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.
