Cutaneous dyspigmentation in patients with ganglioside GM3 synthase deficiency.

Ganglioside GM3 synthase deficiency is a rare autosomal recessive metabolic disorder characterized by infantile onset of severe irritability and epilepsy, failure to thrive, developmental stagnation, and cortical blindness. Because of the lack of easily recognizable dysmorphism and specific neurologic manifestations, identification of patients with this condition is extremely challenging. Here we report on previously undescribed pigmentary abnormalities in 20 of 38 patients with GM3 synthase deficiency. All 20 of the patients showed freckle-like hyperpigmented macules, ranging in size from 2 to 5 mm in diameter and usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Seven of these patients also had depigmented macules and patches, especially on the face and extremities. These cutaneous changes were asymptomatic, and were not associated with the severity or particular phenotype of the neurologic disease. They became visible only after the first years of life with an increased incidence with advancing age. These distinct pigmentary features are not identified in 54 normal siblings, and may provide a useful clue in identifying patients with ganglioside metabolic disorders.

Use of three-dimensional catheter guidance and trans-esophageal echocardiography to eliminate fluoroscopy in catheter ablation of left-sided accessory pathways.

BACKGROUND: Newer technologies such as three-dimensional mapping and echocardiography can decrease x-ray exposure during catheter ablation. Many right-sided tachycardias can now be ablated without fluoroscopy. Left-sided tachycardias, however, have not yet been ablated using a zero fluoroscopy approach. OBJECTIVE: This study sought to examine the utility of trans-esophageal echocardiography (TEE) in providing adequate imaging as an alternative to fluoroscopy for transseptal puncture. When combined with NavX guidance (St. Jude Medical, St. Paul, MN, USA), fluoroscopy may not be necessary. METHODS: Ten pediatric patients with supraventricular tachycardia (SVT) had accessory pathways mapped to the left side. Right atrial and coronary sinus geometries were created using NavX. Once a left-sided pathway was confirmed, a transseptal puncture was performed. A guide wire was placed in the SVC and confirmed by TEE. A transseptal sheath and dilator were advanced over the wire and positioned with TEE guidance so that the tip of the dilator was tenting the fossa ovalis. A transseptal needle was advanced across the fossa. Left atrial location of the needle tip was confirmed on TEE by saline contrast injection. The sheath and dilator were advanced over the needle with continuous pressure monitoring and TEE. Once the sheath was appropriately positioned, the ablation was completed using NavX guidance. RESULTS: All patients had acutely successful ablations and none required the use of fluoroscopy. Number of cryo lesions ranged from five to 19, with a mean of 9. Mean procedure time was 4.4 hours, with a range of 3.2 hours to 7.2 hours. There were no complications. One patient had recurrence. CONCLUSIONS: Three-dimensional mapping combined with TEE shows potential for eliminating fluoroscopy use during catheter ablation.

Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant pattern and has a variable age of onset and prognosis. Mutations in the myosin-binding protein C (MYBPC3) gene are one of the most frequent genetic causes of the disease. Patients with MYBPC3 mutations generally have a late onset and a relatively good prognosis. We report here more than 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene. The affected children typically presented with signs and symptoms of congestive heart failure during the first 3 weeks of life. Echocardiography revealed hypertrophic non-obstructive cardiomyopathy. These children had a life span averaging 3-4 months. All patients died from heart failure before 1 year of age unless they received a heart transplant. A genome-wide mapping study was performed in three patients. The disease related gene was localized to a 4.6 Mb region on chromosome 11p11.2-p11.12. This homozygous block contained MYBPC3, a previously identified cardiomyopathy related gene. We identified a novel homozygous mutation, c.3330 + 2T > G, in the splice-donor site of MYBPC3 intron 30. The mutation resulted in skipping of the 140-bp exon 30, which led to a frame shift and premature stop codon in exon 31 (p.Asp1064GlyfsX38). We have found a substantial incidence of this phenotype in Old Order Amish communities. It is also concerning that many unidentified heterozygous individuals who are at risk for development of hypertrophic cardiomyopathy do not receive proper medical attention in the communities.

Early results of the Ross procedure in simple and complex left heart disease.

BACKGROUND: The Ross procedure has been used increasingly to treat aortic valve disease in children and young adults. Benefits include the lack of anticoagulation after surgery and the potential growth and durability of the autograft. The purpose of this study was to review our institutional experience with the Ross procedure and to compare early outcome in simple aortic valve disease and complex left heart disease. METHODS AND RESULTS: Between January 1995 and October 1998, 66 patients (median age, 10.8 years; range, 6 days to 34.8 years) underwent the Ross procedure. The primary indication for surgery was isolated valvular disease in 41 patients: aortic stenosis (AS; n=3), aortic insufficiency (AI; n=11), and AS/AI (n=27). The remaining 25 patients had multiple levels of left ventricular outflow tract obstruction, 12 of whom had at least moderate AI. Additional left heart disease in the complex group included subaortic stenosis (n=20), arch obstruction (n=7), mitral valve disease (n=5), apical aortic conduit stenosis or insufficiency (n=3), and supravalvar AS (n=2). There were 123 prior interventions performed in 51 patients, including aortic valvotomy/valvuloplasty (n=56), coarctation repair (n=21), subaortic stenosis resection/Konno procedure (n=10), ventricular septal defect closure (n=8), apical aortic conduit placement (n=3), aortic valve replacement (n=3), and other (n=22). An isolated Ross procedure was performed in 41 patients, 10 of whom required concurrent aortic annulus enlargement procedure to accommodate the larger pulmonary autograft. In the remaining 25 patients, 49 concurrent procedures were performed, including the Konno procedure (n=17), aortic annulus enlargement (n=2), subaortic membrane resection (n=9), arch augmentation (n=5), mitral valvuloplasty (n=5), ventricular septal defect closure (n=4), apicoaortic conduit division (n=3), and other (n=4). One patient (1.5%) died 3 days after a Ross-Konno procedure, which included arch reconstruction, from presumed arrhythmia. There were no other early deaths. One patient required ECMO (extracorporeal membrane oxygenation) for 3 days after a ventricular tachycardia (VT)-related cardiac arrest. Transient complete heart block was seen in 4 patients; the duration was <5 days. No patient had left ventricular outflow tract obstruction on discharge echocardiography. Neo-AI was graded as none (n=5), trivial-mild (n=57), or moderate (n=3). All 3 patients with moderate neo-AI at discharge had abnormal pulmonary valves before surgery. Perioperative VT was noted in 18 patients (27.2%), 2 of whom were discharged on antiarrhythmic medication. CONCLUSIONS: The Ross procedure can be performed in isolation or in combination with other complex procedures with low mortality (1.5%) and acceptable short-term results, even in patients with complex left heart disease and multiple prior interventions. Postoperative VT is common. Anatomic abnormalities of the pulmonary valve preclude its use as an autograft.

Perioperative conduction and rhythm disturbances after the Ross procedure in young patients.

BACKGROUND: The Ross procedure is performed for a variety of left ventricular outflow tract diseases in children. The preoperative hemodynamic burden of pressure or volume overload and associated ventricular hypertrophy can predispose to ventricular arrhythmias. Additional procedures performed with the Ross procedure (eg, Konno) may damage the conduction system. METHODS: Between January 1995 and February 1997, the Ross procedure was performed in 42 patients, 31 (74%) of whom had 71 prior interventions. Concomitant procedures (n = 42 in 23 patients) included 17 annular-enlarging procedures. Screening was performed for perioperative conduction and rhythm abnormalities. RESULTS: There was one postoperative death. Perioperative ventricular tachycardia occurred in 12 patients (29%), with 2 receiving antiarrhythmic medication for ventricular tachycardia at discharge. Transient complete heart block occurred in 3 patients, all of whom had concomitant procedures performed in the subaortic area; all patients were discharged in sinus rhythm and no patient received a permanent pacemaker. CONCLUSIONS: The Ross procedure can be performed successfully in children with complex cardiac disease with low mortality and perioperative morbidity. The incidence of perioperative ventricular tachycardia is high (29%), suggesting the need for vigilant perioperative monitoring and long-term surveillance.

Multiple cis- and trans-acting elements mediate the transcriptional response to phorbol esters.

Protein kinase C is important in the transduction of signals generated at the plasma membrane. The physiological activators of protein kinase C are diacylglycerols, and the tumour-promoting phorbol esters, such as 12-O-tetradecanoyl-phorbol-14 acetate (TPA), constitute another group of specific activators. Many cellular substrates for phosphorylation by protein kinase C have been described, but proteins that directly control transcription in response to protein kinase C activation are yet to be identified. TPA treatment leads to induction of various proto-oncogenes, growth factor genes, and genes encoding secreted proteases. In addition. TPA increases the activity of viral enhancer elements. To identify trans-acting factors that mediate the transcriptional response to TPA we chose the simian virus 40 (SV40) enhancer as a model, because it is known to be composed of several discrete cis-acting elements which are recognized by multiple transacting factors. We report here that the SV40 enhancer contains at least four different TPA responsive elements whose activity is dependent on cell-type. The induction response is likely to involve at least two distinct post-translational steps which modulate the activity of the proteins that recognize these elements.