Barth syndrome is an X-linked genetic disorder. The disorder, which affects multiple body systems, is diagnosed almost exclusively in males. It is named after Dutch pediatric neurologist Peter Barth.
Presentation
Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy, neutropenia, underdeveloped skeletal musculature and muscle weakness, growth delay, exercise intolerance, cardiolipin abnormalities, and 3-methylglutaconic aciduria. It can be associated with stillbirth. Barth syndrome is manifested in a variety of ways at birth. A majority of BTHS 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. As patients progress into childhood, their height and weight lag significantly behind other children. While most patients express normal intelligence, a high proportion of BTHS patients also express mild or moderate learning disabilities. Physical activity is also hindered due to diminished muscular development and muscular hypotonia. Many of these disorders are resolved after puberty. Growth accelerates during puberty, and many patients reach a normal adult height. Cardiomyopathy is one of the more severe manifestations of BTHS. The myocardium is dilated, reducing the systolic pump of the ventricles. For this reason, most BTHS patients have left myocardial thickening. While cardiomyopathy can be life-threatening, it is commonly resolved or substantially improved in BTHS patients after puberty. Neutropenia is another deadly manifestation of BTHS. Neutropenia is a granulocyte disorder that results in a low production of neutrophils, the body's primary defenders against bacterial infections. Surprisingly, however, BTHS patients have relatively fewer bacterial infections than other patients with neutropenia.
Cause
in the tafazzingene are closely associated with Barth syndrome. The tafazzin gene product functions as an acyltransferase in complex lipid metabolism. In 2008, Dr. Kulik found that all the BTHS individuals that he tested had abnormalities in their cardiolipin molecules, a lipid found inside the mitochondria of cells. Cardiolipin is intimately connected with the electron transport chain proteins and the membrane structure of the mitochondria which is the energy producing organelle of the cell. The human tafazzin gene, NG_009634, is listed as over 10,000 base pairs in length and the full-length mRNA, NM_000116, is 1919 nucleotides long encoding 11 exons with a predicted protein length of 292 amino acids and a molecular weight of 33.5 kDa. The tafazzin gene is located at Xq28; the long arm of the X chromosome. Mutations in tafazzin that cause Barth syndrome span many different categories: missense, nonsense, deletion, frameshift, splicing. iPLA2-VIA has been suggested as a target for treatment.
Currently there is no treatment for Barth syndrome, although some of the symptoms can be successfully managed. There are currently clinical trials happening for possible treatments in the future like AAV9-mediated TAZ gene replacement strategy. The University of Florida has run a research investigation exploring the TAZ gene that has shown initial promising results, but more research and pre-clinical and clinical testing needs to be done before the gene therapy is approved by the FDA as a treatment.
Epidemiology
It has been documented, to date, in more than 120 males. It is believed to be severely under-diagnosed and may be estimated to occur in 1 out of approximately 300,000 births. Family members of the Barth Syndrome Foundation and its affiliates live in the US, Canada, the UK, Europe, Japan, South Africa, Kuwait, and Australia. Barth syndrome has been predominately diagnosed in males, although by 2012 a female case had been reported.
