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Barth syndrome

Sarah LN Clarke1, Ann Bowron2, Iris L Gonzalez3, Sarah J Groves4, Ruth Newbury-Ecob2, Nicol Clayton2, Robin P Martin2, Beverly Tsai-Goodman2, Vanessa Garratt2, Michael Ashworth5, Valerie M Bowen6, Katherine R McCurdy6, Michaela K Damin7, Carolyn T Spencer8, Matthew J Toth6, Richard I Kelley109 and Colin G Steward1124*

Author Affiliations

1 Department of Paediatrics, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, UK

2 NHS Specialised Services Barth Syndrome Service, Royal Hospital for Children, Upper Maudlin St, Bristol, BS2 8BJ, UK

3 Molecular Diagnostics Laboratory, Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, Delaware, 19899, USA

4 School of Cellular & Molecular Medicine, Faculty of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK

5 Department of Histopathology, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK

6 Barth Syndrome Foundation, Inc., P.O. Box 618, Larchmont, NY, 10538, USA

7 Barth Syndrome Trust, 1, The Vikings, Romsey, SO51 5RG, UK

8 Dept of Pediatrics, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA

9 Department of Pediatrics, John Hopkins University School of Medicine, Baltimore, MD, USA

10 Department of Metabolism, Kennedy Krieger Institute, Baltimore, MD, USA

11 Oncology Day Beds, Royal Hospital for Children, Upper Maudlin St., Bristol, BS2 8BJ, UK

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Orphanet Journal of Rare Diseases 2013, 8:23  doi:10.1186/1750-1172-8-23

Published: 12 February 2013

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.

Keywords:
Barth syndrome; 3-methylglutaconic aciduria; Dilated cardiomyopathy; Stillbirth; Growth delay; Endocardial fibroelastosis; Left ventricular non-compaction; Arrhythmia; Myopathy; Neutropenia