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New clinical and molecular insights on Barth syndrome

Lorenzo Ferri1, Maria Alice Donati2, Silvia Funghini3, Sabrina Malvagia3, Serena Catarzi1, Licia Lugli4, Luca Ragni5, Enrico Bertini6, Frédéréc M Vaz7, David N Cooper8, Renzo Guerrini19 and Amelia Morrone1*

Author Affiliations

1 Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Florence and Paediatric Neurology Unit and Laboratories, Meyer Children’s Hospital, Viale Pieraccini n. 24, 50139, Florence, Italy

2 Metabolic and Muscular Unit, Neuroscience Department, Meyer Childrens’ Hospital, Florence, Italy

3 Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s Hospital, Florence, Italy

4 Neonatology Unit, Department of Mother & Child, University of Modena, Modena, Italy

5 University of Bologna and Azienda Ospedaliera S. Orsola Malpighi, Bologna, Italy

6 Department of Neurosciences, Laboratory of Molecular Medicine, Bambino Gesu’ Children’s Research Hospital, Rome, Italy

7 Department of Clinical Chemistry and Paediatrics, Amsterdam, Netherlands

8 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK

9 IRRCS, Stella Maris, Pisa, Italy

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Orphanet Journal of Rare Diseases 2013, 8:27  doi:10.1186/1750-1172-8-27

Published: 14 February 2013



Barth syndrome (BS) is an X-linked infantile-onset cardioskeletal disease characterized by cardiomyopathy, hypotonia, growth delay, neutropenia and 3-methylglutaconic aciduria. It is caused by mutations in the TAZ gene encoding tafazzin, a protein involved in the metabolism of cardiolipin, a mitochondrial-specific phospholipid involved in mitochondrial energy production.


Clinical, biochemical and molecular characterization of a group of six male patients suspected of having BS. Three patients presented early with severe metabolic decompensation including respiratory distress, oxygen desaturation and cardiomyopathy and died within the first year of life. The remaining three patients had cardiomyopathy, hypotonia and growth delay and are still alive. Cardiomyopathy was detected during pregnancy through a routine check-up in one patient. All patients exhibited 3-methylglutaconic aciduria and neutropenia, when tested and five of them also had lactic acidosis.


We confirmed the diagnosis of BS with sequence analysis of the TAZ gene, and found five new mutations, c.641A>G p.His214Arg, c.284dupG (p.Thr96Aspfs*37), c.678_691del14 (p.Tyr227Trpfs*79), g.8009_16445del8437 and g.[9777_9814del38; 9911-?_14402del] and the known nonsense mutation c.367C>T (p.Arg123Term). The two gross rearrangements ablated TAZ exons 6 to 11 and probably originated by non-allelic homologous recombination and by Serial Replication Slippage (SRS), respectively. The identification of the breakpoints boundaries of the gross deletions allowed the direct detection of heterozygosity in carrier females.


Lactic acidosis associated with 3-methylglutaconic aciduria is highly suggestive of BS, whilst the severity of the metabolic decompensation at disease onset should be considered for prognostic purposes. Mutation analysis of the TAZ gene is necessary for confirming the clinical and biochemical diagnosis in probands in order to identify heterozygous carriers and supporting prenatal diagnosis and genetic counseling.

Barth syndrome; TAZ gene mutation; In utero cardiomyopathy; Metabolic decompensation; Lactic acidosis; 3-methylglutaconic aciduria; Gross deletions; Metabolic cardiomyopathy