New clinical and molecular insights on Barth syndrome

Orphanet Journal of Rare Diseases

Amelia Morrone⁵  Renzo Guerrini⁸  David N Cooper⁴  Frédéréc M Vaz¹  Enrico Bertini³  Luca Ragni⁹  Licia Lugli²  Serena Catarzi⁵  Sabrina Malvagia⁷  Silvia Funghini⁷  Maria Alice Donati⁶  Lorenzo Ferri⁵ 

[1] Department of Clinical Chemistry and Paediatrics, Amsterdam, Netherlands;Neonatology Unit, Department of Mother & Child, University of Modena, Modena, Italy;Department of Neurosciences, Laboratory of Molecular Medicine, Bambino Gesu’ Children’s Research Hospital, Rome, Italy;Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK;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;Metabolic and Muscular Unit, Neuroscience Department, Meyer Childrens’ Hospital, Florence, Italy;Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children’s Hospital, Florence, Italy;IRRCS, Stella Maris, Pisa, Italy;University of Bologna and Azienda Ospedaliera S. Orsola Malpighi, Bologna, Italy

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

Others  :  864118
DOI  :  10.1186/1750-1172-8-27

 received in 2012-10-19, accepted in 2013-01-30,  发布年份 2013

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusions

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.

【 授权许可】

   
2013 Ferri et al.; licensee BioMed Central Ltd.

【 图 表 】

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