Mitochondrial Dysfunction and Barth Syndrome
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
In 1980, Barth et al. described a novel X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leukocytes, at a Neuromuscular Disease Symposium held at Erasmus University1. Three years after this preliminary communication, Barth et al. reported a large Dutch family with cardiomyopathy, skeletal myopathy, neutropenia, and high infant mortality due to infection or cardiac failure2. These clinical characteristics have since become the cardinal features of what is now known as Barth syndrome (BTHS, MIM#302060) (Figure 1)3–6. The incidence of BTHS is estimated to be about 1/300,000–400,000 live births, with fewer than 500 individuals worldwide included in the BTHS Registry & Repository. There is no known racial or ethnic predilection7,8.
Cardiac and cardiovascular disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
This is rarer than hypertrophic cardiomyopathy (around 1 in 2,000 births). Most cases of dilated cardiomyopathy (DCM) are not familial but have a toxic (e.g. alcohol or iron overload), infective, inflammatory or endocrine cause. (Note that iron overload may be associated with other genetic causes, such as haemochromatosis or transfusion for thalassaemia.) In familial cases, less than half have a clear genetic cause. Specific autosomal dominant and X-linked forms are recognised. The dominant forms include mutations affecting sarcomeric or cytoskeletal proteins, lamin A/C and some ion channel proteins. The X-linked Barth syndrome also shows skeletal myopathy and general metabolic changes. Dystrophin-related cardiomyopathies (also X-linked) are another rare group. Mitochondrial disease (including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibres [MERRF] and Kearns-Sayre syndrome) can lead to DCM. Childhood cases may be affected by Alström syndrome, or a mitochondrial disorder, or may be part of a more general metabolic disorder. Families with recessive inheritance are unusual.
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Mary N. Sheppard in Practical Cardiovascular Pathology, 2022
Barth syndrome, initially described as X-linked cardioskeletal myopathy with abnormal mitochondria and neutropenia, typically presents in male infants as HF associated with neutropenia and 3-methylglutaconic aciduria. The genetic basis of Barth syndrome is mutations in the gene tafazzin (TAZ), which encodes the tafazzin protein, an acyltransferase. Mutations in TAZ result in a wide range of findings, including DCM, HCM, endocardial fibroelastosis, or left ventricular noncompaction. Arrhythmias are also frequent in these patients, and syncope or sudden death, acidosis, or infectious complications occur.24
‘You-on-a-chip’ for precision medicine
Published in Expert Review of Precision Medicine and Drug Development, 2018
The promise for rare disease tissue modeling and therapeutic testing is highlighted by work recreating the pediatric mitochondrial cardiomyopathy Barth syndrome, which is caused by a mutation in the gene encoding the protein tafazzin (TAZ), on a tissue chip [97]. iPSC-derived cardiomyocytes were created from two patient donors and seeded onto muscular thin films (MTFs) – flexible films that twitch in a quantifiable manner as the cells beat together [98]. Researchers used the MTFs to compare Barth syndrome sarcomere organization, functional twitching, and peak systolic stress, so uncovering insights into disease pathology. In addition, they used genome edited iPSCs and modified RNA (modRNA) genetic approaches to show that induction of the genetic TAZ mutation caused Barth-like phenotypes in resulting cardiac tissues, which could be rescued upon genetic correction. These kinds of approach hold much promise for understanding and potentially treating other diseases, including mitochondrial disorders and cystic fibrosis.
Significant expression of tafazzin (TAZ) protein in colon cancer cells and its downregulation by radiation
Published in International Journal of Radiation Biology, 2018
Surajit Pathak, Antara Banerjee, Wen-Jian Meng, Suman Kumar Nandy, Madhumala Gopinath, Xiao-Feng Sun
Many transcriptional factors have shown to interact with TAZ and activity of TAZ depends on its binding to different transcription factors (Wang et al. 2008). The present study is a comparative data of how the three genes, Livin, MAC30 and FXYD3 interact with TAZ/WWTR1. In our previous papers on TAZ protein, which is generally responsible for barth syndrome, upregulated in colorectal cancer (Pathak et al. 2014), we have showed the function and overexpression of these genes individually and its essential role played in colorectal cancers. Functional subunits of Livin and TAZ, FXYD3 and TAZ with strong binding of TAZ and Livin with TEAD, TAZ and MAC30 which is specific not only in colon cancer but its function in initiating lymph node metastasis in colorectal cancer was also reported. TAZ and FXYD3 role in germline sex determination as well its ability to directly influence endogenous oocytes was reason for initiating the study. The relationship was further established through the PCR studies which showed that treatment of HCT15 cell lines with 9-fluorenone, a known Hippo pathway inhibitor of TAZ, significantly decreased the levels of not only TAZ but also the level of Livin. This shows that the network regulation of Hippo pathway is regulated by not only TAZ but also certain unknown regulators like Livin, that can be further investigated upon.
Fetal hydrops – a review and a clinical approach to identifying the cause
Published in Expert Opinion on Orphan Drugs, 2020
Esther Dempsey, Tessa Homfray, John M Simpson, Steve Jeffery, Sahar Mansour, Pia Ostergaard
Barth Syndrome is an X-linked disorder of mitochondrial function and stability caused by mutations in TAZ [85]. Clinically the condition results in a dilated cardiomyopathy with endocardial fibroelastosis, which can lead to hydrops antenatally [86]. On fetal echocardiography, crypts are characteristically seen in the apex and free wall [82]. Those that survive may show growth retardation, proximal skeletal myopathy, neutropenia and organic aciduria [85,87].
Related Knowledge Centers
- Cardiomyopathy
- Exercise Intolerance
- Muscle Weakness
- Sex Linkage
- Neutropenia
- Hypertrophy
- Stillbirth
- Genetic Disorder
- 3-Methylglutaconic Aciduria
- Tafazzin