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Are alkylglycerols the new “vitamins” for Barth patients?

It is not surprising that the main focus of research in Barth Syndrome (BTHS) has been to understand the molecular events resulting from changes in both the quantities and the molecular species of the mitochondria-specific phospholipid cardiolipin (CL). This is a reasonable research strategy due to the fact that BTHS is caused by loss-of-function mutations in the gene that encodes tafazzin, the enzyme involved in the last step of CL biosynthesis. However, recently there has been an increased awareness of more widespread changes in the lipid composition of cells depleted of tafazzin function in addition to the well-established alterations in CL.

Of importance for the present study was the observation of a reduced level of plasmalogens in absence of functional tafazzin. For instance, we have shown that the plasmenylcholine level in hearts obtained from tafazzin knock-down mice was half the amount found in controls. This observation was extended to several other organs as well as to lymphoblast cell lines derived from humans with BTHS. In all cases we observed a reduced level of the major plasmalogen of that specimen. This has opened a new possibility, up to now not considered, treating BTHS via the promotion of plasmalogen biosynthesis.

In several diseases characterized by depletion in plasmalogens, promotion of their biosynthesis has been shown as a successful strategy to treat those conditions. While restoring plasmalogen levels is relatively straightforward to accomplish, previous attempts to increase CL levels were not successful by direct administration of this lipid in vivo. Our initial goal was to restore a normal level of plasmalogens in lymphoblasts derived from Barth patients. We achieved this goal by increasing the rate of plasmalogen biosynthesis through the administration of an alkylglycerol (1-O-hexadecylglycerol), a precursor of plasmalogens.

As expected we were able to restore and even slightly surpass the level of plasmalogen found in normal cells. Surprisingly, administration of the alkylglycerol also resulted in some increase in the level of CL in Barth cells. These changes in lipid content were accompanied by improvement in some mitochondria functional properties; that is, the treatment had partly restored the mitochondria copy number and fully restored mitochondrial membrane potential. Overall, the results highlight the potential beneficial effect of a diet supplemented with alkylglycerols to BTHS patients.
 

Richard M. Epand and José Carlos Bozelli, Jr
Department of Biochemistry and Biomedical Sciences, McMaster University, Canada

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