Like many genetic disorders, Barth syndrome is quite variable among different families and sometimes even within a single sibship. Whereas at least 80% of known patients with Barth syndrome manifest all four principal diagnostic criteria at some time during childhood, any or possibly even all of the cardinal findings may be absent in a boy with a proven mutation in the Barth gene. This variability in presentation of symptoms and severity in phenotype makes Barth syndrome a difficult disorder to diagnose. In absence of a family history of related illnesses, the clinician is presented with the challenge to diagnose a child who inherits the disorder through a spontaneous mutation. The diagnosis of Barth syndrome should be considered for any child or adult found to have any one of its four cardinal clinical characteristics, and evaluation for the other diagnostic criteria should be undertaken by obtaining the following studies:

1. Quantitative urine organic acid analysis including quantification of 3-methylglutaconic acid (Type II)
2. Complete blood count and differential
3. Echocardiogram
4. Analysis of growth parameters from birth