Task force 2: special health care needs of adults with congenital heart disease.
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Adaptation, Psychological↗
Biomedical subjects
D J Driscoll
Publications and source records attributed to D J Driscoll.
Molecular autopsy of sudden unexplained death in the young.
Sudden unexplained death (SUD) claims over 4,000 persons between the age of 1 and 22 each year in the United States. Nearly half of all pediatric SUD cases have a normal structural autopsy evaluation and are dismissed without a diagnosis. With the discovery of the genetic basis for potentially fatal arrhythmias associated with the inherited long QT syndrome (LQTS), postmortem molecular diagnosis of this disorder is possible. The authors describe the results of a molecular autopsy performed on a 17-year-old boy found dead in bed. A novel clinical test involving an epinephrine challenge in the decedent's mother implicated a potential defect in the phase 3 potassium current encoded by the gene KVLQT1. Exon-specific amplification by polymerase chain reaction and direct DNA sequencing of KVLQT1 revealed a 5-base pair deletion in the genetic material recovered from the decedent's paraffin-embedded heart tissue. The ability to perform molecular autopsies on archived necropsy material undoubtedly will transform the forensic evaluation of SUD. The combination of catecholamine provocation testing in survivors and a postmortem LQTS gene analysis may unmask families with "concealed" LQTS and establish the cause and manner of death in SUDS.
Adolescent↗
Influence of ventricular morphology on outcome after the Fontan procedure.
The modified Fontan procedure has gained wide acceptance in the treatment of various congenital heart defects. Determination of risk factors for mortality remains an important issue for optimizing patient selection for the Fontan procedure. Conflicting results have been reported about whether ventricular morphology is a risk factor in these patients. Survival free of Fontan takedown or cardiac transplantation was assessed in the first 500 patients undergoing the Fontan procedure at our institution. This survival was correlated with ventricular morphology as evaluated by angiography. Both multivariate and univariate analyses indicated ventricular morphology was predictive of early survival free of Fontan takedown or cardiac transplantation following the procedure. However, there was no statistical evidence for ventricular morphology being a risk factor for mortality in patients alive 6 months after the procedure. Ventricular morphology is a risk factor for early survival in patients undergoing a Fontan procedure, with left ventricular morphology associated with a better early survival than right ventricular morphology.
Adolescent↗
Operation for partial atrioventricular septal defect: a forty-year review.
BACKGROUND: We describe the long-term outcome of repair of partial atrioventricular septal defect by determining the rates of survival, reoperation, and occurrence of left atrioventricular valve regurgitation, left atrioventricular valve stenosis, left ventricular outflow tract obstruction, and arrhythmia. METHODS: We studied 334 patients who underwent repair of partial atrioventricular septal defect before 1995. RESULTS: The 30-day and 5-, 10-, 20-, and 40-year survival were 98%, 94%, 93%, 87%, and 76%, respectively. Closure of the left atrioventricular valve cleft (P =. 03) and age less than 20 years at operation (P <.001) were associated with better survival. Reoperation was performed for 38 patients (11%). Repair of residual/recurrent left atrioventricular valve regurgitation or stenosis was the most common reason for reoperation. Left ventricular outflow tract obstruction occurred in 36 patients, and 7 patients underwent reoperation to relieve this obstruction. Supraventricular arrhythmias were observed in 58 patients (16%) after the operation. Supraventricular arrhythmias increased with increasing age at primary operation (P =.001). Complete atrioventricular block occurred in 9 patients (3%). Permanent pacemakers were implanted in 11 patients. CONCLUSIONS: Long-term survival after repair of partial atrioventricular septal defect is good. It is important to close the cleft in the left atrioventricular valve. Reoperation for persistent or recurrent left atrioventricular valve malfunction and relief of left ventricular outflow tract obstruction is necessary in approximately 11% of patients.
Adolescent↗
Surgical treatment of venous malformations in Klippel-Trénaunay syndrome.
PURPOSE: Klippel-Trénaunay syndrome (KTS) is a complex congenital anomaly, characterized by varicosities and venous malformations (VMs) of one or more limbs, port-wine stains, and soft tissue and bone hypertrophy. Venous drainage is frequently abnormal because of embryonic veins, agenesis, hypoplasia, valvular incompetence, or aneurysms of deep veins. We previously reported on the surgical management of KTS. In this article, we update our experience. METHODS: Twenty patients with KTS underwent surgical treatment for VMs between July 1, 1987, and January 1, 2000. This group represented 6.9% of 290 patients with KTS who were seen at our institution during this 12.5-year study period. Surgical indications, venous anatomy (determined with duplex scan, contrast phlebography, magnetic resonance imaging or magnetic resonance phlebography), operative procedures, and complications were reviewed, and outcomes were recorded. RESULTS: Twelve male and eight female patients (mean age, 23.4 years; range, 7.7-40.6 years) underwent 30 vascular surgical procedures in 21 lower limbs. All 20 patients (100%) had varicose veins or VMs, 13 (65%) had port-wine stains, and 18 (90%) had limb hypertrophy. Pain was the most common complaint, which was present in 16 patients (80%), followed by swelling in 15 (75%), bleeding in 8 (40%), and superficial thrombophlebitis and cellulitis in 3 (15%). Imaging confirmed patent deep veins in 18 patients, hypoplastic femoral vein in 1, and entrapped popliteal veins bilaterally in 1. Four patients (20%) had large persistent sciatic veins (PSVs). The CEAP clinical classification was C-3 for 17 patients (85%), C-4 for 1 patient (5%), and C-6 for 2 patients (10%). Stripping of large lateral veins, avulsion, and excision of varicosities or VMs were performed on all limbs. Three patients required staged resections. The release of entrapped popliteal veins was performed in both limbs of one patient; another underwent a popliteal-saphenous bypass graft. One patient underwent excision of a PSV. Open and endoscopic perforator vein ligation was performed in one patient each. Two patients (12%) had hematomas that required evacuation. No patients had caval filter placement; none had postoperative deep venous thrombosis or pulmonary embolus. The mean follow-up was 63.6 months (range, 0-138 months). All patients reported initial improvement, but some varicosities recurred in 10 patients (50%), an ulcer did not heal in one, and a new ulcer developed in one, 8 years after surgery. Three patients underwent reoperation for recurrent varicosities. Follow-up CEAP scores were C-2 in 10 patients (50%), C-3 in 6 patients (30%), C-4 and C-5 in 1 patient each (5%), and C-6 in 2 patients (10%). Clinical scores improved from 4.3 +/- 2.2 to 3.1 +/- 2.3. (P =.03). CONCLUSIONS: The management of patients with KTS continues to be primarily nonoperative, but those patients with patent deep veins can be considered for excision of symptomatic varicose veins and VMs. Although the recurrence rate is high, clinical improvement is significant, and reoperations can be performed if needed. Occasionally, deep vein reconstruction, excision of PSVs, or subfascial endoscopic perforator surgery is indicated. Because KTS is rare, patients should receive multidisciplinary care in qualified vascular centers.
Adolescent↗
DNA methylation analysis with respect to prenatal diagnosis of the Angelman and Prader-Willi syndromes and imprinting.
The Angelman (AS) and Prader-Willi syndromes (PWS) are clinically distinct neurobehavioural syndromes resulting from loss of maternal (AS) or paternal contributions (PWS) of imprinted genes within the chromosomal 15q11-q13 region. The molecular diagnosis of both syndromes can be made by a variety of techniques, including DNA methylation, DNA polymorphism and molecular cytogenetic analyses. DNA methylation analysis at three major loci (ZNF127, PW71 and 5' SNRPN) has been successfully used for the postnatal diagnosis of AS and PWS. Methylation analysis, in contrast to other techniques, can reliably be used to diagnose all three major molecular classes (deletion, uniparental disomy and imprinting mutation) of PWS, and three of the four major classes of AS. In this study we demonstrate that methylation analysis can also be successfully used in prenatal diagnosis, by examining specimens obtained from amniocentesis and chorionic villus sampling. Correct prenatal diagnoses were obtained in 24 out of 24 samples using the 5' SNRPN locus; 4 out of 15 using the ZNF127 locus; and 10 out of 18 using the PW71 locus. Therefore, our data indicate that although the DNA methylation imprints of ZNF127 and 5' SNRPN arise in the germline and are present in brain, only 5' SNRPN maintains the imprint in tissues suitable for the prenatal diagnosis of AS and PWS.
Amniocentesis↗
A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome.
Loss of imprinting at IGF2, generally through an H19-independent mechanism, is associated with a large percentage of patients with the overgrowth and cancer predisposition condition Beckwith-Wiedemann syndrome (BWS). Imprinting control elements are proposed to exist within the KvLQT1 locus, because multiple BWS-associated chromosome rearrangements disrupt this gene. We have identified an evolutionarily conserved, maternally methylated CpG island (KvDMR1) in an intron of the KvLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of BWS with H19 hypermethylation, methylation at KvDMRl was normal. Thus, inactivation of H19 and hypomethylation at KvDMR1 (or an associated phenomenon) represent distinct epigenetic anomalies associated with biallelic expression of IGF2. Reverse transcription-PCR analysis of the human and syntenic mouse loci identified the presence of a KvDMR1-associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KvLQT1 gene. We propose that KvDMR1 and/or its associated antisense RNA (KvLQT1-AS) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.
Animals↗
Measurement of blood serum cyclosporine levels using capillary "fingerstick" sampling: a validation study.
Capillary blood sampling as a means of monitoring blood cyclosporine levels has replaced venipuncture in some medical centers. As the validity of capillary venipuncture for analysis of cyclosporine has not been documented, we sought to validate the capillary blood collection technique by comparing it with serum samples collected simultaneously by venous phlebotomy. Forty paired capillary- and venous samples were collected from 36 cardiac transplantation patients and analyzed, using a polyclonal immunoassay. The values obtained were compared using regression correlation. The correlation coefficient for all 40 samples was 0.859. However, we discovered that the first 7 capillary specimens were processed incorrectly. The correlation coefficient for the other 33 samples was 0.995 (99% confidence interval 0.987-0.998). The excellent correlation between serum samples obtained from capillary sampling and from venous sampling, together with the ease of obtaining capillary blood specimens, make "fingerstick" sampling the method of choice for monitoring cyclosporine levels in infants and children.
Adult↗
Left-to-right shunt lesions.
A left-to-right shunt lesions exists when blood from the left atrium, left ventricle, or aorta transits to the right atrium or its tributaries, the right ventricle, or the pulmonary artery. This article discusses: the incidence, types, embryology, clinical presentations, physical examinations, electrocardiographic features, chest radiographs, echocardiographic and cardiac catheterization issues, treatment, natural history of atrial septal defects, and outcomes of treatment of atrial septal defects, ventricular septal defects, patent ductus arteriosus, and endocardial cushion defects.
Cardiac Catheterization↗
Molecular mechanism of angelman syndrome in two large families involves an imprinting mutation.
Patients with Angelman syndrome (AS) and Prader-Willi syndrome with mutations in the imprinting process have biparental inheritance but uniparental DNA methylation and gene expression throughout band 15q11-q13. In several of these patients, microdeletions upstream of the SNRPN gene have been identified, defining an imprinting center (IC) that has been hypothesized to control the imprint switch process in the female and male germlines. We have now identified two large families (AS-O and AS-F) segregating an AS imprinting mutation, including one family originally described in the first genetic linkage of AS to 15q11-q13. This demonstrates that this original linkage is for the 15q11-q13 IC. Affected patients in the AS families have either a 5.5- or a 15-kb microdeletion, one of which narrowed the shortest region of deletion overlap to 1.15 kb in all eight cases. This small region defines a component of the IC involved in AS (ie., the paternal-to-maternal switch element). The presence of an inherited imprinting mutation in multiple unaffected members of these two families, who are at risk for transmitting the mutation to affected children or children of their daughters, raises important genetic counseling issues.
Adolescent↗
Imprinting-mutation mechanisms in Prader-Willi syndrome.
Microdeletions of a region termed the "imprinting center" (IC) in chromosome 15q11-q13 have been identified in several families with Prader-Willi syndrome (PWS) or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in 15q11-q13 during gametogenesis. We have identified a larger series of cases of familial PWS, including one case with a deletion of only 7.5 kb, that narrows the PWS critical region to <4. 3 kb spanning the SNRPN gene CpG island and exon 1. Identification of a strong DNase I hypersensitive site, specific for the paternal allele, and six evolutionarily conserved (human-mouse) sequences that are potential transcription-factor binding sites is consistent with this region defining the SNRPN gene promoter. These findings suggest that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. We also identified three patients with sporadic PWS who have an imprinting mutation (IM) and no detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental spermatogenesis. These studies allow a better understanding of a novel mechanism of human disease, since the epigenetic effect of an IM in the parental germ line determines the phenotypic effect in the patient.
Adult↗
Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of approximately.67-1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.
Angelman Syndrome↗
A novel imprinted gene, encoding a RING zinc-finger protein, and overlapping antisense transcript in the Prader-Willi syndrome critical region.
We describe a complex imprinted locus in chromosome 15q11-q13 that encodes two genes, ZNF127 and ZNF127AS. The ZNF127 gene encodes a protein with a RING (C3HC4) zinc-finger and multiple C3H zinc-finger motifs, the former being closely related to a protein from variola major virus, the smallpox etiological agent. These motifs allow prediction of ZNF127 function as a ribonucleoprotein. The intronless ZNF127 gene is expressed ubiquitously, but the entire coding sequence and 5' CpG island overlaps a second gene, ZNF127AS, that is transcribed from the antisense strand with a different transcript size and pattern of expression. Allele-specific analysis shows that ZNF127 is expressed only from the paternal allele. Consistent with this expression pattern, in the brain the ZNF127 5' CpG island is completely unmethylated on the paternal allele but methylated on the maternal allele. Analyses of adult testis, sperm and fetal oocytes demonstrates a gametic methylation imprint with unmethylated paternal germ cells. Recent findings indicate that ZNF127 is part of the coordinately regulated imprinted domain affected in Prader-Willi syndrome patients with imprinting mutations. Therefore, ZNF127 and ZNF127AS are novel imprinted genes that may be associated with some of the clinical features of the polygenic Prader-Willi syndrome.
Adolescent↗
Imprinting of a RING zinc-finger encoding gene in the mouse chromosome region homologous to the Prader-Willi syndrome genetic region.
A novel locus in the human Prader-Willi syndrome (PWS) region encodes the imprinted ZNF127 and antisense ZNF127AS genes. Here, we show that the mouse ZNF127 ortholog, Zfp127, encodes a homologous putative zinc-finger polypeptide, with a RING (C3HC4) and three C3H zinc-finger domains that suggest function as a ribonucleoprotein. By the use of RT-PCR across an in-frame hexamer tandem repeat and RNA from a Mus musculus x M.spretus F1interspecific cross, we show that Zfp127 is expressed only from the paternal allele in brain, heart and kidney. Similarly, Zfp127 is expressed in differentiated cells derived from androgenetic embryonic stem cells and normal embryos but not those from parthogenetic embryonic stem cells. We hypothesize that the gametic imprint may be set, at least in part, by the transcriptional activity of Zfp127 in pre- and post-meiotic male germ cells. Therefore, Zfp127 is a novel imprinted gene that may play a role in the imprinted phenotype of mouse models of PWS.
Amino Acid Sequence↗
Report of the fourth international workshop on human chromosome 15 mapping 1997.
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Angelman Syndrome↗
Predictors of early- and late-onset supraventricular tachyarrhythmias after Fontan operation.
BACKGROUND: The objectives of our study were to determine the frequency of supraventricular tachyarrhythmias (SVTAs) among modifications of the Fontan operation and identify risk factors for developing SVTA. METHODS AND RESULTS: The population consisted of all patients who had any modification of the Fontan operation at the Mayo Clinic between 1985 and 1993. Clinically significant SVTAs were those requiring initiation or change of antiarrhythmic treatment, and they were divided into early SVTAs (<30 days after the operation) and late SVTAs (>/=30 days after the operation). Clinical histories were reviewed, and health status questionnaires were sent. Four hundred ninety-nine patients had various modifications of the Fontan operation. Frequency of early SVTA was 15%. Risk factors identified by multivariate analysis for early SVTA were AV valve regurgitation, abnormal AV valve, and preoperative SVTA. Frequency of late SVTA was 6% by 1 year, 12% by 3 years, and 17% by 5 years. Risk factors for late SVTA were age at operation (<3 or >/=10 years) and systemic AV valve replacement. By univariate and multivariate analysis, the type of Fontan operation was not a significant risk factor for late SVTA when all 6 modifications were considered. However, when we analyzed the frequency of late SVTA for the 2 recently used modifications, we found a lower frequency of late SVTA in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection. CONCLUSIONS: Postoperative SVTA continues to be a significant problem. Risk factors for SVTA are AV valve regurgitation, abnormal AV valve, preoperative SVTA, and age at operation. Frequency of SVTA does not appear to be related to type of Fontan procedure except for slightly lower frequency in patients with atriopulmonary connection with lateral tunnel compared with those with total cavopulmonary connection.
Adolescent↗
Cardiovascular preparticipation screening of competitive athletes: addendum: an addendum to a statement for health professionals from the Sudden Death Committee (Council on Clinical Cardiology) and the Congenital Cardiac Defects Committee (Council on Cardiovascular Disease in the Young), American Heart Association.
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American Heart Association↗
Methylenetetrahydrofolate reductase deficiency in a patient with phenotypic findings of Angelman syndrome.
Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal.
Angelman Syndrome↗