Barth Syndrome: TAFAZZIN Gene, Cardiologic Aspects, and Mitochondrial Studies-A Comprehensive Narrative Review

Abstract

Barth syndrome (BTHS) is inherited through an X-linked pattern. The gene is located on Xq28. Male individuals who inherit the TAFAZZIN pathogenic variant will have the associated condition, while female individuals who inherit the TAFAZZIN pathogenic variant generally do not experience the condition. There are several organs that may be affected, but striking is the cardiological involvement. Cardiovascular disease, which may be the trigger starting the diagnostic procedure in a proband, may include a range of diseases from a severely dilated heart to a hypertrophic heart in the spectrum of anomalies encountered. Left ventricular non-compaction of the heart is also occasionally encountered. This cardiac event may reveal the prognosis of the affected patients. In this narrative review, we highlight the gene's characteristics, the reactome, the cardiological features of the cardiovascular disease observed in patients affected with BTHS, emphasize the most current studies on BTHS cardiomyopathy, and delineate the biological underlying mechanisms supporting the proposal of new therapeutic options.

Keywords: BTHS; Barth syndrome; TAFAZZIN; TAZ; cardiac surgery; cardiovascular disease; left ventricular non-compaction; metabolic disease; outcome; prognosis.

Figure 1

Cytogenetic localization and amino acid sequence of TAFAZZIN. Source: NCBI Bethesda, MD, USA, and GeneCards®: The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses (PMID: 27322403) Stelzer G., Rosen R., Plaschkes I., Zimmerman S., Twik M., Fishilevich S., Iny Stein T., Nudel R., Lieder I., Mazor Y., Kaplan S., Dahary D., Warshawsky D., Guan-Golan Y., Kohn A., Rappaport N., Safran M., and Lancet D. Current Protocols in Bioinformatics(2016), 54: 1.30.1–1.30.33.doi: https://doi.org/10.1002/cpbi.5 “URL (accessed on 25 March 2025)”. Source: Universal Protein Resource (UniProt). The UniProt is a comprehensive resource for protein sequence and annotation data. The amino acid sequence is Q16635-3, which is the isoform that has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. The UniProt Consortium, UniProt: The Universal Protein Knowledgebase in 2025 is reported in Nucleic Acids Res. 53: D609–D617 (2025). UniProt: https://www.uniprot.org/help/license “URL (accessed on 25 March 2025)”. UniProt has chosen to apply the Creative Commons Attribution 4.0 International (CC BY 4.0) License to all copyrightable parts of our databases. UniProt is a Global Biodata Coalition (GBC)-supported global core biodata resource. The GBC was created in 2020 as a consortium of international research funders dedicated to improve our understanding of the global biodata resource ecosystem The mission of UniProt is to provide the scientific community with a comprehensive, high-quality, and freely accessible resource of protein sequence and functional information.

Figure 2

Mutation identified in a patient harboring BTHS. The DNA sequence of the TAFAZZIN gene on chromosome Xq28 shows a c.280C>T mutation (p.Arg94Cys), which leads to an amino acid exchange (courtesy of Professor Dr. MMAM Mannens, Dept. of Clinical Genetics, University of Amsterdam, Netherlands, to Dr. D. Karall and further courtesy to Dr. C. Sergi, email: 9 April 2025). Source: This case report was published in Karall, D. et al. (2014), Barth Syndrome and Left-Ventricular Non-Compaction: Case Report and Surveillance Plan Prior to Cardiac Transplantation. Enliven: Surgery and Transplantation. 01. 10.18650/2379-5719.12004 [22]. This is an open-access article published and distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Figure 3

Tafazzin/TAFAZZIN in the mitochondrial inner membrane. Cardiolipin (CL) and 1-acyl lysophosphatidylethanolamine (LPE) are converted to monolysocardiolipin (MLCL) and phosphatidylethanolamine (PE), respectively, at the inner mitochondrial membrane (IM). The enzyme TAFAZZIN plays a critical role in cells by ensuring that the mitochondrial membranes incorporate the proper form of CL. In addition to providing structural support for the mitochondria, the membranes of these organelles also serve as a platform for a wide variety of critical chemical reactions, including those that generate cellular energy. CL levels drop, and levels of a precursor to it, mono-lyso-CL, or MLCL, rise in the setting of a TAFAZZIN gene mutation. Although scientists are aware that high concentrations of the precursor MLCL damage mitochondria, the precise mechanisms that lead from A (defunct TAFAZZIN) to B (BTHS symptoms) remain unclear. This extensive and persuasive study demonstrates that an excess of the precursor MLCL causes it to build up on the lipid membrane’s side, where it is in close contact with a protein known as cytochrome c. Cytochrome c undergoes a conformational and behavioral shift upon interaction with MLCL, enabling it to undergo a peroxidase transformation that results in the formation of hazardous phospholipids. The mitochondrial lipids are damaged when the precursor MLCL, mature CL, and other phospholipids undergo peroxidation. Experiments on yeast cells deficient in Tafazzin, mouse cells with reduced or absent Tafazzin, cells isolated from individuals suffering from BTHS, cardiac tissue from those individuals with mutated TAFAZZIN, and a fruit fly model of BTHS demonstrated the conversion of cytochrome c to a peroxidase following interaction with MLCL. Researchers demonstrated in both cell and fruit fly studies that the chemical imidazole oleic acid inhibits cytochrome c peroxidase activity and, in fruit flies, protects against exhaustion brought on by TAFAZZIN depletion. When TAFAZZIN is lost, the precursor to CL, MLCL, builds up to toxic levels. This causes the mitochondrial lipid membrane to become misorganized and causes MLCL to interact abnormally with cytochrome c. Cytochrome c produces harmful lipid byproducts because of this interaction, which in turn reduces energy generation and causes other mitochondrial dysfunctions. Source: Figure adapted and modified from Kagan et al. [40] (Kagan, V.E., Tyurina, Y.Y., Mikulska-Ruminska, K. et al. Anomalous peroxidase activity of cytochrome c is the primary pathogenic target in Barth syndrome. Nat Metab 5, 2184–2205 (2023). https://doi.org/10.1038/s42255-023-00926-4). The photograph was created using Microsoft PowerPoint, Windows 11, 2025 Update.

Figure 4

STRING-derived connectome of TAFAZZIN. Network nodes represent proteins. Splice isoforms or post-translational modifications are collapsed, i.e., each node represents all the proteins produced by a single, protein-coding gene locus. Colored nodes: query proteins and first shell of interactors; white nodes: second shell of interactors. Node Content: empty nodes represent proteins of unknown 3D structure, while filled nodes represent a 3D structure that is known or predicted. The edges represent protein–protein associations. Source: STRING Platform [41]. STRING is a database of known and predicted protein–protein interactions. The interactions include direct (physical) and indirect (functional) associations; they stem from computational prediction, from knowledge transfer between organisms, and from interactions aggregated from other (primary) databases. The STRING database currently covers 59′309′604 proteins from more than 10,000 organisms. All data and download files in STRING are freely available under a ‘Creative Commons BY 4.0’ license.

Figure 5

LVNC morphology in a patient with BTHS. This low-power microphotograph shows the trabeculation of the left ventricle using a transversal cut (hematoxylin and eosin staining, 2× original magnification, bar = 1 mm or 1000 μm). This microphotograph illustrates the left ventricle non-compaction histology of a patient affected with BTHS arises from the personal archive of the author (C. Sergi).

Figure 6

Echocardiography at the age of 2 weeks (A,B) and 8 months (C,D) of a patient with BTHS: Parasternal short axis view (left row) and atypical four-chamber view (right row). Normal systolic LV function (A,B) and minor pericardial effusion (arrow) at 2 weeks. Marked systolic dysfunction and LV dilatation at the age of 8 months, before heart transplantation (C,D). Abbreviations: RV, right ventricle; LV, left ventricle. Adapted from the following source: Karall et al. [22]. This is an open-access article published and distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Figure 7

Pre-transplant strategic monitoring of BTHS patients. Adapted and updated (4 April 2025) from Karall et al. (2014), Barth Syndrome and Left-Ventricular Non-Compaction: Case Report and Surveillance Plan Prior to Cardiac Transplantation, Enliven: Surgery and Transplantation. 01. 10.18650/2379-5719.12004. Notes: CL, cardiolipin; LVNC, left ventricle non-compaction; MLCL, monolysocardiolipin; TX, transplantation. Source: [22]. This is an open-access article published and distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.