Mutations of ATP7B gene in two Thai siblings with Wilson disease

Background: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in ATP7B gene. Objective: Report the clinical data and mutation analysis of two Thai siblings suspected of WD. Subject and methods: A 13-year-old boy who presented with cirrhosis, arthralgia, hypoalbuminemia, and coagulopathy, and his 11-year-old sister who was asymptomatic but had hepatomegaly with elevation of transaminases, were studied. Mutation analysis of ATP7B gene and mRNA analysis was performed in both patients and their parents. Results: Investigations were consistent with WD, and their liver diseases improved after standard treatment for WD. DNA analyses in these two patients revealed two novel mutations, which were a deletion of the first 2bp of exon 6 (c.1870_1871delGA), and a single base substitution from A to G at nucleotide 4075 (c.4075A>G) in the exon 20 (p.M1359V). PCR-restriction digestion with NcoI restriction enzyme was employed as the second method for confirmation of the c.4075A>G mutation and for rapid screening in 100 chromosomes from unrelated healthy controls, and this variant was not present in the controls. The c.1870_1871delGA deletion caused a frameshift effect, which results in a premature stop codon (p.E624fsX753), and the p.M1359V mutation is a substitution of methionine with valine, which may have effects upon its orientation and interaction with other adjacent amino acids. Conclusion: Two novel mutations of ATP7B gene were identified in two Thai siblings with WD.

Reduction of rotavirus infection in children receiving bifidobacteria-supplemented formula.

This study was conducted at Pakkred Babies Home, Bangkok, Thailand; with the hypothesis that children receiving probiotic-supplemented milk-based formula may be protected from developing diarrheal diseases. Salivary rotavirus-specific IgA antibody was used as an indicator of rotavirus infection. One hundred and seventy-five children, aged 6-36 months, were enrolled in the study. They were divided into 3 groups according to the type of formula given. There were 81 episodes of diarrhea during an 8-month study period, most of which were caused by bacterial enteropathogens. Ninety-seven pairs of salivary samples were adequate for the analysis of rotavirus antibody. Among 23 children receiving milk-based follow-up formula and serving as control group, 30.4 per cent of them had > or = 4-fold increase in the antibody titre, indicating subclinical rotavirus infection. The majority of children in the other 2 study groups, receiving the same formula supplemented with either Bifidobacterium Bb12 alone or together with Streptococcus thermophilus, had no significant change in the antibody titres between the two time points. The results of this study support our hypothesis that children receiving bifidobacteria-supplemented milk-based formula may be protected against symptomatic rotavirus infection.

Disseminated intravascular coagulation findings in 100 patients.

A retrospective study of 100 patients with disseminated intravascular coagulation from 1993 to 1997 is reported. Forty-five patients were neonates with a mean age of 12.6 days and 55 patients were infants, children and adolescents with a mean age of 6 years and 3 months. Most of them (91.5%) had complicated underlying conditions which included congenital anomalies, prematurity, malignancy, hematological and various diseases. Additionally, every patient had triggering conditions commonly identified as gram-negative septicemia. Bleeding and thromboembolic manifestations were found in 59.4 per cent and 19.8 per cent, respectively. The laboratory findings revealed red blood cell fragmentation, 89.6 per cent and thrombocytopenia, 85.8 per cent. Natural anticoagulants were studied in a few cases and revealed low levels of antithrombin III and protein C. The prompt effective management included treatment of underlying diseases, identification and relief of triggering conditions, correction of thrombocytopenia and coagulopathy, and fully supportive care. The overall case-fatality rate was 41.6 per cent which was not correlated with age, underlying diseases, triggering conditions, manifestation of bleeding, thromboembolism or shock, and exchange transfusion. However, a significant lower case-fatality rate was found in patients with positive culture (25%) as compared to those with sepsis and negative culture (51.7%) (p = 0.044). In addition, the febrile neutropenic patients, who showed good response to the administrated granulocyte-colony stimulating factor (G-CSF), survived from the DIC.

Gastroesophageal reflux in children: correlation of symptoms with 24-hour esophageal pH monitoring.

To evaluate the clinical significance of suspected symptoms of GER, 24-hour esophageal pH monitoring was performedin 55 children (mean age of 23.9 months). We used 24-hour esophageal pH monitoring as a gold standard for the diagnosis of pathological GER. The primary indication for the study included frequent vomiting, dysphagia and respiratory diseases (recurrent pneumonia, aspiration pneumonia, hyperreactive airway, apnea and stridor). Forty-seven per cent of these 55 children had pathological GER and 61.5 per cent of them were less than 1-year-old. The sensitivity of frequent vomiting, dysphagia and aspiration pneumonia as symptoms of GER was lowest (7.7%) Recurrent pneumonia had highest sensitivity (50%) but had lowest specificity (31%) among other presenting symptoms. All the other symptoms had high specificity (82.8-100%). Dysphagia, hyperreactive airway and apnea were the presenting symptoms with high positive predictability (100%, 80%, and 75% respectively). We suggest that all children who have a history of dysphagia, hyperreactive airway and apnea should be evaluated for GER.

HBsAg carrier rate among institutionalised children from Phyathai Institute.

To identify the evidence supporting the horizontal transmission of hepatitis B virus, HBsAg carrier rate among institutionalised children is determined and compared to children of the same age-group from the well baby clinic, Ramathibodi hospital. The results of this study show that HBsAg is detected four times more frequently in institutionalised children than in children from a well baby clinic. The chance of becoming an HBsAg carrier increases with age and duration of stay in the institution. Repeated study one year later shows that the HBsAg carrier rate among the same group of institutionalised children had increased by 35 per cent. The evidence supports the hypothesis that hepatitis B virus can be transmitted nonparenterally. To prevent this mode of transmission in both institutions and the community, hepatitis B vaccine should be given to these children.

Etiology of diarrhea in measles.

Thirty-six measles cases with diarrhea were studied with two age and sex matched control groups, measles without diarrhea (75 cases) and acute diarrhea (70 cases). Bacterial pathogens were isolated from 5 out of 36 (13.9%) in measles with diarrhea but rotavirus, coronavirus and parasites were not detected in any case. The bacterial and viral etiology of measles with diarrhea were statistically significant different from the acute diarrhea group (p less than 0.005) and p less than 0.01 respectively) but not from the measles without diarrhea group (p greater than 0.05). 83.3 per cent of cases had diarrhea during 4 days before and after the appearance of rash. Watery diarrhea was frequently observed in this study (63.9%). Although measles virus was not identified in stools, data from this study suggested that measles may be the viral agent causing diarrhea. Watery stools are often observed and the presence of faecal white blood cell may be seen.

Liver size and serum alkaline phosphatase in normal Thai school-aged children.

The purpose of this study is to determine liver size in normal Thai school children aged 6 to 11 years, using both the clinical and ultrasonographic methods. Normal value of serum alkaline phosphatase in this age-group is also obtained. To confirm that liver function is normal, serum alanine transaminase and hepatitis B virus profile were performed. One hundred and fifty-nine normal children from Phyathai School were included in the study. They were divided into 5 age-groups: 6-7, 7-8, 8-9, 9-10 and 10-11 years. Six children were found to be asymptomatic HBsAg carriers (3.8%) and were excluded from the analysis. Mean liver sizes examined separately by two pediatricians were not significantly different, they were 8.47, 9.32, 10.06, 9.64 and 9.38 cm respectively, whereas those obtained by the ultrasonogram were 9.37, 9.17, 9.71, 10.57 and 10.21 cm respectively. Liver was palpable in 15.7 per cent of the children and liver edge did not exceed 2 cm below right costal margin. The mean value of serum alkaline phosphatase, obtained by the automate method, in these children was 223.1 unit/litre and in 97.3 per cent of them, the value did not exceed 350 unit/litre. The results of this study showed that liver size obtained clinically is comparable to size determined by ultrasonogram. Liver size in school children does not increase with age but tends to increase with body weight and height of the children.

Failure of norfloxacin to eradicate intestinal colonization of non-typhoidal salmonella in infants.

Infant colonization with non-typhoidal Salmonella (NTS) is common and eradication is problematic. Oral norfloxacin has promising properties for solving this problem, though it has potential toxicity to infants. The drug has been available in Thailand since 1987. Since then, some infants who had diarrhea or NTS colonization were treated with oral norfloxacin 15-20 mg/kg/day for 3-5 days on individual physician's judgement. This observational study was performed in infants and children who had NTS in stool, seen at Ramathibodi hospital from September 1987 to February 1988, in order to give preliminary information. Sixteen of 48 infants received oral norfloxacin treatment. Nine infants had established failure of NTS eradication from follow-up rectal swab cultures. Five infants did not have follow-up rectal swab culture, and two had negative culture once on day 7 after treatment. Considering that 7 infants who did not have evidence of bacteriologic failure were free from colonization, the excretion rate during the first two weeks could be estimated as 56 per cent which is not less than the natural history of this disease. This observation suggests failure of oral norfloxacin, 15 mg/kg/day given in 2 divided doses for 3 days, in eradication NTS colonization in infants.

Severe hepatitis B in infants born to HBsAg carrier mothers.

Five infants admitted consecutively with severe hepatitis B were treated with exchange transfusion, correction of coagulation defects and supportive measures. All were born to HBsAg carrier mothers and one had received hepatitis B immune globulin (HBIG) within 24 hours after birth. All of them presented with nonspecific symptoms such as vomiting, loose stools, low grade fever and progressed to acute liver failure. Three of them survived with full recovery and two died from hepatic encephalopathy one and two weeks after admission. Early recognition of hepatic failure and prompt exchange transfusions with intensive supportive treatment may save these infants.