Barth Syndrome Cardiomyopathy: An Update

Abstract

Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies.

Cardiolipin Regulates Mitochondrial Ultrastructure and Function in Mammalian Cells

“…Our recent study using a cardiac-specific PTPMT1 mouse model demonstrated that deficiency in CL biosynthesis induced by PTPMT1 deletion in mouse cardiomyocytes decreased embryonic cardiac cell proliferation, resulting in decreased thickening of ventricular walls, arrestment of heart development and growth, and eventually embryonic lethality [ 13 ]. Furthermore, various cardiac defects, including dilated cardiomyopathy, hypertrophic cardiomyopathy, left ventricular myocardial noncompaction, and ventricular arrhythmia, have been observed in patients with Barth syndrome, a rare X-linked genetic disorder caused by mutations in TAZ [ 17 , 96 , 133 , 134 ]. Such cardiac phenotypes can be partially recapitulated in genetically engineered mouse models with knockdown [ 52 , 56 , 58 , 107 ], germline deletion [ 113 ], or cardiac-cell-specific knockout of the mouse TAZ gene [ 14 , 51 , 113 ].…”

“…Thus, CL can play multiple roles, including the formation and stability of the mitochondrial cristae respiration supercomplex [ 12 , 13 , 14 ], mitochondrial quality control and dynamics [ 15 ], as well as mitochondrial biogenesis and protein import [ 16 ]. Notably, the roles of CL in regulating mitochondrial structure and functioning have been discussed in many excellent reviews [ 12 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Therefore, in this review, we will instead emphasize the recent advances in our understanding of its physiological roles in different mammalian cells and discuss the relationships of an abnormal CL content, composition, and oxidation with mitochondrial dysfunction and structural abnormality, as well as their implications in pathophysiological conditions and diseases.…”

Prenatal case report of Barth syndrome caused by novel TAFAZZIN mutation: Clinical characteristics of fetal dilated cardiomyopathy with ascites

“…TAFAZZIN , also known as G4.5, causes BTHS. It was previously named TAZ and is located in the gene-rich region Xq28 ( 12 ). TAFAZZIN protein can participate in phospholipid biosynthesis and remodeling of the acyltransferase superfamily.…”

Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice

“…TAFAZZIN knockdown was induced in utero and maintained postnatally by TD.01306 chow (Envigo, IN, USA) supplemented with 625 mg/kg dox. The different dox administration strategies and concentrations resulted in variable cardiac phenotypes and results 33 , 34 . Dox was administered to female mice continuously to induce the embryonic transgene throughout gestation.…”

“…Although tafazzin-deficient hearts exhibit CL alterations similar to BTHS patients (i.e. high MLCL/CL ratio), it is important to underlie that Taz KD mice present relatively mild and late-onset cardiomyopathy phenotypes 31 , 33 – 35 .…”