syndrome. However, treatments focus on managing the symptoms and preventing complications to improve the quality of life for affected individuals. This includes medications for heart problems, treatments for low white blood cell counts, and supportive therapies.
Where can I find support for Barth syndrome in the UK?
In the UK, support for Barth syndrome can be accessed through specialist NHS services, including clinical genetics teams and rare disease centres. Patient advocacy groups also offer valuable resources, information, and a community for affected individuals and their families.
References
- El-Hattab AW, Scaglia F. Mitochondrial Cardiomyopathies. Frontiers in cardiovascular medicine. 2016. PMID: 27504452
- Jefferies JL. Barth syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2013. PMID: 23843353
- Shirley M. Elamipretide: First Approval. Drugs. 2026. PMID: 41335372
- Thompson WR, Manuel R, Abbruscato A. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genetics in medicine : official journal of the American College of Medical Genetics. 2024. PMID: 38602181
- Clarke SL, Bowron A, Gonzalez IL. Barth syndrome. Orphanet journal of rare diseases. 2013. PMID: 23398819
- Masud SN, Srivastava A, Mero P. Genetic suppression features ABHD18 as a Barth syndrome therapeutic target. Nature. 2025. PMID: 40903572
- DiMauro S. Mitochondrial myopathies. Current opinion in rheumatology. 2006. PMID: 17053512
- Mejia EM, Nguyen H, Hatch GM. Mammalian cardiolipin biosynthesis. Chemistry and physics of lipids. 2014. PMID: 24144810