First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare 
X-linked genetic disease characterised by cardiomyopathy (CM), skeletal 
myopathy, growth delay, neutropenia and increased urinary excretion of 
3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known 
worldwide, but evidence is accumulating that the disorder is substantially 
under-diagnosed. Clinical features include variable combinations of the 
following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic 
cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular 
non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged 
QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, 
neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), 
compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic 
acidosis, growth and pubertal delay, feeding problems, failure to thrive, 
episodic diarrhoea, characteristic facies, and X-linked family history. 
Historically regarded as a cardiac disease, BTHS is now considered a 
multi-system disorder which may be first seen by many different specialists or 
generalists. Phenotypic breadth and variability present a major challenge to the 
diagnostician: some children with BTHS have never been neutropenic, whereas 
others lack increased 3-MGCA and a minority has occult or absent CM. 
Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal 
death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at 
Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal 
phospholipid of the inner mitochondrial membrane. A definitive biochemical test, 
based on detecting abnormal ratios of different cardiolipin species, was first 
described in 2008. Key areas of differential diagnosis include metabolic and 
viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia 
and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ 
sequencing now provide relatively rapid diagnostic testing, both prospectively 
and retrospectively, from a range of fresh or stored tissues, blood or neonatal 
bloodspots. TAZ sequencing also allows female carrier detection and antenatal 
screening. Management of BTHS includes medical therapy of CM, cardiac 
transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte 
colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are 
essential for minimising hospital attendances and allowing many more individuals 
with BTHS to live into adulthood.