Abstract
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.
Highlights
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 3methylglutaconic acid (3-MGCA)
Definition Dr Peter Barth first described a triad of cardiomyopathy (CM), skeletal myopathy and neutropenia in 1983 in a large Dutch kindred with high infant mortality due to infection or cardiac failure [1], the first description of the disorder widely known as Barth Syndrome (BTHS) may have occurred in 1979 [2]
For 25 years after its first description, BTHS was generally regarded as an extremely rare disease. It was usually only considered when patients presented with a combination of CM, neutropenia and excessive urinary excretion of 3-MCGA
Summary
This review contains some references to previously unpublished data collated by the Barth Syndrome Foundation (BSF) Registry. The urine level of 3-MGCA may be normal or, being only mildly to moderately increased, is sometimes missed by laboratories that do not perform quantitative studies or are not sensitive to the significance of mild to moderate 3-MGCAciduria Such problems in diagnosis have been partially overcome by the development of a straightforward diagnostic assay measuring the MLCL:L4-CL ratio [26,28,78], which can be applied to a variety of cells and tissues, including stored dried bloodspot cards [7]. Many unanswered questions remain in areas such as the variability of clinical severity with age in individual patients or between family members, lack of phenotype/genotype correlation and the exact mechanism by which altered cardiolipin metabolism causes BTHS This has hindered understanding of the unusual features of BTHS (such as the waxing and waning of neutropenia, fluctuating severity of cardiomyopathy and constitutional growth delay), as well as the approach to managing patients. There is no definitive epidemiological data on the frequency of BTHS
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