title: Barth syndrome.
abstract: First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay, neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer than 200 living males are known worldwide, but evidence is accumulating that the disorder is substantially under-diagnosed. Clinical features include variable combinations of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones, proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent, intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems, failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system disorder which may be first seen by many different specialists or generalists. Phenotypic breadth and variability present a major challenge to the diagnostician: some children with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin, a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical test, based on detecting abnormal ratios of different cardiolipin species, was first described in 2008. Key areas of differential diagnosis include metabolic and viral cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots. TAZ sequencing also allows female carrier detection and antenatal screening. Management of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients), antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy. Multidisciplinary teams/clinics are essential for minimising hospital attendances and allowing many more individuals with BTHS to live into adulthood.
authors: NHS Specialised Services Barth Syndrome Service, Royal Hospital for Children, Upper Maudlin St, Bristol, BS2 8BJ, UK. colin.steward@uhbristol.nhs.uk
authors: Sarah L N
authors: SL
authors: Clarke
authors: Ann
authors: A
authors: Bowron
authors: Iris L
authors: IL
authors: Gonzalez
authors: Sarah J
authors: SJ
authors: Groves
authors: Ruth
authors: R
authors: Newbury-Ecob
authors: Nicol
authors: N
authors: Clayton
authors: Robin P
authors: RP
authors: Martin
authors: Beverly
authors: B
authors: Tsai-Goodman
authors: Vanessa
authors: V
authors: Garratt
authors: Michael
authors: M
authors: Ashworth
authors: Valerie M
authors: VM
authors: Bowen
authors: Katherine R
authors: KR
authors: McCurdy
authors: Michaela K
authors: MK
authors: Damin
authors: Carolyn T
authors: CT
authors: Spencer
authors: Matthew J
authors: MJ
authors: Toth
authors: Richard I
authors: RI
authors: Kelley
authors: Colin G
authors: CG
authors: Steward
mesh_terms: D056889:Barth Syndrome / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006331:Heart Diseases / Q000150:complications; D006801:Humans; D008297:Male
references: J Child Neurol. 2006 Sep;21(9):805-7
references: 16970891
references: J Lipid Res. 2008 Dec;49(12):2545-56
references: 18703489
references: Pediatr Transplant. 2007 May;11(3):327-31
references: 17430492
references: Prenat Diagn. 2003 Dec 30;23(13):1042-4
references: 14691988
references: Am Heart J. 1994 Jan;127(1):64-70
references: 8273757
references: Prog Lipid Res. 2000 May;39(3):257-88
references: 10799718
references: Mol Genet Metab. 2012 May;106(1):115-20
references: 22410210
references: Curr Opin Hematol. 2009 Jan;16(1):14-9
references: 19057200
references: Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11584-8
references: 16855048
references: Am J Med Genet. 1994 Apr 15;50(3):255-64
references: 8042670
references: Biochim Biophys Acta. 2009 Oct;1788(10):2048-58
references: 19539604
references: J Biol Chem. 2011 Jan 14;286(2):899-908
references: 21068380
references: Anal Biochem. 2009 Apr 15;387(2):230-7
references: 19454236
references: Lab Invest. 2005 Jun;85(6):823-30
references: 15806137
references: Circ Res. 2006 Jul 21;99(2):201-8
references: 16794186
references: Eur J Pediatr. 2008 Aug;167(8):941-4
references: 17846786
references: J Pediatr. 1991 Nov;119(5):738-47
references: 1719174
references: Pediatr Cardiol. 2005 Sep-Oct;26(5):632-7
references: 16235007
references: Biochem J. 2002 May 15;364(Pt 1):317-22
references: 11988106
references: J Neurol Sci. 1992 Mar;108(1):105-13
references: 1320661
references: J Neurol Sci. 1983 Dec;62(1-3):327-55
references: 6142097
references: Am J Med Genet. 1997 Oct 31;72(3):257-65
references: 9332651
references: Prenat Diagn. 2006 May;26(5):462-5
references: 16548007
references: Acta Paediatr. 2001 May;90(5):584-6
references: 11430723
references: Am J Clin Nutr. 2008 Nov;88(5):1272-6
references: 18996862
references: Fetal Pediatr Pathol. 2005 Jul-Oct;24(4-5):239-54
references: 16396830
references: Am J Hum Genet. 1997 Oct;61(4):868-72
references: 9382097
references: Am J Hum Genet. 1998 Nov;63(5):1457-63
references: 9792874
references: Lab Invest. 2007 Jan;87(1):40-8
references: 17043667
references: J Pediatr. 1999 Sep;135(3):273-6
references: 10484787
references: Pediatrics. 2006 Aug;118(2):e337-46
references: 16847078
references: J Am Heart Assoc. 2012 Apr;1(2):
references: 23130124
references: Am J Med Genet A. 2005 May 1;134(4):409-14
references: 15793838
references: Biochem Cell Biol. 2010 Aug;88(4):595-602
references: 20651830
references: Ann Neurol. 2002 May;51(5):634-7
references: 12112112
references: J Inherit Metab Dis. 2012 Jan;35(1):13-22
references: 20882351
references: Prenat Diagn. 1997 Oct;17(10):983-8
references: 9358581
references: Biochim Biophys Acta. 2007 Mar;1771(3):432-41
references: 16904369
references: J Am Coll Cardiol. 2003 Dec 3;42(11):1994-9
references: 14662265
references: Am J Med Genet A. 2004 May 1;126A(4):349-54
references: 15098233
references: J Lipid Res. 2005 Jun;46(6):1182-95
references: 15805542
references: Pediatrics. 1979 Jul;64(1):24-9
references: 572031
references: Am J Med Genet A. 2012 Nov;158A(11):2726-32
references: 23045169
references: Mol Genet Metab. 2010 Jun;100(2):198-203
references: 20303308
references: Biophys J. 2011 May 4;100(9):2184-92
references: 21539786
references: Biochem Biophys Res Commun. 2000 Dec 20;279(2):378-82
references: 11118295
references: Br Heart J. 1994 Oct;72(4):349-53
references: 7833193
references: N Engl J Med. 2003 Apr 24;348(17):1639-46
references: 12711738
references: J Dev Behav Pediatr. 2007 Feb;28(1):22-30
references: 17353728
references: J Pediatr. 1988 Sep;113(3):511-4
references: 3411399
references: Mitochondrion. 2009 Apr;9(2):86-95
references: 19114128
references: Curr Biol. 2009 Dec 29;19(24):2133-9
references: 19962311
references: Am J Hum Genet. 1997 Oct;61(4):862-7
references: 9382096
references: J Med Genet. 2006 May;43(5):385-93
references: 16055927
references: Nat Genet. 1996 Apr;12(4):385-9
references: 8630491
references: Am J Physiol Heart Circ Physiol. 2011 Nov;301(5):H2122-9
references: 21873497
references: J Inherit Metab Dis. 2013 Sep;36(5):741-6
references: 23109063
references: Clin Chem. 2008 Feb;54(2):371-8
references: 18070816
references: Acta Paediatr. 2004 Mar;93(3):419-21
references: 15124852
references: J Inflamm (Lond). 2012 Jun 21;9(1):25
references: 22721508
references: J Med Genet. 1995 May;32(5):383-8
references: 7616547
references: Am J Med Genet. 1993 Feb 1;45(3):327-34
references: 8434619
references: Mol Genet Metab. 2003 Dec;80(4):408-11
references: 14654353
references: J Lipid Res. 2006 Oct;47(10):2346-51
references: 16873891
references: Curr Biol. 1997 Aug 1;7(8):R465-6
references: 9259571
references: Prenat Diagn. 2010 Oct;30(10):970-6
references: 20812380
references: Am J Hum Genet. 1991 Mar;48(3):481-5
references: 1998334
references: Prog Lipid Res. 2006 Mar;45(2):91-101
references: 16442164
references: Am J Med Genet A. 2009 May;149A(5):1082-5
references: 19396829
references: Apoptosis. 2007 May;12(5):877-85
references: 17294083
references: Blood. 2004 May 15;103(10):3915-23
references: 14764526
references: Eur J Pediatr. 2011 Nov;170(11):1481-4
references: 21932011
references: J Inherit Metab Dis. 2006 Oct;29(5):684
references: 16906470
references: Pediatr Res. 2012 Oct;72(4):432-7
references: 22797137
references: Pediatr Cardiol. 2012 Dec;33(8):1430-4
references: 22427193
references: Mol Genet Metab. 2012 Nov;107(3):428-32
references: 23031367
references: Prenat Diagn. 2010 Oct;30(10):918-23
references: 20721878
references: Clin Dysmorphol. 2009 Oct;18(4):185-7
references: 19648820
references: J Pediatr. 1999 Sep;135(3):311-5
references: 10484795
references: Hum Mol Genet. 2013 Feb 1;22(3):483-92
references: 23100323
references: Am J Med Genet A. 2007 May 1;143A(9):907-15
references: 17394203
references: Cardiol Young. 2007 Apr;17(2):215-7
references: 17244376
references: Circulation. 2003 Nov 25;108(21):2672-8
references: 14623814