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Barth syndrome is a condition found almost entirely in males and is typically characterised by cardiomyopathy, diseases of the heart that cause the organ to become enlarged, and skeletal myopathy, defined as abnormalities in skeletal cell structure that cause weakness (Darseeetal., 1979). Other symptoms can include: growth retardation, neutropenia (decreased levels of neutrophils), increased levels of 3-methyl glutamic acid (3-MGA) in the urine and chronic fatigue (Jefferies, 2013). It was first discussed in a paper by Neusteinetal., published in 1979 which reported a patient who had X-linked mitochondrial cardiomyopathy.
In 1983, Dr Peter Barth used multiple case studies and family pedigrees to describe the syndrome as an X-linked recessive disorder (Barth etal., 1983).
This is a disease with a poor prognosis and mortality from complications of the symptoms e.g. heart failure or severe infection due to a compromised immune system (Jefferies, 2013).
As of 2013, there were less than 500 patients diagnosed and included in the Barth syndrome registry. Approximately one in every 300,000 to 400,000 babies are born with Barth syndrome, although this has been disputed suggesting the condition is severely underdiagnosed with a possible prevalence nearer to one in every 140,000 live births (Jefferies, 2013).
Mutation in the Taz gene, Tafazzin and cardiolipin
Mutations of the TAZ gene lead to the sequence of events that cause Barth syndrome.
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The TAZ gene (comprised of eleven exons) has been highly conserved throughout evolution. DNA sequencing has shown over 160 mutations in the TAZ gene and they can occur in every exon (Jefferies, 2013). The majority of these mutations are insertions or deletions of small DNA sequences.
Missense mutations have also been reported.
Mutations in the TAZ gene on chromosome Xq28 (aka G4.5) result in the loss of function in the protein Tafazzin (Jefferies, 2013). This links to abnormal mitochondria and can be used to explain some of the classic symptoms of Barth’s.
The wildtypeTAZ will translate and transcribe a protein called Tafazzin (Jefferies, 2013). Non-mutated Tafazzin has a role in the remodelling of cardiolipin (CLs) which are initially made with acyl groups. CLs can be described as a negatively charged mitochondrial polyglycerophospholipid (Acehanetal., 2010). The synthesis of CLs occurs through multiple steps and occurs in the mitochondria only (Damschroder, Reynolds and Wessells, 2018). In the remodelling phase (figure 1), which is catalysed by Tafazzin, the acyl groups are replaced with linoleic acid, forming L4CLs (Jefferies, 2013). Barth’s patients have deficiency of L4CLs and an accumulation of the immature form with acyl groups attached. measuring CL levels is a diagnostic tool (Houtkooperetal., 2009). Diagnosis is also made based on presentation of symptoms or by genetically testing for a mutation in the TAZ gene.
In Barth’s patients the levels of total cardiolipins are low but there is an increase in the monolysocardiolipin (Acehanetal., 2010).
Mitochondria are the primary source of energy in cells and are vital in tissues that require a lot of energy to carry out their normal function (Dudek, 2017). They produce adenosinetriphosphate (ATP) from cellular respiration. Mature CLs have many roles and functions in mitochondria including the signalling pathway such as mitophagy, inflammation and apoptosis. However, their most important role is maintaining the mitochondrial structure, especially formation of the mitochondrial cristae (Jefferies, 2013).
CLs mediate the assembly and stabilisation of electron transport chain (ETC) complexes. Specifically, there are binding sites for CL in complexes I, III and IV (Ikon and Ryan, 2017). The ETC when working correctly has a vital role in producing energy in the form of ATP therefore CLs help optimise cellular energy production (Jefferies, 2013).
High energy tissues with defected mitochondria are not able to carry out their function effectively and then be able to efficiently recover, leading to muscle fatigue (Ikon and Ryan, 2017).
When the cristae of the mitochondria are compromised, it can disrupt the ETC. Barth’s patients show a decreased activity of the ETC. The ETC is driven by a proton gradient and the mitochondrial structural differences in Barth’s patients indicate a proton leakage explaining why they have a less active ETC and decreased ATP production (Ikon and Ryan, 2017). Cardiomyocytes and skeletal muscle cells therefore have less energy for contraction.
Barth’s patients also have a reduced level of succinate dehydrogenase (complex II) and the disfunction of the complexes in the ETC cause abnormal transfer of electrons onto the oxygen molecule forming superoxides and increasing the reactive oxygen species level (Dudek, 2017). Further damaging the mitochondria and causing cell death through toxicity.
Barth’s paper in 1983 highlighted ultrastructural abnormalities in the mitochondria found in cardiac muscle fibres, neutrophil bone marrow cells and skeletal muscle fibres (Barth etal., 1983). The mitochondrial CL content is higher in more oxidative tissues explaining why the muscles which undergo the most oxidative stress are the most effected i.e. the heart and skeletal muscles (Acehanetal., 2010). Structural differences in mitochondria affect their function and are a cause of the symptoms seen in Barth patients.
The same structural distortion has been seen in both cardiac and skeletal mitochondria. With an onion like morphology observed in both, showing the multiple layers of densely packed cristae. As shown in figure 2.
Figure 2: A comparison of a normal mitochondrion with the mitochondrion from a TAZ deficient skeletal muscle cell
The effects of a TAZ mutation and the consequential CL abnormality on the cardiac muscle lead to disorders of cardiac enlargement. Including left ventricular dilation, hypertrophy, congestive heart failure and endocardialfibroelastosis (Spencer etal., 2006). These are caused by the cardiac muscle not having sufficient ATP to contract efficiently over a long period of time resulting in tissue damage. This highlights a direct link between defective ATP metabolism and cardiomyopathy (Ikon and Ryan, 2017).
When the filling of the left ventricle is followed by a partial contraction the tissue is stretched, increasing the chamber volume and thinning the tissue (Ikon and Ryan, 2017). An enlarged heart prevents the chambers of the heart filling with blood correctly. Coupling this with ATP depletion, it has been observed that cardiac sarcomeres will not contract in unison which causes the cardiac tissue to weaken and the volume of blood ejected to decrease (Ikon and Ryan, 2017). This in turn affects blood flow and oxygen transport (Acehanetal., 2010).
Mitochondria associated membranes (MAMs) are also heavily affected as they have a key role in cross communication and transport between the endoplasmicreticulum (ER) of the cell and the mitochondrion. This cross communication breaks down when MAMs are defected, disrupting calcium transport. This is seen in cardiomyocytes and cardiac conducting cells. This can have the effect of causing lethal arrhythmias, another symptom of Barth syndrome, as calcium is a requirement in cardiac muscle contraction (Acehanetal., 2010).
The cardiac effects are so severe that some Barth syndrome patients have required cardiac transplantation and sudden cardiac death or ventricular arrhythmias have been reported.
The healthy mitochondria in a skeletal muscle e.g. extensordigitorumlongus (EDL) will vary in shape and size with most exhibiting a laminar or tubular shape. Yet the onion morphology is present.
Skeletal myopathy can also occur with the disruption of the ETC, where aerobic respiration alone cannot meet the energy demands of the muscle, requiring anaerobic respiration to be utilised. This leads to a build up of lactic acid which causes skeletal muscle weakness (Ikon and Ryan, 2017). In Barth-affected skeletal muscle, poor oxygen extraction from red blood cells and poor utilisation of the oxygen to recover from fatigue is common (Spencer etal., 2011).
In Barth syndrome the effects of CL depletion on cardiac and skeletal muscle will link together and worsen the prognosis. For example, skeletal myopathy will cause easy fatigue which can then be exaggerated by the cardiovascular complications associated with syndrome as impaired cardiac function results in less oxygen able to reach the tiring muscles (Spencer etal., 2011).
It is clear to see how the TAZ mutation in Barth’s patients will lead to major disruption of mitochondria structure via defected Tafazzin and hence CLs. These mitochondrion defects will ultimately result in disrupted respiration reducing available ATP, the energy of a cell. Without this energy, cardiac tissue will be unable to beat correctly and with the correct rhythm (Ikon and Ryan, 2017). Skeletal muscle will also suffer with a reduction in ATP which impairs their contraction and reduces efficient movement.
Whilst treatments managing symptoms of Barth’s have improved the prognosis, research into finding a cure is continuing with some research treatments targeting mitochondria (Jefferies, 2013). Experimental procedures carried out on Drosophila have also discovered that inhibiting a calcium independent phospholipase A2 known as iPLA2-VIA supressing the phenotype of mutated TAZ and prevent CL depletion. Applying this to a treatment where lymphoblasts were placed in tissue culture with bromoenollactone (an iPLA2 inhibitor) would partially restore CL homeostasis (Malhotraetal., 2009).
Understanding Barth Syndrome: Mitochondrial Dysfunction and Muscular Impact. (2024, Feb 22). Retrieved from https://studymoose.com/document/understanding-barth-syndrome-mitochondrial-dysfunction-and-muscular-impact
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