Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy (dilated or hypertrophic, possibly with left ventricular noncompaction and/or endocardial fibroelastosis),[4][5] neutropenia (chronic, cyclic, or intermittent),[5] underdeveloped skeletal musculature and muscle weakness,[6] growth delay,[5] exercise intolerance, cardiolipin abnormalities,[7][8] and 3-methylglutaconic aciduria.

A majority of patients are hypotonic at birth; show signs of cardiomyopathy within the first few months of life; and experience a deceleration in growth in the first year, despite adequate nutrition.

[10] Neutropenia, a granulocyte disorder that results in a low production of neutrophils, the body's primary defenders against bacterial infections, is another severe manifestation of Barth Syndrome.

[13] Cardiolipin is intimately connected with the electron transport chain proteins and the membrane structure of the mitochondrion, the energy-producing organelle of the cell.

Diagnosis is established based upon several tests, among which can be blood tests (neutropenia, white blood cell count), urinalysis (increased urinary organic acid levels), echocardiography (cardiac ultrasound, to assess (and detect abnormalities in) the heart's structure, function and condition), and, with reasonable suspicion of Barth Syndrome, DNA sequencing (to verify TAZ gene status).

[citation needed] Based on symptoms at time of presentation, the differential diagnosis may include other hereditary and/or nutritional causes of (dilated) cardiomyopathy and (cyclic or idiopathic) neutropenia.

In the fall of 2024 the Cardiovascular and Renal Drugs Advisory Committee voted 10-6 that elamipretide is effective for this rare disease caused by TAFAZZIN gene mutations.

Elamipretide is proposed as a first-in-class mitochondrial protective agent that theoretically improves the function of cardiolipin-deficient mitochondria in patients with Barth syndrome.

[citation needed] Geographical distribution is homogenous, with patients (and their family members) on every continent (with known cases in, for example, the US, Canada, Europe, Japan, South Africa, Kuwait, and Australia).