Barth syndrome

Abstract

Barth syndrome (BTHS) is an X-linked recessive disorder that is typically characterized by cardiomyopathy (CMP), skeletal myopathy, growth retardation, neutropenia, and increased urinary levels of 3-methylglutaconic acid (3-MGCA). There may be a wide variability of phenotypes amongst BTHS patients with some exhibiting some or all of these findings. BTHS was first described as a disease of the mitochondria resulting in neutropenia as well as skeletal and cardiac myopathies. Over the past few years, a greater understanding of BTHS has developed related to the underlying genetic mechanisms responsible for the disease. Mutations in the TAZ gene on chromosome Xq28, also known as G4.5, are responsible for the BTHS phenotype resulting in a loss-of-function in the protein product tafazzin. Clinical management of BTHS has also seen improvement. Patients with neutropenia are susceptible to life-threatening bacterial infections with sepsis being a significant concern for possible morbidity and mortality. Increasingly, BTHS patients are suffering from heart failure secondary to their CMP. Left ventricular noncompaction (LVNC) and dilated CMP are the most common cardiac phenotypes reported and can lead to symptoms of heart failure as well as ventricular arrhythmias. Expanded treatment options for end-stage myocardial dysfunction now offer an opportunity to change the natural history for these patients. Herein, we will provide a current review of the genetic and molecular basis of BTHS, the clinical features and management of BTHS, and potential future directions for therapeutic strategies.

Keywords: Barth syndrome; cardiomyopathy; genetics; heart failure.

Figure 1

During its biosynthesis, cardiolipins are made as immature forms with different non-symetric acyl groups. During remodeling, these different acyl groups are replaced with lynoleic acids and 80% of CL in cardiac and muscle cells is symmetric L4CL. In contrast, brain has very large diversity of CL molecular forms. Mutations in the TAZ gene cause BTHS. BTHS patients have deficiency of mature L4CLs and accumulation of immature CLs and lysocardiolipins, or CLs missing one or two acyl groups. (Image generously supplied by Zaza Khuchua, Division of Molecular and Cardiovascular Biology, Cincinnati Children’s Research Foundation, Cincinnati, OH.)

Figure 2

Echocardiogram (apical 4-chamber view) of patient with BTHS depicting LVNC with associated DCM phenotype. Note the deep LV trabeculations and dilated left ventricular chamber.