Mitsuhiro Kamisago

Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect.

Recently, GATA4 and NKX2.5 were reported as the disease genes of atrial septal defect (ASD) but the relationship between the locations of their mutations and phenotypes is not clear. We analyzed GATA4 and NKX2.5 mutations in 16 familial ASD cases, including four probands with atrioventricular conduction disturbance (AV block) and two with pulmonary stenosis (PS), by PCR and direct sequencing, and examined their phenotypes clinically. Five mutations, including two GATA4 and three NKX2.5 mutations, were identified in 31.3% of the probands with ASD, and three of them were novel. The two GATA4 mutations in the probands without AV block were S52F and E359Xfs (c.1075delG) that was reported previously, and three NKX2.5 mutations in the probands with AV block were A88Xfs (c.262delG), R190C, and T178M. Additionally, we observed some remarkable phenotypes, i.e., dextrocardia with E359Xfs (c.1075delG) and cribriform type ASD with R190C, both of which are expected to be clues for further investigations. Furthermore, progressive, most severe AV block was closely related with a missense mutation in a homeodomain or with a nonsense/frame‐shift mutation of NKX2.5 for which classification has not been clearly proposed. This pinpoints essential sites of NKX2.5 in the development of the conduction system.

The impact of cardiac surgery in patients with trisomy 18 and trisomy 13 in Japan

Congenital heart defects (CHD) are very common in patients with trisomy 18 (T18) and trisomy 13 (T13). The surgical indication of CHD remains controversial since the natural history of these trisomies is documented to be poor. To investigate the outcome of CHD in patients with T18 and T13, we collected and evaluated clinical data from 134 patients with T18 and 27 patients with T13 through nationwide network of Japanese Society of Pediatric Cardiology and Cardiac Surgery. In patients with T18, 23 (17%) of 134 were alive at this survey. One hundred twenty‐six (94%) of 134 patients had CHDs. The most common CHD was ventricular septal defect (VSD, 59%). Sixty‐five (52%) of 126 patients with CHD developed pulmonary hypertension (PH). Thirty‐two (25%) of 126 patients with CHD underwent cardiac surgery and 18 patients (56%) have survived beyond postoperative period. While palliative surgery was performed in most patients, six cases (19%) underwent intracardiac repair for VSD. Operated patients survived longer than those who did not have surgery (P < 0.01). In patients with T13, 5 (19%) of 27 patients were alive during study period. Twenty‐three (85%) of 27 patients had CHD and 13 (57%) of 27 patients had PH. Atrial septal defect was the most common form of CHD (22%). Cardiac surgery was done in 6 (26%) of 23 patients. In this study, approximately a quarter of patients underwent surgery for CHD in both trisomies. Cardiac surgery may improve survival in selected patients with T18.

Silent Myocardial ischemia in Kawasaki disease : Evaluation of percutaneous transluminal coronary angioplasty by dobutamine stress testing

BACKGROUND Myocardial ischemia and myocardial infarction are the most serious complications of coronary artery lesions in children with Kawasaki disease (KD). Therefore, early detection and treatment of myocardial ischemia in patients with KD is essential. We studied the effectiveness of percutaneous transluminal coronary angioplasty (PTCA) in patients with silent myocardial ischemia detected by dobutamine stress 99mTc myocardial scintigraphy (TMS), body surface mapping (BMS), and signal-averaged ECG late potentials (ELP). METHODS AND RESULTS Eight of 76 asymptomatic patients with a coronary stenosis >25% and a positive dobutamine stress test were considered to have silent myocardial ischemia. All eight patients had >95% stenoses demonstrated by coronary angiography (CAG) just before PTCA. After PTCA, CAG showed that all of the coronary artery stenoses had been reduced to <50%. Additionally, intravascular ultrasonography (IVUS) performed in five patients before and after PTCA demonstrated adequate dilation of the coronary stenosis after PTCA. All eight patients underwent dobutamine stress TMS, BMS, and ELP 2 to 3 months after PTCA, which demonstrated no regions of myocardial ischemia. Approximately 6 months later, CAG was performed in all eight patients, and only one patient had developed restenosis. CONCLUSIONS PTCA effectively dilates stenotic coronary arteries in children with KD. Moreover, dobutamine stress TMS, BMS, and ELP are useful for detecting silent myocardial ischemia and estimating the effectiveness of PTCA. Furthermore, IVUS is useful for evaluating the severity of coronary artery lesions before and after PTCA in patients with KD.

Possible Synergic Effect of Angiotensin-I Converting Enzyme Gene Insertion/Deletion Polymorphism and Angiotensin-II Type-1 Receptor 1166A/C Gene Polymorphism on Ischemic Heart Disease in Patients with Kawasaki Disease

ACE I/D and AT1R 1166A/C polymorphisms are considered to comprise individual risk factors for the development of coronary disease. We sought to demonstrate that the ACE I/D and AT1R 1166A/C polymorphisms affect coronary artery stenosis in patients with Kawasaki disease (KD). We examined 147 healthy controls and 281 Japanese children with KD. The patients were further divided into group N (n = 246, no ischemia) and group I (n = 35, severe coronary artery stenosis with myocardial ischemia), and we studied the genotype of ACE I/D and AT1R 1166A/C polymorphisms. We also examined ACE activity in patients with acute KD. We did not detect any prevalent genotypes of the ACE and AT1R polymorphisms between controls and KD patients. However, the prevalence of the D allele in the ACE polymorphism and of the C allele in the AT1R polymorphism tended to be higher in group I than in group N (odds ratios, 2.00 and 2.32, respectively). In addition, the presence of the D and/or C alleles significantly increased the relative risk of developing myocardial ischemia (odds ratio, 2.71; p = 0.038). During the convalescent phase of KD, ACE activity was increased despite significant attenuation during the acute phase. These results suggested that the renin-angiotensin system is associated with the formation of severe coronary artery stenosis and myocardial ischemia.

A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT syndrome

Two missense mutations and a nine‐nucleotide deletion of the cardiac sodium channel (SCN5A) gene have been shown to cause long QT syndrome (LQTS) in several familial cases. We identified a novel missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic LQTS. We used polymerase chain reaction, single‐strand conformation polymorphism analysis and DNA sequence analysis to identify a mutation of the SCN5A gene in the patient. A single nucleotide substitution of guanine to adenine, in codon 1623, changed the coding sense of the SCN5A from arginine to glutamine (R1623Q) in the S4 segment of domain IV which is a highly conserved region of the SCN5A. This mutation was not identified in the unaffected biological parents and brother of the patient, and 100 normal, unrelated individuals. This finding is the first evidence of a de novo mutation in SCN5A associated with LQTS. Hum Mutat 11:481, 1998.

Evaluation of myocardial ischemia and infarction by signal-averaged electrocardiographic late potentials in children with Kawasaki disease

We investigated myocardial ischemia and old myocardial infarction noninvasively using signal-averaged electrocardiographic late potentials (LPs) in patients with Kawasaki disease. Patients were divided into 4 groups: a noncoronary artery lesion group (n=136), a coronary artery lesion group (without myocardial ischemia and an old myocardial infarction; n=33), an ischemia group (n=16), and an old myocardial infarction group (n=13). Grouping was based on exercise thallium-201 myocardial scintigraphy, thallium-201 myocardial scintigraphy, exercise electrocardiography, coronary angiography, left ventriculography, and echocardiography. Signal-averaged electrocardiograms were recorded using a high-resolution system. Values of filtered QRS duration (f-QRSd), root-mean-square voltage, and duration of low-amplitude signal were judged using our own body surface area-related criteria (n=205) to determine positive rates of LPs and sensitivities and specificities to ischemia and infarction. These data were also interpreted using published criteria for adults and compared with those interpreted by our criteria. Positive rates by our criteria were 0% in the noncoronary artery lesion group, 9.1% in the coronary lesion group, 56.3% in the ischemia group, and 69.2% in the old myocardial infarction group. However, using the criteria for adults, these values were 0%, 3.0%, 25%, and 46.2%, respectively. Sensitivities to ischemia and infarction using our criteria were significantly higher (56.3% and 69.2%) than those using the criteria for adults (p < 0.05). Moreover, specificities to ischemia and infarction were very high (93.4% and 93.5%, respectively) using our criteria, and there were no significant differences from specificities using the criteria for adults. Also, we examined the reproducibility of values of LPs and LP parameters. The values of filtered QRS duration showed a high reproducibility in both LP-positive and -negative groups, followed by low-amplitude signal and then root-mean-square voltage. The results of LP presence or absence showed 100% reproducibility for both the LP-positive and -negative groups, supporting the utility of LPs for clinical applications. Thus, LPs provide useful information in a noninvasive manner for clarifying ischemia and infarction in patients with Kawasaki disease.

Increased plasma endothelin-1 concentration in Kawasaki disease.

We compared the variation in plasma endothelin-1 (ET-1) levels by the sandwich-enzyme RIA method during each of the clinical stages of Kawasaki disease, a systemic vasculitis occurring in children (30 cases, ages 4-62 months) and examined whether ET-1 could be a clinical parameter for predicting coronary artery dilatation. The results revealed that the ET-1 level in the acute stage was higher than that in the recovery stage, the chronic stage, or in healthy controls (3.46 +/- 1.22 versus 2.20 +/- 0.56, 1.55 +/- 0.52, and 1.57 +/- 0.45 pg/ml, respectively; p < 0.01). Furthermore, in the acute stage the ET-1 level in the group with coronary artery dilatation (positive group, five cases) increased more than that in the negative group (25 cases) (5.13 +/- 1.64 versus 3.09 +/- 0.70 pg/ml, respectively; p < 0.01). When the ET-1 value was more than 4.5 pg/ml in the acute stage, our prediction for coronary artery dilatation demonstrated a high value in indices of both sensitivity (100%) and specificity (96.1%). Thus, plasma concentration of ET-1 was increased in the acute stage of Kawasaki disease and was very high in patients with coronary artery dilatation. The plasma ET-1 level was considered to be an important factor in predicting the dilatational lesions of the coronary artery in the acute stage of Kawasaki disease.

Phenotype-Genotype Correlation in a Patient With Co-Occurrence of Marfan and LEOPARD Syndromes

Here we report on a patient with multiple lentigines, hypertelorism, short stature, arachnodactyly, scoliosis, dissecting aneurysm, hypertrophic cardiomyopathy and developmental delay, and a family history of Marfan syndrome. The patient is affected with both Marfan and LEOPARD syndromes. Mutational screening of the FBN1 gene showed a c.1464T>A (p.C488X) mutation and screening of the PTPN11 gene showed a c.836A>G (p.Y279C) mutation. We conclude that each mutation contributed independently to individual features in the ocular and cardiovascular systems, although short stature was more significantly influenced by the p.Y279C change in PTPN11 rather than the mutation in FBN1. To our knowledge, this is the first report of mutations in both FBN1 and PTPN11 with combined phenotypes of Marfan and LEOPARD syndromes.

A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT sydrome. Mutations in brief no. 140. Online.

Two missense mutations and a nine‐nucleotide deletion of the cardiac sodium channel (SCN5A) gene have been shown to cause long QT syndrome (LQTS) in several familial cases. We identified a novel missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic LQTS. We used polymerase chain reaction, single‐strand conformation polymorphism analysis and DNA sequence analysis to identify a mutation of the SCN5A gene in the patient. A single nucleotide substitution of guanine to adenine, in codon 1623, changed the coding sense of the SCN5A from arginine to glutamine (R1623Q) in the S4 segment of domain IV which is a highly conserved region of the SCN5A. This mutation was not identified in the unaffected biological parents and brother of the patient, and 100 normal, unrelated individuals. This finding is the first evidence of a de novo mutation in SCN5A associated with LQTS. Hum Mutat 11:481, 1998.

The Incidence of Pediatric Invasive Bacterial Diseases in Nippon Medical School Chiba Hokusoh Hospital before and after the Introduction of Conjugate Vaccines

The introduction of the Haemophilus influenzae type b (Hib) vaccine and the 7-valent pneumococcal conjugate vaccine (PCV7) has led to dramatic reductions in cases of invasive H. influenzae disease and invasive pneumococcal disease (IPD). After the introduction of the PCV7 and the 13-valent pneumococcal conjugate vaccine (PCV13), the number of children with IPD markedly decreased in our hospital. However, since 2015, three children with IPD have been admitted to our hospital. We analyzed the serotype, multilocus sequence type, and antimicrobial susceptibility of Streptococcus pneumoniae strains isolated in these newly diagnosed cases. The strains were serotypes 7F and 12F. In addition, we analyzed the incidence of invasive bacterial disease before and after the introduction of conjugate vaccines and found no change in the incidences. We found that cases of IPD and invasive H. influenzae disease clearly decreased following the introduction of the PCV7, the PCV13, and the Hib vaccine, as well as disease caused by antibiotic-resistant strains.