Cardiac Pathology in Glycogen Storage Disease Type III.

PURPOSE: To investigate the distribution and clinical impact of glycogen accumulation on heart structure and function in individuals with GSD III. METHODS: We examined cardiac tissue and the clinical records of three individuals with GSD IIIa who died or underwent cardiac transplantation. Of the two patients that died, one was from infection and the other was from sudden cardiac death. The third patient required cardiac transplantation for end-stage heart failure with severe hypertrophic cardiomyopathy. RESULTS: Macro- and microscopic examination revealed cardiac fibrosis (n = 1), moderate to severe vacuolation of cardiac myocytes (n = 3), mild to severe glycogen accumulation in the atrioventricular (AV) node (n = 3), and glycogen accumulation in smooth muscle cells of intramyocardial arteries associated with smooth muscle hyperplasia and profoundly thickened vascular walls (n = 1). CONCLUSION: Our findings document diffuse though variable involvement of cardiac structures in GSD III patients. Furthermore, our results also show a potential for serious arrhythmia and symptomatic heart failure in some GSD III patients, and this should be considered when managing this patient population.

Ventricular arrhythmia in the X-linked cardiomyopathy Barth syndrome.

Barth syndrome is an X-linked disorder characterized by dilated cardiomyopathy, cyclic neutropenia, skeletal myopathy, abnormal mitochondria, and growth deficiency. The primary defect is a mutation in the TAZ gene on the X chromosome at Xq28, resulting in abnormal phospholipid biosynthesis and cardiolipin deficiency. To date, there has been no systematic evaluation of the cardiac phenotype. We report five cases of cardiac arrest and/or placement of an internal cardiac defibrillator with documented ventricular arrhythmia. We suggest that ventricular arrhythmia is part of the primary phenotype of the disorder and that patients should be screened accordingly.

Complex modular cis-acting elements regulate expression of the cardiac specifying homeobox gene Csx/Nkx2.5.

The murine homeobox gene Csx/Nkx2.5 is an evolutionarily highly conserved gene related to the Drosophila tinman gene, which specifies cardiac and visceral mesoderm. Since Csx/Nkx2.5 plays an essential role in heart development, studying its regulation is essential for the better understanding of molecular mechanisms of cardiogenesis and the pathogenesis of congenital heart disease in humans. In this study, we characterized the murine Csx/Nkx2.5 gene and identified two novel untranslated exons, 1a, and 1b, resulting in three different Csx/Nkx2.5 transcripts. To examine the tissue-specific transcriptional regulation in vivo, we analyzed a total of 23 kb of Csx/Nkx2.5 upstream and downstream sequences by generating transgenic embryos carrying lacZ reporter constructs containing various lengths of flanking sequence. With 14 kb of 5' flanking sequence, lacZ expression was observed in the cardiac crescent at E7.5, and in the outflow tract, the interatrial groove, the atrioventricular canal and right and left ventricles, as well as in pharyngeal floor, thyroid primordia, and stomach at E10.5. In adult animals, lacZ expression of the transgene was limited to the atrioventricular junction and the subendocardium of the ventricular septum. Reducing the size of flanking sequence to 3.3 kb of intron 2 restricted lacZ expression to the outflow tract and the basal part of the right ventricle in E10.5 embryos. In contrast, the addition of 6 kb of 3' flanking sequence caused strong expression of the reporter gene in the entire right ventricle. Interestingly, Csx/Nkx2. 5 seems to be negatively regulated by its own gene product, because when lacZ was "knocked-in" to replace the entire coding exons, lacZ expression was much higher in the heart of homozygous embryos than that in the heterozygote. These results indicate that the transcriptional regulatory elements of Csx/Nkx 2.5 seems unexpectedly highly modular, and is temporally regulated in a dynamic manner by different enhancer regions. Since Csx/Nkx2.5-like genes are expressed in all species having a heart, their complex modular organization with multiple enhancers probably reflects progressive addition of regulatory elements during the evolution from a simple heart tube to a complex four-chambered organ.

Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx.

BACKGROUND: Csx/Nkx2.5, a murine nonclustered homeobox gene expressed primarily in the heart, has significant sequence similarity to the Drosophila tinman gene. Tinman is essential for heart and gut formation in Drosophila. Targeted mutation in the mouse gene, Csx/Nkx2.5, arrests cardiac development during early embryonic stages, suggesting an evolutionary conservation in cardiogenesis. MATERIALS AND METHODS: We have isolated and characterized a human homolog, hCsx, from an adult cardiac cDNA library. Northern blotting and ribonuclease protection was used to define the pattern of expression during normal development and in disease states. Chromosomal localization of the gene was determined by somatic cell hybrid analysis and fluorescent in situ hybridization. RESULTS: The predicted amino acid sequence of hCsx has 87% overall homology to the murine gene with 100% identity in the homeodomain. The homeodomain sequence of hCsx is 95% identical to its Xenopus homolog, and 65% to tinman. hCsx mRNA was detected exclusively in the heart. hCsx transcript was detected at 12 weeks in human embryonic heart, the earliest time point examined, and was up-regulated 5-fold between 12 and 19 weeks. There was no significant alteration of hCsx message level in the myocardium of 14 patients with end stage heart failure compared to a normal control. The human gene mapped to the distal portion of chromosome 5, the 5q34-q35 region. This defines a new synteny region between human chromosome 5q and the t-locus of mouse chromosome 17, where the mouse Csx gene is located. CONCLUSIONS: hCsx, the human homolog of Drosophila tinman, is expressed in heart in a tissue restricted manner. Distal 5q trisomies produce several phenotypic abnormalities, including a high incidence of congenital heart disease. Isolation of the hCsx gene will allow further studies of mutations in this gene and their potential associations with some forms of congenital heart disease in humans.