Medicine:Barth syndrome

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Short description: Human genetic metabolism disorder
Barth Syndrome
Other names3-Methylglutaconic aciduria type II, X-linked cardioskeletal myopathy and neutropenia, BTHS, Cardioskeletal myopathy with neutropenia and abnormal mitochondria, Cardioskeletal myopathy-neutropenia syndrome
SymptomsDilated cardiomyopathy, neutropenia, short stature, muscle weakness.[1]
ComplicationsHeart failure, delayed motor skills, infections.[1]
Usual onsetInfancy.[1]
CausesGenetic mutation.[1]
PrognosisReduced life expectancy.[1]
Frequency1-9 / 1 000 000[2]

Barth syndrome (BTHS) is a rare but serious X-linked genetic disorder, caused by changes in phospholipid structure and metabolism. It may affect multiple body systems (though mainly characterized by pronounced pediatric-onset cardiomyopathy), and is potentially fatal.[3] The syndrome is diagnosed almost exclusively in males.



Though not always present, the cardinal characteristics of this multi-system disorder include: cardiomyopathy (dilated or hypertrophic, possibly with left ventricular noncompaction and/or endocardial fibroelastosis),[4][5] neutropenia (chronic, cyclic, or intermittent),[5] underdeveloped skeletal musculature and muscle weakness,[6] growth delay,[5] exercise intolerance, cardiolipin abnormalities,[7][8] and 3-methylglutaconic aciduria.[5] It can be associated with stillbirth.[9]

Barth Syndrome is manifested in a variety of ways at birth. A majority of patients are hypotonic at birth; show signs of cardiomyopathy within the first few months of life; and experience a deceleration in growth in the first year, despite adequate nutrition. As patients progress into childhood, their height and weight lag significantly behind average. While most patients express normal intelligence, a significant proportion of patients also express mild or moderate learning disabilities. Physical activity is also hindered due to diminished muscular development and muscular hypotonia. Many of these disorders are resolved after puberty. Growth accelerates during puberty, and many patients reach a normal adult height.[10]

Cardiomyopathy is one of the more severe manifestations of Barth Syndrome. The myocardium is dilated, reducing the systolic pump of the ventricles. For this reason, most patients have left myocardial thickening (hypertrophy). While cardiomyopathy can be life-threatening, it is commonly resolved or substantially improved in Barth Syndrome patients after puberty.[10]

Neutropenia, a granulocyte disorder that results in a low production of neutrophils, the body's primary defenders against bacterial infections, is another severe manifestation of Barth Syndrome. In general, lower levels of neutrophils render a patient more vulnerable to bacterial infections;[4] in Barth Syndrome patients, however, there are reports of relatively fewer bacterial infections as compared to non-Barth patients with neutropenia.[11]


The tafazzin gene (TAZ, also called G4.5 or NG_009634) is highly expressed in cardiac and skeletal muscle; its gene product, Taz1p, functions as an acyltransferase in complex lipid metabolism.[7][8] Any type of mutation of TAZ (missense, nonsense, deletion, frameshift, and/or splicing) is closely associated with Barth syndrome.[12]

In 2008, Dr. Kulik found that every patient with Barth Syndrome that he tested had abnormalities in their cardiolipin, a lipid found inside the mitochondria of cells.[13] Cardiolipin is intimately connected with the electron transport chain proteins and the membrane structure of the mitochondrion, the energy-producing organelle of the cell. iPLA2-VIA has been suggested as a target for treatment.[14]

The human tafazzin gene is over 10,000 base pairs in length, the full-length mRNA, NM_000116, being 1919 nucleotides long, encoding 11 exons with a predicted protein length of 292 amino acids and a molecular weight of 33.5 kDa. It is located at Xq28;[15] the long arm of the X chromosome. This explains the X-linked nature of Barth Syndrome.

There are some case reports of women who are asymptomatic carriers of the TAZ mutation. Any of their children might inherit the modified gene with a 50% probability, with the males developing Barth Syndrome and the females going on to be carriers themselves. Thus, it is vitally important to take familial histories of Barth Syndrome patients to determine genetic risk. Ideally, any male who is matrilineally related to an individual with Barth Syndrome should be tested for TAZ mutation(s). Because the phenotype can vary widely, even among affected siblings, symptomatology (or lack thereof) by itself is insufficient for diagnosis.[16]


Early diagnosis of the syndrome is complicated, but of critical importance. Clinical presentation in Barth Syndrome is highly variable, with the only common denominator being early-onset and pronounced cardiomyopathy. Diagnosis is established based upon several tests, among which can be blood tests (neutropenia, white blood cell count), urinalysis (increased urinary organic acid levels), echocardiography (cardiac ultrasound, to assess (and detect abnormalities in) the heart's structure, function and condition), and, with reasonable suspicion of Barth Syndrome, DNA sequencing (to verify TAZ gene status).

Differential diagnosis

Based on symptoms at time of presentation, the differential diagnosis may include other hereditary and/or nutritional causes of (dilated) cardiomyopathy and (cyclic or idiopathic) neutropenia.


Currently, there is no treatment for Barth syndrome, although some of the symptoms can be successfully managed. Clinical trials for possible treatments are ongoing, and preliminary research into AAV9-mediated TAZ gene replacement by the University of Florida has been promising. However, more research and (pre-)clinical testing is needed before the gene therapy is eligible for approval by the FDA as a treatment modality.[17][18]


Being X-linked, Barth syndrome has been predominantly diagnosed in males (as of July 2009: 120+ males[12]), although by 2012 a female case had been reported.[19]

The syndrome is believed to be severely under-reported due to the complexity of (early) diagnosis.[20] Reports on its incidence and prevalence in the international literature vary; around 1 in every 454,000 individuals are thought to suffer from Barth Syndrome. Incidence has been estimated at anywhere between 1:140,000 (South West England, South Wales) and 1:300,000 - 1:400,000 live births (United States).[citation needed] Geographical distribution is homogenous, with patients (and their family members) on every continent (with known cases in, for example, the US, Canada, Europe, Japan, South Africa, Kuwait, and Australia).[citation needed]


The syndrome was named for Dr. Peter Barth (b. 1932), a Dutch pediatric neurologist, for his research into and the discovery of the syndrome in 1983.[6] He described a pedigree chart, showing that this is an inherited trait and not a 'communicated' (i.e. infectious) disease.[citation needed]

See also


  1. 1.0 1.1 1.2 1.3 1.4 "Barth syndrome: MedlinePlus Genetics". 
  2. "Orphanet: Barth syndrome". 
  3. "The cardiolipin transacylase, tafazzin, associates with two distinct respiratory components providing insight into Barth syndrome". Mol. Biol. Cell 19 (12): 5143–55. December 2008. doi:10.1091/mbc.E08-09-0896. PMID 18799610. 
  4. 4.0 4.1 "Cardiac and clinical phenotype in Barth syndrome". Pediatrics 118 (2): e337–46. August 2006. doi:10.1542/peds.2005-2667. PMID 16847078. 
  5. 5.0 5.1 5.2 5.3 "X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria". The Journal of Pediatrics 119 (5): 738–47. November 1991. doi:10.1016/S0022-3476(05)80289-6. PMID 1719174. 
  6. 6.0 6.1 "An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes". Journal of the Neurological Sciences 62 (1–3): 327–55. December 1983. doi:10.1016/0022-510X(83)90209-5. PMID 6142097. 
  7. 7.0 7.1 "Phospholipid abnormalities in children with Barth syndrome". Journal of the American College of Cardiology 42 (11): 1994–9. December 2003. doi:10.1016/j.jacc.2003.06.015. PMID 14662265. 
  8. 8.0 8.1 "Defective remodeling of cardiolipin and phosphatidylglycerol in Barth syndrome". Biochemical and Biophysical Research Communications 279 (2): 378–82. December 2000. doi:10.1006/bbrc.2000.3952. PMID 11118295. 
  9. "Barth syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth". Prenat. Diagn. 30 (10): 970–6. October 2010. doi:10.1002/pd.2599. PMID 20812380. 
  10. 10.0 10.1 Kelley RI, [cited 6 Dec 2011]. "Barth Syndrome - X-linked Cardiomyopathy and Neutropenia". Department of Pediatrics, Johns Hopkins Medical Institutions. Available from: "Barth Syndrome - X-linked Cardiomyopathy and Neutropenia". 
  11. Barth Syndrome Foundation, 28 Jun 2011. "Diagnosis of Barth Syndrome". Available from: "Barth Syndrome Foundation : Home". 
  12. 12.0 12.1 "Barth Syndrome Foundation : Home". 
  13. "Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome". Clinical Chemistry 54 (2): 371–8. February 2008. doi:10.1373/clinchem.2007.095711. PMID 18070816. 
  14. "Role of calcium-independent phospholipase A2 in the pathogenesis of Barth syndrome". Proc. Natl. Acad. Sci. U.S.A. 106 (7): 2337–41. February 2009. doi:10.1073/pnas.0811224106. PMID 19164547. Bibcode2009PNAS..106.2337M. 
  15. "A novel X-linked gene, G4.5. is responsible for Barth syndrome". Nature Genetics 12 (4): 385–9. April 1996. doi:10.1038/ng0496-385. PMID 8630491. 
  16. Ferreira, Carlos; Pierre, Germaine; Thompson, Reid; Vernon, Hilary (July 9, 2020). "Barth Syndrome". University of Washington, Seattle. 
  17. Suzuki-Hatano, Silveli; Saha, Madhurima; Rizzo, Skylar A.; Witko, Rachael L.; Gosiker, Bennett J.; Ramanathan, Manashwi; Soustek, Meghan S.; Jones, Michael D. et al. (2018-08-02). "AAV-Mediated TAZ Gene Replacement Restores Mitochondrial and Cardioskeletal Function in Barth Syndrome" (in en). Human Gene Therapy 30 (2): 139–154. doi:10.1089/hum.2018.020. ISSN 1043-0342. PMID 30070157. 
  18. "Gene therapy for heart, skeletal muscle disorder shows promise in preclinical model | UF Health, University of Florida Health". 13 December 2018. 
  19. "Barth syndrome in a female patient". Mol Genet Metab 106 (1): 115–20. May 2012. doi:10.1016/j.ymgme.2012.01.015. PMID 22410210. 
  20. "Genetic analysis of the G4.5 gene in families with suspected Barth syndrome". The Journal of Pediatrics 135 (3): 311–5. September 1999. doi:10.1016/S0022-3476(99)70126-5. PMID 10484795. 

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