Barth syndrome

Barth syndrome is caused by variants in the TAFAZZIN gene, which decreases production of cardiolipin. The penetrance of the condition’s features is variable. Features can include dilated cardiomyopathy, left ventricular non-compaction and skeletal myopathy. The condition is inherited in an X-linked recessive pattern, with females usually being unaffected. Onset in males is usually in early childhood.

Barth syndrome is caused by a single gene variant, and there is variable penetrance of phenotypic features. The most frequent presenting manifestation is dilated cardiomyopathy, which may be associated with non-compaction and fibroelastosis. The condition most commonly manifests with phenotypic symptoms in males during early childhood, from the ages of two to 11. Features include:

• dilated cardiomyopathy;
• left ventricle non-compaction and/or endocardial fibroelastosis (diffuse thickening of the ventricular endocardium and associated myocardial dysfunction);
• skeletal myopathy (low muscle mass and weakness);
• neutropenia;
• pre-pubertal growth delay or short stature;
• distinct facial features;
• increased monolysocardiolipin: cardiolipin (MLCL:CL) ratio in the blood, tissue or fibroblasts;
• increased levels of 3-methylglutaconic aciduria in the urine (a five- to 20-fold increase above normal); and
• increased urine organic acids (2-ethylhydracrylic acid, aconitate, fumarate and ɑ-ketoglutarate).

Although all of the above are features of other conditions, the severity of their manifestation and the presence of cardiomyopathy should prompt genomic testing for Barth syndrome.

A raised MLCL:CL ratio is a highly sensitive biochemical marker for the condition, and supports the diagnosis alongside molecular confirmation.

Barth syndrome is caused by pathogenic variants in the TAFAZZIN gene (formerly known as TAZ) on the long arm of the X chromosome (Xq28). These variants result in decreased production of cardiolipin, an important phospholipid (specialized type of fat), in the inner membrane of the mitochondria.

Signs which may indicate the presence of Barth syndrome include male babies or boys with one of the following:

• dilated cardiomyopathy;
• left ventricular non-compaction; or
• unexplained neutropenia.

Barth syndrome should also be considered in families with a pattern of males with hypertrophic cardiomyopathy where no genetic cause can be found and the presence of other suggestive features.

Individuals with a suspected diagnosis of Barth syndrome have their diagnosis confirmed by cardiolipin analysis (MLCL:CL ratio).

For information about genomic testing, see Child with suspected Barth syndrome.

Barth syndrome may be identified before any symptoms appear, for example through the Generation Study. Confirmation of the diagnosis will require referral to paediatric cardiology services. Please refer to the local pathway for your region for this condition.

Barth syndrome is inherited in an X-linked recessive pattern.

• X-linked recessive conditions are usually only present in males.
• Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
• Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
• Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.

All at-risk male first-degree relatives of individuals with Barth syndrome should be tested, because the penetrance is variable and some males who are phenotypically normal may still have the variant.

Mothers and female relatives should be referred to clinical genetics and genetic counselling services to discuss the risk of recurrence in any future male pregnancies.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management of children with Barth syndrome requires a multidisciplinary team approach. Historically, individuals with the condition died at a young age from heart failure and infection. Advances in recognition and care have made it more common for their lives to be extended into adulthood.

Cardiology

• The myocardial dysfunction in Barth syndrome can change rapidly and dramatically. Systolic function can go suddenly from mildly reduced to significantly impaired, especially during intercurrent infections. The reverse is also true, with reports of children having their function improve enough to be removed from the heart transplant list once their metabolic demands are managed appropriately.
• Life-threatening arrhythmia can occur even when the myocardial function is within the normal range.

Immunology

• Neutropenia occurs frequently in patients with Barth syndrome. It can be chronic or cyclical and places the patient at increased risk of infection and developing sepsis. Prompt treatment with antibiotics is recommended. Sometimes granulocyte colony stimulating factor may be used.
• Recurrent aphthous ulcers may occur, but these are not always related to periods of neutropenia.

Metabolic

• Individuals with Barth syndrome have low muscle mass, which reduces their ability to fast. They may require a high-energy feed prior to sleep to prevent hypoglycaemia and further muscle wasting.
• Severe hypoglycaemia can occur and must be treated promptly with minimal fasting times. As such, diarrhoea and vomiting is not tolerated well.
• High dietary protein and arginine supplements may be required to maintain normal energy production with cardiac and skeletal cells.

Growth

• Typically the patient will have growth delay in the first few years of life, and will then follow a normal trajectory – albeit below the third centile for height. Puberty is often delayed but continues for longer, resulting in a normal final adult height.
• Weight and BMI are typically low due to the reduced muscle mass. Some infants may require assistive feeding devices.

Neurology

• Global muscle weakness or a ‘floppy baby’ may be referred to the neurology team for assessment. The affected child may have reduced coordination secondary to muscle weakness.
• In general, patients have normal intelligence, although some have mild learning difficulties.

Gene-directed therapies and trials

• There are no current gene-directed therapies to cure Barth syndrome, though the Barth Syndrome Foundation is supporting research in this area (see the resources list below).
• In September 2025, elamipretide received FDA approval for improving muscle strength in individuals with Barth syndrome.

Barth syndrome may be identified before any symptoms appear, for example through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• Barth Syndrome Foundation: FDA approves first medication for Barth syndrome
• Barth Syndrome Foundation: Assessment of elamipretide in Barth syndrome: TAZPOWER clinical trial
• Barth Syndrome Foundation: CARDIOMAN clinical trial
• Gene Reviews: Barth syndrome
• Genetic and Rare Diseases Information Center: 3-Methylglutaconic aciduria type 2
• National Institutes of Neurological Disorders and Stroke: Mitochondrial disorders
• NHS England: National Genomic Test Directory
• University Hospitals Bristol NHS Foundation Trust: NHS National Barth Syndrome Service

For patients

• Barth Syndrome Foundation
• Barth Syndrome UK