Barth syndrome (BTHS), also known as 3-Methylglutaconic aciduria type II, 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 Masa Barth.
PresentationThough 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), neutropenia (chronic, cyclic, or intermittent), 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.Kelley RI, 6 Dec 2011. “Barth Syndrome - X-linked Cardiomyopathy and Neutropenia”. Department of Pediatrics, Johns Hopkins Medical Institutions. Available from: 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 (hypertrophy). 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.Barth Syndrome Foundation, 28 Jun 2011. “Diagnosis of Barth Syndrome”. Available from:
CauseMutations in the tafazzin gene (TAZ, also called G4.5) 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 (see Human Tafazzin (TAZ) Gene Mutation & Variation Database). iPLA2-VIA has been suggested as a target for treatment.
EpidemiologyIt has been documented, to date, in more than 120 males (see Human Tafazzin (TAZ) Gene Mutation & Variation Database). 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.
HistoryThe syndrome was named for Dr. Peter Barth (pediatric neurologist) (1932-) in the Netherlands for his research and discovery in 1983. He described a pedigree chart, showing that this is an inherited trait.
- 3-Methylglutaconic aciduria
- noncompaction cardiomyopathy: mutations to the affected genes in Barth syndrome are also present here.
- Barth Syndrome Foundation
- Human Tafazzin Gene Mutation & Variation Database
- Barth Syndrome Trust (United Kingdom & Europe)
- Barth Syndrome Foundation of Canada
- Barth Trust of South Africa
- Clinical Mass Spectrometry Laboratory - Kennedy Krieger Institute
- Barth Syndrome at National Organization for Rare Disorders (NORD)