Barth syndrome ... (Barth syndrome) - Gen TAZ.

Barth syndrome is a rare disease characterized by dilated cardiomyopathy, skeletal myopathy, recurrent infections of neutropenia and short stature. This disease occurs almost exclusively in males and is one of a group of metabolic disorders which can be diagnosed by the presence of higher concentrations of 3-methylglutaconic in urine (3-methylglutaconic aciduria) acid.

Frequently in affected individuals, dilated cardiomyopathy is present at birth or develops within the first months of life. Eventually, the heart muscle becomes progressively weaker and less able to pump blood more than once. Affected individuals may have endocardial fibroelastosis leading to a thickening of the muscle that impairs its ability to pump blood. In those affected, cardiac problems can lead to heart failure. In rare cases, cardiomyopathy improves with time and people affected have no symptoms of heart disease. Meanwhile, skeletal myopathy, particularly of the proximal muscles, usually noticeable at birth and causes hypotonia. Often, muscle weakness leads to delayed development of motor skills. In addition, affected individuals tend to have severe fatigue during strenuous physical activity.

Most men with Barth syndrome have neutropenia. Concentrations of leukocytes can be consistently low, intermittent or cyclic. Neutropenia makes it more difficult for the body to fight foreign invaders such as bacteria and viruses, so affected individuals are at increased risk for recurrent infections. On the other hand, men with Barth syndrome often have distinctive facial features, including prominent cheeks. People usually have normal intelligence but often have difficulty performing tasks involving math or visual-spatial skills such as puzzles. Individuals with Barth syndrome have a reduced life expectancy. Many affected children die of heart failure or infection in infancy or early childhood, but those who live in adulthood can survive up to 40 or 50 years old.

Barth syndrome is due to mutations in the TAZ gene, located on the long arm of chromosome X (Xq28). This gene encodes a protein called tafazina. Several isoforms of the protein are encoded tafazina from TAZ gene. Most isoforms are found in all tissues but some, are found only in certain cell types. The tafazina is in the mitochondria and is involved in altering a lipid known as cardiolipin, which plays a critical role in the mitochondrial inner membrane. The tafazina added to linoleic acid cardiolipin molecule, allowing cardiolipin to perform its functions. Cardiolipin is necessary to maintain the mitochondrial form, energy production, and transport of proteins within cells.

They have identified more than 160 mutations in the TAZ gene responsible for Barth syndrome. These mutations lead to tafazina encoding proteins with little or no function. Accordingly, linoleic acid is not added to the cardiolipin, causing problems with normal mitochondrial shape and functions such as energy production and transport of the protein. Tissues with high energy demands, as the heart and other muscles, are the most susceptible to cell death due to the reduction of energy production in mitochondria. In addition, white blood cells affected abnormally formed in the mitochondria, which may affect their ability to proliferate and differentiate, resulting in a weakened immune system and recurrent infections. Dysfunctional mitochondria probably lead to other signs and symptoms of Barth syndrome.

This disease is inherited in a recessive X - linked pattern in males, who have only one X chromosome, an altered copy of the gene in each cell it is sufficient to express the disease. In females, having two X chromosomes, a mutation would have to occur in both copies of the gene lead to disease. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Barth syndrome, by complete PCR amplification of the exons of the gene TAZ, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).