Barth syndrome without tetralinoleoyl cardiolipin deficiency: a possible ameliorated phenotype.

Ann Bowron,Graham J Shortland,Lucy Jones,Maggie Williams,Nicol Clayton,Shakeel A Qureshi,Julie Honeychurch,Simon J R Heales,Colin G Steward,Beverley Tsai‐Goodman

doi:10.1007/s10545-014-9747-y

Abstract

Barth syndrome (BTHS) is an X-linked disorder characterised by cardiac and skeletal myopathy, growth delay, neutropenia and 3-methylglutaconic aciduria (3-MGCA). Patients have TAZ gene mutations which affect metabolism of cardiolipin, resulting in low tetralinoleoyl cardiolipin (CL4), an increase in its precursor, monolysocardiolipin (MLCL), and an increased MLCL/CL4 ratio. During development of a diagnostic service for BTHS, leukocyte CL4 was measured in 156 controls and 34 patients with genetically confirmed BTHS. A sub-group of seven subjects from three unrelated families was identified with leukocyte CL4 concentrations within the control range. This had led to initial false negative disease detection in two of these patients. MLCL/CL4 in this subgroup was lower than in other BTHS patients but higher than controls, with no overlap between the groups. TAZ gene mutations in these families are all predicted to be pathological. This report describes the clinical histories of these seven individuals with an atypical phenotype: some features were typical of BTHS (five have had cardiomyopathy, one family has a history of male infant deaths, three have growth delay and five have 3-MGCA) but none has persistent neutropenia, five have excellent exercise tolerance and two adults are asymptomatic. This report also emphasises the importance of measurement of MLCL/CL4 ratio rather than CL4 alone in the biochemical diagnosis of the BTHS.

Highlights

Barth syndrome (BTHS, OMIM 3020660) is an X-linked disorder of cardiomyopathy (CM) and skeletal myopathyCommunicated by: Robert SteinerA
We describe seven patients from three families with BTHS confirmed by TAZ mutation analysis who have some biochemical and clinical features which differ from other BTHS cases previously described, notably lack of severe deficiency of CL4 in leukocytes and absence of neutropenia; two are asymptomatic adults, one of whom has never had any features of BTHS
We have described seven subjects from three families with BTHS confirmed by the finding of a mutation in the TAZ gene

Summary

Introduction

Barth syndrome (BTHS, OMIM 3020660) is an X-linked disorder of cardiomyopathy (CM) and skeletal myopathy. BTHS is caused by mutations in the tafazzin (TAZ) gene (Bione et al 1996) which encodes proteins that belong to a family of acyltransferases known as tafazzins (Schlame et al 2002) These are involved in phospholipid biosynthesis, in the incorporation of linoleic acid into phosphatidylglycerol and cardiolipin (Vreken et al 2000). Deficiency of CL4 has been identified in a range of tissues in patients with BTHS (Schlame et al 2002), as well as increased concentrations of its precursor, monolysocardiolipin (MLCL) (Houtkooper et al 2009; Valianpour et al 2002a, b) These findings have been described in TAZ deficient yeast (Li et al 2007), Drosophila (Xu et al 2006) and a knock-down mouse model of BTHS (Acehan et al 2011), and are consistent with the hypothesis that the disorder is caused by defective cardiolipin remodelling. We describe seven patients from three families with BTHS confirmed by TAZ mutation analysis who have some biochemical and clinical features which differ from other BTHS cases previously described, notably lack of severe deficiency of CL4 in leukocytes and absence of neutropenia; two are asymptomatic adults, one of whom has never had any features of BTHS

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