The Barth Syndrome Service at Bristol Royal Hospital for Children is a multidisciplinary service for the management of this complex multisystem disease and the first of its type in the World.

A clinic for males affected by Barth Syndrome had been run informally in Bristol since 2004 in conjunction with the Barth Syndrome Trust. Since April 2010 NHS Specialised Services have provided funding for a full multidisciplinary service for patients from throughout the UK. This involves input from Consultants in all of the relevant areas of paediatrics - genetics, cardiology, haematology, metabolic medicine, neurology, gastroenterology and endocrinology - together with Clinical Nurse Specialist (CNS), dietetic, psychology, physiotherapy and occupational therapy care.

Boys at Barth Syndrome Clinic Central to the service is the opportunity to attend a multidisciplinary clinic at a frequency determined by clinical needs. The aim of the service is to minimise the number of hospital visits which boys require as well as providing expert care for a disease with many unique features. Clinics are run on a six monthly basis, with patients seen at other times where necessary.

Diagnostic biochemical and genetic testing for the disease is provided free of charge to referring UK doctors.

Dr Peter Barth first described the disease which carries his name in 1983. A detailed review of our modern understanding of the disease was compiled by the Bristol team in 2013 in conjunction with experts in the disease from the USA and members of the Barth Syndrome Trust and Barth Syndrome Foundation (USA). This is freely available to all by clicking on this link.

Dr Barth described a disease which affected only males (X-linked genetic inheritance) which was inherited through the female line of the family and could therefore affect males in multiple generations.

This disease is characterised by:

cardiomyopathy (heart failure), commonly starting at birth or during infancy
skeletal myopathy (muscle weakness and fatigue)
failure to thrive and
neutropaenia (low white blood cells)

Excessive excretion of organic acid in the urine, particularly of 3-methylglutaconic acid (3-MGC), was subsequently recognised. Testing for 3-MGC was used as the major biochemical test for the disease until recent years, although this test is unreliable and has now been superseded.

We now realise, however, that there are many additional features to Barth Syndrome and that these vary greatly from boy to boy, or even during the life of a particular person.

Some patients will have all features but others just one or a few. This makes the disease both difficult to diagnose and easy to miss.

This is a list of the major disease features and links for more information.

Cardiomyopathy: dilated cardiomyopathy (DCM) (and sometimes hypertrophic cardiomyopathy [HOCM]), congestive cardiac failure, left ventricular noncompaction (LVNC), endocardial fibroelastosis (EFE), ventricular arrhythmias (ventricular tachycardia or ventricular fibrillation), fetal cardiomyopathy, neonatal cardiomyopathy
Delayed motor milestones and myopathy: especially proximal myopathy (muscle weakness) affecting the muscles of the upper legs, waddling gait
Exercise intolerance: difficulties in running or playing sport
Hypoglycaemia (low blood sugar) and /or lactic acidosis: particularly in babies and infants
Neutropenia: low numbers of the white cells which fight bacterial and fungal infections): the neutropaenia may be chronic, cyclical or intermittent, mild to severe, and may not be present at all in some boys.
Mouth ulcers and infections: including septicaemia due to neutropaenia
Growth delay: during childhood, often rapid growth late in adolescence
Fetal cardiomyopathy, hydrops, miscarriage and stillbirth causing late loss of male fetuses; there may also be a history of fetal loss in other relatives on the female side of the family
Feeding problems: often requiring nasogastric tube feeding or gastrostomy feeding; savoury food fads
Episodic diarrhoea: diarrhoea is a common problem; often no infectious cause can be found
Characteristic facial appearance: prominent ears, deep-set eyes
Underdiagnosis: experience from the UK suggests that the disease is underdiagnosed, principally due to the immense variability of symptoms

The Bristol Barth Syndrome Service team is able to offer children with Barth Syndrome, and their families, the opportunity to come to an annual clinic. At this they will be able to meet healthcare professionals who specialise in the disease, as well as meeting with other families. Patients come from across the UK and Europe.

Barth Syndrome Clinic activities

Each family are offered an appointment with each of the specialists in the team. The professionals see patients and offer any advice and support around issues and questions that families may have.

These range from wanting to know about whether to give amino acid supplements, through giving G-CSF with the least amount of stress, to how they can help their child cope with peer pressure.

Feedback from patients and families is used by the medical professionals and Barth Syndrome Trust to constantly improve the clinic experience. Comments received following recent clinics are given here.

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.

http://www.itv.com/news/2012-04-10/toddlers-record-time-with-artificial-heart/

http://www.itn.co.uk/home/42936/Little+Joe27s+heart+transplant

http://www.bbc.co.uk/news/health-17663497

http://www.telegraph.co.uk/health/healthnews/9195667/Three-year-old-survives-251-days-with-artificial-heart.html

http://www.dailymail.co.uk/health/article-2127761/Boy-3-fighting-fit-kept-alive-record-251-days-artificial-heart.html

http://www.mirror.co.uk/news/uk-news/toddler-kept-alive-for-251-days-786531

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.

Abstract

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

Posters on Barth Syndrome

These posters have been developed to raise targeted awareness of Barth Syndrome amongst medical professionals and relevant interested groups. They highlight common presenting symptoms within each area and give details of how to access advice and testing.

We are very grateful to the boys who have kindly given permission for their photographs to be published. In order to download a poster for use, please click on the picture of the relevant poster.

If you have any suggestions for improvement or for other specialised areas where teaching material would be of value, please contact the team through one of the addresses listed here.

For GENETICS teams

For PATHOLOGY teams

For CARDIOLOGY teams

Information on Testing for Barth Syndrome

Testing for Barth syndrome in the past has so far mostly been restricted to boys with dilated cardiomyopathy (DCM) AND neutropenia AND excessive amounts of 3-methylglutaconic acid in their urine. However, it is increasingly clear that the disease can behave very differently between affected males. As just two examples: 10% of boys do NOT have low blood neutrophil counts and it is well recognised that the level of 3-methylglutaconic acid can sometimes be normal in urine.

Previously, definitive testing for Barth Syndrome relied on sequencing of the responsible TAZ gene, but this is expensive and time-consuming. A more practical approach to testing is now possible since the development of a biochemical "cardiolipin test" which can be performed very reliably on only a small volume of blood. The test result is usually available within one to two weeks and this is a more straightforward test than DNA sequencing (although gene testing would usually still be performed as further confirmation in someone with a positive cardiolipin test). When done on blood samples sent by first class post, cardiolipin testing discriminates extremely well between normal boys and those with Barth Syndrome.

It has been estimated that between 3 and 5% of all young males with DCM may have Barth Syndrome as the cause of their heart failure. This percentage may be even higher in those who are in heart failure at birth or develop it within the first year of life. We therefore recommend routine cardiolipin testing in all young males with dilated cardiomyopathy (DCM). Cardiolipin testing should also be considered in male babies/boys with left ventricular noncompaction (LVNC), unexplained neutropenia (especially with poor growth, developmental delay or weak muscles and easy fatigue) and in families with a male pattern of hypertrophic cardiomyopathy (HCM) but where no genetic cause can be found and other features suggestive of Barth Syndrome are present.

Routine blood testing: Cardiolipin Analysis

Cardiolipin analysis is temporarily unavailable in the UK. The laboratory at Bristol Royal Infirmary continues however to facilitate testing for Barth syndrome by forwarding samples to the Academic Medical Centre (AMC) in Amsterdam for analysis. Analysis of samples sent via the Bristol laboratory to the AMC are free of charge.

Please take 1-3 ml of whole blood collected into a K-EDTA (full blood count) tube, Monday to Thursday only and send within 24 hours of collection by first class post to the:

Metabolic, Neuroendocrine and Nutrition Laboratory
Department of Clinical Biochemistry
Bristol Royal Infirmary
Bristol
BS2 8HW

Please label the box 'Urgent clinical sample - for immediate delivery to the Metabolic, Neuroendocrine and Nutrition Laboratory'.

Alternatively a blood spot can be sent directly to The Academic Medical Centre (AMC), Amsterdam (see https://www.amc.nl/web/Het-AMC/Afdelingen/Medische-afdelingen/Laboratory-Genetic-Metabolic-Diseases-1/Cardiolipins.htm).
Please note that samples sent directly to the AMC will incur a charge.

Post mortem testing

If a patient is suspected to have died as a result of Barth Syndrome, cardiolipin analysis can be performed in cultured fibroblasts (skin cells). If fibroblasts are unavailable, please contact Vicki Powers to discuss details on 0117 342 2590 or by email at: victoria.powers@UHBristol.nhs.uk

Genetic testing by TAZ Gene Sequencing

Further information on genetic testing in Bristol, and a proforma for referral of samples are given here.

Consultants

Professor Colin Steward
Telephone: 0117 342 8102 / 0117 342 8044

For urgent advice out of hours, Professor Steward can be contacted though Switchboard at Bristol Royal Infirmary on 0117 923 0000.

Dr Alison Hayes
Telephone: 0117 342 8848

Professor Ruth Newbury-Ecob
Telephone: 0117 342 5107

Multidisciplinary team

Members of the team can be contacted either via the telephone numbers or email addresses below or via the website of Patients Know Best (PKB). Access to this for those involved in a patient's care can be organised via Mrs Brenda Harding, Service Administrator.

Miss Hayley Smith / Mrs Christina Morris - Barth Syndrome Clinical Nurse Specialists
Telephone: 0117 342 1693 / 0117 342 8077
Email: Hayley.Smith@uhbristol.nhs.uk

Ms Vicki Powers - Principal Clinical Biochemist
Telephone: 0117 342 2590
Email: Victoria.Powers@uhbristol.nhs.uk

Mrs Brenda Harding - Administrator
Telephone: 0117 342 8102
Email: Rachel.Baker@uhbristol.nhs.uk

Dr Vanessa Garratt - Prinicipal Clinical Psychologist
Telephone: 0117 342 8163
Email: Vanessa.Garratt@uhbristol.nhs.uk

Mrs Nicol Clayton - Specialist Dietitian
Telephone: 0117 323 5428
Email: Nicol.Clayton@nbt.nhs.uk

Useful links

Barth Syndrome Trust (UK)

http://www.barthsyndrome.org.uk/

The Barth Syndrome Trust offers support to patients and their families, access to latest information from around the world, a regular newsletter and invitation to the international conference held every two years in the USA and organised by the Barth Syndrome Foundation (USA).

Barth Syndrome Foundation (USA)

http://www.barthsyndrome.org/

The Barth Syndrome Foundation (BSF) was the first charity established to help patients and families across the World affected by Barth Syndrome. Based in the USA, BSF organises an international conference, which acts as the major focal point for families. BSF and BST fund many research projects looking into the scientific basis and new treatments for the disease. Dr Steward is a member of the Scientific & Medical Advisory Board of BSF.

Cardiomyopathy Association

http://www.cardiomyopathy.org/

The Cardiomyopathy Association helps sufferers, their families, and their medical advisors to best manage the impact of cardiomyopathy.

Children's Heart Federation

http://www.childrens-heart-fed.org.uk/

CHF is a federation of support groups in the UK and Ireland for families with (or expecting) a child with a heart condition.

GUCH

http://www.guch.org.uk/

Grown Up Congenital Heart patients Association (GUCH) provide support for families and patients suffering from cardiomyopathy.

The Miscarriage Association

http://www.miscarriageassociation.org.uk/

The Miscarriage Association acknowledges the distress associated with pregnancy loss and strives to make a positive difference to those whom it affects.

SANDS

http://www.uk-sands.org/

SANDS is an organisation which can offer support to parents whose baby has died during pregnancy or after birth. Many of the staff of SANDS have been through this experience themselves, and are able to offer support and information.

We have a number of factsheets to help young people to understand more about Barth Syndrome. Please find links to these below. If you have any questions or want to know more about Barth Syndrome, please don't hesitate to give the team a call using the links on our Contacts tab.

Living with Barth Syndrome

Cardiomyopathy in Barth Syndrome

Neutropenia in Barth Syndrome

Genetics of Barth Syndrome

Healthy Eating for Teenagers with Barth Syndrome

Overview

The Barth Syndrome Service at Bristol Royal Hospital for Children is a multidisciplinary service for the management of this complex multisystem disease and the first of its type in the World.

Diagnostic biochemical and genetic testing for the disease is provided free of charge to referring UK doctors.