Barthe Syndrome

Description of Barth Syndrome :

Barth Syndrome is a genetic condition that primarily affects the heart. It affects males, and is caused by mutations, or alterations, in the BTHS gene, which is located on the X chromosome. People with Barthe Syndrome may exhibit symptoms which include a deficiency of white blood cells, heart defects, abnormal mitochondria, short stature, poor muscle tone, and elevated levels of certain organic acids in the urine (1,2). Some Barthe Syndrome symptoms may be transitory, although in some individuals, symptoms can be severe, and the disorder may be lethal (3). As with any serious disorder, the impact on the entire family of coping with Barth Syndrome can be enormous. Congestive heart failure is a complication of many common heart conditions, and is seen not only in newborns with severe Barth Syndrome, but also in some of their male relatives (4). It is possible that an understanding of the BTHS protein may lead to improved understanding and treatment for other heart diseases, as well as mitochondrial disorders.

The normal function of the BTHS structure and function of the BTHS gene is now known (5). The BTHS gene is located in a gene-rich region of the long arm of the X chromosome in region 28. The first clue to the normal function of the BTHS gene was the discovery that the predicted protein sequence resembles those of a group of enzymes known as acyltransferases (6). Acyltransferases are enzymes that catalyze the transfer of organic groups from one molecule to another. The BTHS protein is hypothesized to catalyze the transfer of acyl groups (an organic side chain) to cardiolipin forming modified cardiolipin molecules. Since some Barth Syndrome patients have abnormally shaped mitochondria (see mitochondria diagrams in the Questions section) in some of their tissues, it is possible that the BTHS proteins have a role in the remodeling of the mitochondrial membrane. Since intact Mitochondria are required for the production of energy, they are particularly important to the normal function of muscle cells, especially the heart. Unpublished Observations from the laboratory of Dr. Vreken in the Netherlands has solved the primary metabolic defect for this disease. A reduction in cardiolipin is thought to be the primary defect. Cardiolipin comprises approximately 20% of the inner mitochondrial membrane and the inability to remodel this membrane is thought to decouple the creatine-phosphate/respiration chain and lead to the variety of biochemical defects. This is the first known example of a remodeling enzyme, that when mutated, can cause disease in humans. There is likely to be other diseases (not Barth Syndrome) that are caused by mutations in other enzymes in lipid remodeling. Future research projects will be looking for these enzymes and genes. There is also speculation that the BTHS gene may encode different versions (isoforms) of the BTHS protein from the same gene, and these forms may be expressed in different quantities in different cell types (5).

Based on our observations, Barth Syndrome is a biochemical disorder involving the loss of function of a single enzyme in one of our many biochemical pathways. It is suspected that some of the clinical symptoms are indirect, secondary consequences of the primary metabolic defect.

Last year, three new articles on Barth Syndrome were published. The first paper describes work conducted by an international group of scientists led by Dr. Karen Orstavik at the Ulleval University Hospital in Oslo, and deals with X-inactivation in women who have Barth Syndrome in their family. The authors give evidence that the X chromosome carrying the Barth mutation tends to be "turned off" in most cells in unaffected female carriers of the disorder (7).

The discoverer of Barth Syndrome, Dr. P.G. Barth, has written the most current paper. This article is a review on Barth Syndrome. It is an excellent resource for anyone interested in learning what is currently known about Barth Syndrome. And the paper also contains new information on leucine loading in three boys with Barth Syndrome (8).

The newest paper was led by Ann Cantlay in Bristol, England. Her team discovered 5 new Barth Syndrome Families in one hospital during a 7 year study. Their study suggests that Barth Syndrome may be underdiagnosed and more common than previously thought (9). She is continuing her studies at this time.

Note: There is another (allelic) version of Barth Syndrome that is called,"isolated noncompaction of the left ventricular myocardium (INVM)." This disorder is also caused by alterations in the BTHS gene, but only involves the heart defect, and not the other symptoms normally associated with Barth Syndrome (10).

For further details on Barth Syndrome see the Comprehensive History of Barth Syndrome in :

1. Ades, L.C.; Gedeon, M.J.; Wilson, M.L.; Partington, M.W.; Mulley,
J.C.; Nelson, J.; Lui, K.; Sillence, D.O. "Barth Syndrome: Clinical
Features and Confirmation of Gene Localization to Distal Xq28." Am. J.
Med. Genet. 45: 327-334 (1993).
2. Barth, P.G.; Scholte, H.R.; Berden, J.A.; Van Der Klei-Van Moorsel,
J.M.; Luyt-Houwen, I.E.M.; Van't Veer-Korthof, E.T.H.; Van Der Harten,
J.J.; Sobotka-Plojhar, M.A.; Ketel, A.G. "An X-linked Mitochondrial
Disease Affecting Cardiac Muscle, Skeletal and Neutrophil Leukocytes."
J. Neur. Sci. 62: 327-355 (1983).
3. Barth, P.G.; Van den Bogert, C.; Bolhuis, P.A.; Scholte, H.R.; van
Gennip, A.H.; Schutgens, R.B.; Ketel, A.G. "X-linked Cardioskeletal
Myopathy and Neutropenia (Barth Syndrome): Respiratory-chain
Abnormalities in Cultured Fibroblasts." J. Inherit. Metab. Dis. 19 (2):
157-160 (1996).
4. Kelley, R.I.; Cheatham, J.P.; Clark, B.J.; Nigro, M.A.; Powell, B.R.;
Sherwood, G.W.; Sladky, J.T.; Swisher, W.P. "X-linked Dilated
Cardiomyopathy with Neutropenia, Growth Retardation and
3-methylglutaconic Aciduria." J.Pediatr. 119: 738-747 (1991).
5. Bione, S.; D'Adamo, P.; Maestrini, E.; Gedeon, A.K.; Bolhuis, P.A.;
Toniolo, D. "A Novel X-linked Gene, G4.5 is Responsible for Barth
Syndrome."Nature Genet. 12, 385-389 (1996).
6. Neuwald, A.F. "Barth Syndrome may be due to an Acyltransferase
Deficiency."Curr. Biol. 7: R465-466 (1997).
7. Orstavik, K.H.; Orstavik, R.E.; Naumova, A.K.; D'Adamo, P.; Gedeon,
A.; Bolhuis, P.A.; Barth, P.G.; Toniolo, D. "X-chromosome inactivation
in carriers of Barth Syndrome." Am. J. Hum. Genet. 63:1457-63 (1998).
8. Barth, P.G.; Wanders, R.J.; Vreken, P.; Janssen, E.A.M.; Lam, J.;
Baas, F. "X-linked cardioskeletal myopathy and neutropenia (Barth
Syndrome)." J. Inher. Metab. Dis. 22: 555-567 (1999).
9. Cantlay, Ann M., et. al. "Genetic Analysis of the G4.5 gene in
families with Suspected Barth Syndrome." J. Ped. 135(3):311-315 (1999).

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