Barth syndrome in a female patient

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Abstract

Background

Barth syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy, skeletal myopathy and cyclic neutropenia in male patients. It is caused by mutations in the TAZ gene coding for the tafazzin, a protein involved in the remodeling of cardiolipin. Loss of cardiolipin in the inner mitochondrial membrane results in respiratory chain dysfunction. No specific symptom has been identified in female carriers.

Case report

We report the first case of BTHS confirmed by TAZ gene analysis in a female patient. This girl experienced severe heart failure at 1-month of age. Echocardiography diagnosed dilated-hypokinetic and hypertrophic cardiomyopathy with noncompaction of the left ventricle. Initial metabolic screening was normal, except for a cyclic neutropenia. Respiratory chain analysis performed on skin fibroblasts revealed a decreased activity of complexes I, III and IV. Screening on a bloodspot showed abnormal monolysocardiolipin:cardiolipin ratio, later confirmed on cultured fibroblasts, indicative of BTHS. Genetic analyses finally confirmed the diagnosis of BTHS, by showing a large intragenic deletion of exons 1 through 5 in the TAZ gene. Cytogenetic analysis showed mosaicism for monosomy X and for a ring X chromosome with a large deletion of the long arm including the Xq28 region. The girl presented recurrent episodes of severe acute heart failure, progressive muscle weakness, and had a fatal septic shock at 3 years.

Conclusion

This case highlights that the diagnosis of BTHS should also be suspected in female patients presenting a phenotype similar to affected boys. In these cases, analysis of the monolysocardiolipin:cardiolipin ratio in bloodspots is a rapid and sensitive screening tool for BTHS. However clinical expression in a carrier female requires hemizygosity for the mutated allele of the TAZ gene, which supposes a rearrangement of the TAZ gene region on the other X chromosome.

Highlights

► First case of Barth syndrome in a female patient with mosaic ring X.

Introduction

Barth syndrome (BTHS, MIM#302060) is an X-linked recessive disorder firstly described in 1983 and characterized by cardiomyopathy, skeletal myopathy, neutropenia, growth delay, increased urinary excretion of 3-methylglutaconic acid and respiratory chain dysfunction in male patients [[1], [2], [3]]. It is caused by mutations in the TAZ gene, located at Xq28 and coding for tafazzin, a protein involved in the remodeling of cardiolipin [[4], [5], [6], [7], [8]]. Until now, more than 150 mutations in the TAZ gene have been identified, mainly point mutations. Loss of cardiolipin in the inner mitochondrial membrane results in respiratory chain dysfunction, most specifically of complexes I, III and IV [2], [7], [9]. Recently, a mouse model of human BTHS confirmed the pathophysiological relationship between altered mitochondrial phospholipids, myocardial and mitochondrial dysfunction and the clinical outcome [10]. Male patients present cardiomyopathy, mainly of the dilated type, during the first year of life, associated with cardiac arrhythmias or abnormal electrocardiogram patterns for most of them [2], [3]. Growth deficiency, muscle weakness and increased exertional fatigue are also reported later in the clinical course. Neutropenia and low levels of plasma cholesterol have been noted in some patients. Survival rate indicates high mortality in infancy and childhood, even if early diagnosis and rigorous treatment of infections and cardiomyopathy may have contributed to improve the prognosis [2]. In contrast, no specific symptom has been identified in female carriers. We report the case of a girl with a severe clinical phenotype compatible with the diagnosis of BTHS, further confirmed by TAZ gene analysis.

Section snippets

Patient

This girl, first child of unrelated healthy parents with no family history, was born at full term after uneventful pregnancy and delivery, except for intrauterine growth retardation (birth weight 2530 g, height 46 cm, and head circumference 32 cm, all below the third percentile). During the first weeks of life, she had feeding difficulties associated with a progressive polypnea. At one month of age, she was admitted to intensive care unit for severe acute heart failure. Physical examination

Discussion

BTHS is an X-linked recessive disorder caused by mutations in the TAZ gene, located at Xq28, and coding for tafazzin, a protein involved in the remodeling of cardiolipin. BTHS affects male patients, whereas female carriers are usually non-symptomatic [2], [3]. We report the first case of a girl with a severe clinical phenotype in keeping with the diagnosis of BTHS, further confirmed by TAZ gene analysis.

This girl presented many similarities with the clinical and biochemical features of BTHS

Acknowledgments

We are grateful to Philippe Reuge and Wolfgang Berger (Institute of Medical Genetics, University Hospital, Zurich, Switzerland) for their contribution to the molecular analysis of the TAZ gene.

References (21)

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