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Description of an Intermediate Form of Barth Syndrome

Males with Barth Syndrome usually have low levels of a phospholipid chemical called cardiolipin in the membranes of their mitochondria. The NHS Barth Syndrome Service have identified males from 3 separate families who have higher cardiolipin levels than most boys or men with the disease. In several cases this had caused the diagnosis to be missed on initial biochemical testing. Males with this form of the disease on average appear to be more mildly affected than the average person with Barth Syndrome. A paper describing this finding can be accessed here. We are grateful to the Barth Syndrome Foundation (USA) and Barth Syndrome Trust (UK) for sponsoring open access of this publication.

Detailed Review Article on Barth Syndrome

Clinicians and parents from the NHS Barth Syndrome Service, the Barth Syndrome Clinic at the Kennedy Krieger Institute, Johns Hopkins Hospital, Baltimore, the Barth Syndrome Trust (UK) and the Barth Syndrome Foundation (USA) have put together a comprehensive review on Barth Syndrome which is available as a free download from the Orphanet Journal of Rare Diseases. This can be accessed by anyone by clicking here

Reports about a boy with Barth Syndrome who underwent successful heart transplantation

These links, from UK broadcasters and the national press from April 2012, tell the heartwarming story of a boy with Barth Syndrome who received a successful cardiac transplant following a record 251 days on artificial support with a "Berlin ventricular assist device". Approximately 15% of patients with the disease worldwide have required cardiac transplantation and there are many long-term survivors.


Barth Syndrome as a cause of stillbirth and miscarriage

Barth Syndrome: an X-linked cause of fetal cardiomyopathy and stillbirth

Steward CG, Newbury-Ecob RA, Hastings R, Smithson SF, Tsai-Goodman B, Quarrell OW, Kulik W, Wanders R, Pennock M, Williams M, Cresswell JL, Gonzalez IL, Brennan P. Prenatal Diagnosis Oct;30(10):970-6.


OBJECTIVE:  Barth Syndrome (BTHS) is an X-linked multisystem disorder (OMIM 302060) usually diagnosed in infancy and characterized by cardiac problems [dilated cardiomyopathy (DCM) ± endocardial fibroelastosis (EFE) ± left ventricular non-compaction (LVNC)], proximal myopathy, feeding problems, growth retardation, neutropenia, organic aciduria and variable respiratory chain abnormalities. We wished to determine whether BTHS had a significant impact on fetal and perinatal health in a large cohort of family groups originating from a defined region.

METHOD:  Case note review on 19 families originating from the UK and known to the Barth Syndrome Service of the Bristol Royal Hospital for Children.

RESULTS:  Details are presented on six kindreds (32%) with genetically and biochemically proven BTHS that demonstrate a wider phenotype including male fetal loss, stillbirth and severe neonatal illness or death. In these families, 9 males were stillborn and 14 died as neonates or infants but there were no losses of females. BTHS was definitively proven in five males with fetal onset of DCM ± hydrops/EFE/LVNC.

CONCLUSION:  These findings stress the importance of considering BTHS in the differential diagnosis of unexplained male hydrops, DCM, EFE, LVNC or pregnancy loss, as well as in neonates with hypoglycemia, lactic acidosis and idiopathic mitochondrial disease.

The full text of this article is available here to anyone with computer access, kindly funded by the Barth Syndrome Foundation (USA) and Barth Syndrome Trust (UK).  


Description of the typical facial appearance of boys with Barth Syndrome

Dysmorphology of Barth syndrome

Hastings R, Steward CG, Tsai-Goodman B, Newbury-Ecob R. Clinical Dysmorphology 2009 Oct;18(4):185-7.

This paper describes the typical facial appearance of boys with Barth Syndrome, including deep-set eyes, chubby cheeks and prominent ears. 


Development of reliable testing for Barth Syndrome

Diagnosis of Barth syndrome using a novel LC-MS/MS method for leukocyte cardiolipin analysis

Bowron A, Frost R, Powers VE, Thomas PH, Heales SJ, Steward CG. J Inherit Metab Dis. 2013 Sep;36(5):741-6.

This paper describes a novel method used for cardiolipin analysis (BTHS) by reversed-phase ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), which is less complicated and faster than previously described methods. This can therefore be incorporated into the routine work of a clinical biochemistry laboratory. It shows 100 % sensitivity and specificity for BTHS, making it a suitable diagnostic test.

Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes and tissues using HPLC-mass spectrometry as a diagnostic test for Barth Syndrome.

Houtkooper RH, Rodenburg RJ, Thiels C, van Lenthe H, Stet F, Poll-The BT, Stone JE, Steward CG, Wanders RJ, Smeitink J, Kulik W, Vaz FM. Analytical Biochemistry 2009 Apr 15;387(2):230-7.

This paper describes development of a validated laboratory test for Barth Syndrome, based on high-performance liquid chromatography-mass spectrometry (HPLC-MS). The method was used to test cultured skin cells (fibroblasts), lymphocytes, and skeletal muscle, looking at levels of the phospholipids cardiolipin and monolysocardiolipin, as well as the monolysocardiolipin/cardiolipin ratio. This study also involved retrospective analysis of 121 muscle samples from patients who were thought to have mitochondrial myopathies and one patient was identified with cardiolipin abnormalities similar to Barth Syndrome patients. Genetic analysis of this patient subsequently showed a disease-causing mutation of the TAZ gene. This shows the importance of considering Barth Syndrome in the differential diagnosis of patients with mitochondrial myopathy of unknown cause.

Bloodspot assay using HPLC-tandem mass spectrometry for detection of Barth syndrome

Kulik W, van Lenthe H, Stet FS, Houtkooper RH, Kemp H, Stone JE, Steward CG, Wanders RJ, Vaz FM. Clinical Chemistry 2008 Feb;54(2):371-8.

This paper describes analysis of the ratio of monolysocardiolipin to cardiolipin in dried bloodspots from Guthrie cards from known Barth patients and normal controls. 31 patients with Barth Syndrome and 215 normals were examined. None of the controls had abnormal ratios and the sensitivity and specificity of the test was 100%. It was shown that bloodspots could be stored at 4°C or room temperature for longer than one year without affecting test outcome. Furthermore, three Guthrie cards from Barth Syndrome patients taken 3.6 to 5.8 years earlier when they were neonates were correctly identified as having Barth Syndrome. This shows the potential for rapid screening of neonatal bloodspots to exclude the disease.


The first paper describing under-diagnosis of Barth syndrome and development of genetic testing in Bristol

Genetic analysis of the G4 .5 gene in families with suspected Barth Syndrome

Cantlay AM, Shokrollahi K, Allen JT, Lunt PW, Newbury-Ecob RA, Steward CG. Journal of Pediatrics 1999;135(3):311-5

This paper describes the finding of mutations of the tafazzin (TAZ) gene in boys from five unrelated families from South-West England and South Wales. In four of these families a male child had all of the major features of Barth Syndrome. A mutation was also found in a fifth family with an extensive history of early death from heart disease. It was suggested that the finding of five unrelated families in one single regional hospital during a seven-year period indicated that Barth Syndrome might be significantly under-diagnosed.  


Development of lymphoma following cardiac transplantation for Barth Syndrome

Non-Epstein-Barr virus associated T-cell lymphoma following cardiac transplantation for Barth Syndrome 

Ronghe MD, Foot AB, Martin R, Ashworth M, Steward CG. Acta Paediatrica 2001 May;90(5):584-6.

Non-Hodgkin lymphoma (NHL) can develop in some boys in the years following cardiac transplantation. It is usually caused by glandular fever virus (Epstein-Barr virus, EBV) causing excessive growth of B-lymphocytes in the patient's body (due to the immune suppressive drugs required to stop rejection of the transplanted heart hampering the body's natural defences against EBV). These tumours are collectively called "Post-Transplant Lymphoproliferative Disease" (PTLD). This paper, however, describes the development of a much more unusual lymphoma five years after successful cardiac transplantation. The tumour was a T-cell Non-Hodgkin's lymphoma and EBV virus could not be detected. The patient was very intolerant of chemotherapy and died soon after commencing treatment.

NHS Specialised Services website 

The Contact a Family site

Orphanet Description of Barth Syndrome