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Barth Syndrome “Lipid Disorers”

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Barth Syndrome “Lipid Disorers” BARTH SYNDROME “LIPID DISORERS” Name: Aly Salah Aly Al-Sawasany Under supervision of/ Dr. Nagwaa Assem Contents Introduction: .................................................................................................................. 2 Cardiolipin (CL): ........................................................................................................... 3 Functions of cardiolipin: ............................................................................................... 4 Disorder of cardiolipin (Barth syndrome): .................................................................... 5 Causes of Barth syndrome: ........................................................................................ 6 Inheritance pattern: ..................................................................................................... 7 Diagnosis: ................................................................................................................... 8 Treatment: .................................................................................................................. 8 References: .................................................................................................................... 9 1 Introduction: Lipid is demarcated as any group of organic compounds unable to solve in water but they are solving in organic solvents and they are found in a wide range of molecules, including fatty acids, phospholipids, sterols, sphingolipids, terpenes, and others. Generally, fatty acids consist of a straight alkyl chain contains a various number of carbons ending with a carboxyl group and the compound may be either saturated (with no double bonds) or unsaturated (with one or more double bonds). A phospholipid is a type of lipid molecule that is the main component of the cell membrane. Lipids are molecules that include fats, waxes, and some vitamins, among others. Each phospholipid is made up of two fatty acids, a phosphate group, and a glycerol molecule. When many phospholipids line up, they form a double layer that is characteristic of all cell membranes. A phospholipid is made up of two fatty acid tails and a phosphate group head. Fatty acids are long chains that are mostly made up of hydrogen and carbon, while phosphate groups consist of a phosphorus molecule with four oxygen molecules attached. These two components of the phospholipid are connected via a third molecule, glycerol. The first phospholipid identified in 1847 as such in biological tissues was lecithin, or phosphatidylcholine, in the egg yolk of chickens by the French chemist and pharmacist Theodore Nicolas Gobley. Purified phospholipids are produced commercially and have found applications in nanotechnology and materials science. Lecithin (q.v.; phosphatidyl choline) and the cephalins (phosphatidyl ethanolamine and phosphatidyl serine) are groups of phospholipids of widespread occurrence in plants and animals; lecithin is the most abundant, but is rare in microorganisms. Other phospholipids include plasmalogens, present in brain and heart and apparently of limited occurrence in nonanimal tissues; phosphoinositides, present in brain; and cardiolipin, initially isolated from heart. 2 Cardiolipin (CL): Cardiolipin is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. The name "cardiolipin" is derived from the fact that it was first found in animal hearts. It was first isolated from beef heart in the early 1940s. In mammalian cells, cardiolipin (CL) is found almost exclusively in the inner mitochondrial membrane, where it is essential for the optimal function of numerous enzymes that are involved in mitochondrial energy metabolism. Cardiolipin (CL) is a kind of diphosphatidylglycerol lipid. Two phosphatidic acid moieties connect with a glycerol backbone in the center to form a dimeric structure. So, it has four alkyl groups and potentially carries two negative charges. As there are four distinct alkyl chains in cardiolipin, the potential for complexity of this molecule species is enormous. Figure 1: General structure of phospholipids Figure 2: Structure of cardiolipin 3 Functions of cardiolipin: 1. Regulates aggregate structures: Because of cardiolipin's unique structure, a change in pH and the presence of divalent cations can induce a structural change. CL shows a great variety of forms of aggregates. It is found that in the presence of Ca2+ or other divalent cations, CL can be induced to have a lamellar-to- hexagonal (La-HII) phase transition. And it is believed to have a close connection with membrane fusion. 2. Facilitates the quaternary structure: The enzyme cytochrome C oxidase or complex IV oxidase is a large transmembrane protein complex found in bacteria and the mitochondrion. It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane. It receives an electron from each of four cytochrome c molecules, and transfers them to one oxygen molecule, converting molecular oxygen to two molecules of water. Complex IV has been shown to require two associated CL molecules in order to maintain its full enzymatic function. Cytochrome bc1(Complex III) also needs cardiolipin to maintain its quaternary structure and functional role. Complex V of the oxidative phosphorylation machinery also displays high binding affinity for CL, binding four molecules of CL per molecule of complex V. 3. Triggers apoptosis: Cardiolipin distribution to the outer mitochondrial membrane would lead to apoptosis of the cells, as evidenced by cytochrome c (cyt c) release, Caspase-8 activation, MOMP induction and NLRP3 inflammasome activation. During apoptosis, cyt c is released from the intermembrane spaces of mitochondria into the cytosol. Cyt c can then bind to the IP3 receptor on endoplasmic reticulum, stimulating calcium release, which then reacts back to cause the release of cyt c. When the calcium concentration reaches a toxic level, this causes cell death. Cytochrome c is thought to play a role in apoptosis via the release of apoptotic factors from the mitochondria. 4 4. Serves as proton trap for oxidative phosphorylation: During the oxidative phosphorylation process catalyzed by Complex IV, large quantities of protons are transferred from one side of the membrane to another side causing a large pH change. CL is suggested to function as a proton trap within the mitochondrial membranes, thereby strictly localizing the proton pool and minimizing the changes in pH in the mitochondrial intermembrane space. This function is due to CL's unique structure. As stated above, CL can trap a proton within the bicyclic structure while carrying a negative charge. Thus, this bicyclic structure can serve as an electron buffer pool to release or absorb protons to maintain the pH near the membranes. Disorder of cardiolipin (Barth syndrome): Barth syndrome is a rare condition characterized by an enlarged and weakened heart (dilated cardiomyopathy), weakness in muscles used for movement (skeletalmyopathy), recurrent infections due to small numbers of white blood cells (neutropenia) an short stature. Barth syndrome occurs almost exclusively in male. In males with Barth syndrome, dilated cardiomyopathy is often present at birth or develops within the first months of life. Over time, the heart muscle becomes increasingly weakened and is less able to pump blood. Individuals with Barth syndrome may have elastic fibers in place of muscle fibers in some areas of the heart muscle, which contributes to the cardiomyopathy. This condition is called endocardial fibroelastosis; it results in thickening of the muscle and impairs its ability to pump blood. In people with Barth syndrome, the heart problems can lead to heart failure. In rare cases, the cardiomyopathy gets better over time and affected individuals eventually have no symptoms of heart disease. Additionally, affected individuals tend to experience extreme tiredness (fatigue) during strenuous physical activity. Most males with Barth syndrome have neutropenia. The levels of white blood cells can be consistently low (persistent), can vary from normal to low (intermittent). 5 Males with Barth syndrome have increased levels of a substance called 3- methylglutaconic acid in their blood and urine. The amount of the acid does not appear to influence the signs and symptoms of the condition. Barth syndrome is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels of 3- methylglutaconic acid in urine (3-methylglutaconic aciduria). The severity of signs and symptoms among affected individuals is also highly variable. Males 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 into adulthood can survive into their late forties. Barth syndrome is estimated to affect 1 in 300,000 to 400,000 individuals worldwide. More than 150 cases have been described in the scientific literature. Causes of Barth syndrome: Mutations in the TAZ gene cause Barth syndrome. The TAZ gene provides instructions for making a protein called tafazzin. Tafazzin is located in structures called mitochondria, which are the energy-producing centers of cells. Tafazzin is involved in altering a fat (lipid) called cardiolipin, which plays critical roles in the mitochondrial inner membrane. Once altered by tafazzin, cardiolipin is key in maintaining mitochondrial shape, energy production, and protein transport within
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