Published online July 17, 2006
PEDIATRICS Vol. 118 No. 2 August 2006, pp. e337-e346 (doi:10.1542/peds.2005-2667)
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ARTICLE

Cardiac and Clinical Phenotype in Barth Syndrome

Carolyn T. Spencer, MDa, Randall M. Bryant, MDb, Jane Day, PT, PhDc, Iris L. Gonzalez, PhDd, Steven D. Colan, MDe, W. Reid Thompson, MDf, Julie Berthy, ARNPa, Sharon P. Redfearn, MSN, ARNPb and Barry J. Byrne, MD, PhDa

a Congenital Heart Center, College of Medicine
c Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida
b Health Science Center Jacksonville, Jacksonville, Florida
d Nemours Biomedical Research, Alfred I. DuPont Hospital for Children, Wilmington, Delaware
e Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts
f Division of Pediatric Cardiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland

OBJECTIVE. Barth syndrome, an X-linked disorder that is characterized by cardiomyopathy, neutropenia, skeletal myopathy, and growth delay, is caused by mutations in the taffazin gene at Xq28 that result in cardiolipin deficiency and abnormal mitochondria. The clinical phenotype in Barth syndrome has not been characterized systematically, and the condition may be underrecognized. We sought to evaluate extent of cardioskeletal myopathy, potential for arrhythmia, delays in growth, and biochemical correlates of disease severity in patients with this disorder.

METHODS. We conducted an observational, cross-sectional study of the largest cohort of patients with Barth syndrome to date (n = 34; age range: 1.2–22.6 years). Evaluation included echocardiography, electrocardiography (standard and signal-averaged), microvolt T wave alternans analysis, biochemical and hematologic laboratory analyses, and physical therapy evaluation of skeletal myopathy.

RESULTS. Family history was positive for confirmed or suspected Barth syndrome in 63%. Ninety percent of patients had a clinical history of cardiomyopathy (mean age at diagnosis of cardiomyopathy: 5.5 months; at genetic confirmation of Barth syndrome: 4.6 years). Echocardiography revealed a mean ejection fraction of 50% ± 10%, mean fractional shortening of 28% ± 5%, and mean left ventricular end-diastolic volume z score of 1.9 ± 1.8. Left ventricular morphology demonstrated increased trabeculations or true noncompaction in 53%. Of 16 patients who were evaluated at ≥11 years of age, 7 (43%) had documented ventricular arrhythmia. Growth deficiency was present (mean weight percentile: 15%; mean height percentile: 8%). Laboratory analysis revealed low total white blood cell count (absolute count: <4000 cells per µL) in 25% of those who were not on granulocyte colony-stimulating factor. Hypocholesterolemia was present in 24%, decreased low-density lipoprotein cholesterol in 56%, low prealbumin in 79%, and mildly elevated creatine kinase in 15%.

CONCLUSIONS. Our cohort demonstrated clinical variability, but most had cardiomyopathy and diminished growth velocity, with a propensity toward neutropenia and low cholesterol. There was increased incidence of ventricular arrhythmia, predominantly in adolescents and young adults. Barth syndrome should be considered when boys present with cardiomyopathy, especially when associated with increased left ventricular trabeculations, neutropenia, skeletal muscle weakness, or family history indicating an X-linked pattern of inheritance.

Key Words: Barth syndrome • cardiomyopathy • neutropenia

Abbreviations: BTHS—Barth syndrome • TAZ—taffazin gene • LV—left ventricular • VA—ventricular arrhythmia • ECG—electrocardiography • SA-ECG—signal-averaged ECG • TWA—microvolt T wave alternans • PCR—polymerase chain reaction • EF—ejection fraction • LVIDd—LV internal diastolic dimension • LVNC—left ventricle noncompaction • DCM—dilated cardiomyopathy • QTc—corrected QT interval • bpm—beats per minute • LDL—low-density lipoprotein • CK—creatine kinase • CK-MB—creatine kinase myocardial band • BNP—brain natriuretic peptide • GCSF—granulocyte colony-stimulating factor • SF—shortening fraction • ICD—implantable cardioverter defibrillator • WBC—white blood cell

Accepted Mar 2, 2006.




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