Barth syndrome

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;
• reduced plasma cardiolipin;
• 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, fumerate 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.

Barth syndrome is caused by pathogenic variants in the TAZ gene (also called the TAFAZZIN gene) on the long arm of the X chromosome (Xq28). These variants result in decreased production of cardiolipin, an important enzyme in phospholipid metabolism and the inner membrane of the mitochondria.

Barth syndrome is inherited in an X-linked recessive pattern. All at-risk male first-degree relatives should be tested, because the penetrance is variable and some males who are phenotypically normal may still have the variant.

Females carrying the variant are usually asymptomatic, though they can experience mild to moderate symptoms. Mothers and female relatives of individuals with Barth syndrome should be referred to clinical genetics and genomic counselling services to discuss risk of recurrence in any future male pregnancies.

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

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 for Barth syndrome, though the Barth Syndrome Foundation is supporting research in this area (see the resources list below).

For clinicians

• Barth Syndrome Foundation: Assessment of elamipretide in Barth syndrome: TAZPOWER clinical trial
• Barth Syndrome Foundation: CARDIOMAN clinical trial
• Genetic and Rare Diseases Information Center: Barth syndrome
• National Institutes of Neurological Disorders and Stroke: Barth syndrome
• 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