title: New clinical and molecular insights on Barth syndrome.
abstract: 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.
authors: 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.
authors: Lorenzo
authors: L
authors: Ferri
authors: Maria Alice
authors: MA
authors: Donati
authors: Silvia
authors: S
authors: Funghini
authors: Sabrina
authors: S
authors: Malvagia
authors: Serena
authors: S
authors: Catarzi
authors: Licia
authors: L
authors: Lugli
authors: Luca
authors: L
authors: Ragni
authors: Enrico
authors: E
authors: Bertini
authors: Frédéric M
authors: FM
authors: Vaz
authors: David N
authors: DN
authors: Cooper
authors: Renzo
authors: R
authors: Guerrini
authors: Amelia
authors: A
authors: Morrone
mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics; D000217:Acyltransferases; D056889:Barth Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D006580:Genetic Carrier Screening; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D009503:Neutropenia / Q000235:genetics; D010375:Pedigree; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human