Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations.

OBJECTIVE: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management. STUDY DESIGN: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians. RESULTS: Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management. CONCLUSIONS: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management.

Biallelic Mutations in the LSR Gene Cause a Novel Type of Infantile Intrahepatic Cholestasis.

We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.

Characteristics of hospitalized children infected with macrolide-resistant Mycoplasma pneumoniae

BACKGROUND: The aim of this study was to clarify retrospectively the characteristics of children hospitalized for respiratory tract infection caused by macrolide-resistant Mycoplasma pneumoniae (M. pneumoniae). METHODS: Children who were hospitalized for respiratory tract infection due to M. pneumoniae were enrolled in this study. The diagnosis of M. pneumoniae infection was made on the grounds of polymerase chain reaction results. RESULTS: Thirty-three children were hospitalized due to lower respiratory tract infection with M. pneumoniae. Of the 33 children, 31 (median age five years) were identified as being infected with macrolide-resistant M. pneumoniae (A2063G:30, A2064G:1) by sequence analysis. Of the 31 children infected with macrolide-resistant M. pneumoniae, 21 (68%) had received 14- or 15-membered macrolide antibiotics and four (13%) had received minocycline before hospitalization. During hospitalization, minocycline was administered to 16 (52%) of the 31 children infected with macrolide-resistant M. pneumoniae. Of the 20 children infected with macrolide-resistant M. pneumoniae under eight years of age, six (30%) were treated with minocycline during hospitalization. The difference in total febrile days between children receiving minocycline treatment before hospitalization and children not receiving minocycline treatment was three days. CONCLUSIONS: The majority of hospitalized children with respiratory tract infection due to macrolide-resistant M. pneumoniae infection was of preschool age and had received 14- or 15-membered macrolide antibiotics before hospitalization. Because macrolide-resistant M. pneumoniae is widespread in Japan, the administration of minocycline as a second-line antibiotic in children under eight years of age cannot be withheld when clinical symptoms do not improve with macrolide antibiotics. .

Improved liver function and relieved pruritus after 4-phenylbutyrate therapy in a patient with progressive familial intrahepatic cholestasis type 2.

To examine the effects of 4-phenylbutyrate (4PB) therapy in a patient with progressive familial intrahepatic cholestasis type 2. A homozygous c.3692G>A (p.R1231Q) mutation was identified in ABCB11. In vitro studies showed that this mutation decreased the cell-surface expression of bile salt export pump (BSEP), but not its transport activity, and that 4PB treatment partially restored the decreased expression of BSEP. Therapy with 4PB had no beneficial effect for 1 month at 200 mg/kg/day and the next month at 350 mg/kg/day but partially restored BSEP expression at the canalicular membrane and significantly improved liver tests and pruritus at a dosage of 500 mg/kg/day. We conclude that 4PB therapy would have a therapeutic effect in patients with progressive familial intrahepatic cholestasis type 2 who retain transport activity of BSEP per se.

Characteristics of hospitalized children infected with macrolide-resistant Mycoplasma pneumoniae.

BACKGROUND: The aim of this study was to clarify retrospectively the characteristics of children hospitalized for respiratory tract infection caused by macrolide-resistant Mycoplasma pneumoniae (M. pneumoniae). METHODS: Children who were hospitalized for respiratory tract infection due to M. pneumoniae were enrolled in this study. The diagnosis of M. pneumoniae infection was made on the grounds of polymerase chain reaction results. RESULTS: Thirty-three children were hospitalized due to lower respiratory tract infection with M. pneumoniae. Of the 33 children, 31 (median age five years) were identified as being infected with macrolide-resistant M. pneumoniae (A2063G:30, A2064G:1) by sequence analysis. Of the 31 children infected with macrolide-resistant M. pneumoniae, 21 (68%) had received 14- or 15-membered macrolide antibiotics and four (13%) had received minocycline before hospitalization. During hospitalization, minocycline was administered to 16 (52%) of the 31 children infected with macrolide-resistant M. pneumoniae. Of the 20 children infected with macrolide-resistant M. pneumoniae under eight years of age, six (30%) were treated with minocycline during hospitalization. The difference in total febrile days between children receiving minocycline treatment before hospitalization and children not receiving minocycline treatment was three days. CONCLUSIONS: The majority of hospitalized children with respiratory tract infection due to macrolide-resistant M. pneumoniae infection was of preschool age and had received 14- or 15-membered macrolide antibiotics before hospitalization. Because macrolide-resistant M. pneumoniae is widespread in Japan, the administration of minocycline as a second-line antibiotic in children under eight years of age cannot be withheld when clinical symptoms do not improve with macrolide antibiotics.

International collaborative survey on epidemiology of hepatitis E virus in 11 countries.

We conducted seroepidemiological studies on antibody prevalence to hepatitis E virus (HEV) in 5,233 sera from 11 countries to ascertain the present state of HEV infection on a global basis. The prevalence of anti-HEV IgG increased with age in these tested countries, but the rate of antibody positivity was over 20% in the 16-30 year-old group in most of the participating countries, except for Japan, the USA, and Spain. Of patients with acute hepatitis of unknown etiology from Nepal, 56% (14/25) were positive for the IgM class of anti-HEV antibody. In addition, HEV RNAs in the serum from 3 Nepali patients who had the IgM antibody were detected by nested PCR and all of the HEV genes isolated belonged to genotype 1. Our results indicate that HEV is spreading worldwide, not only in developing countries, but also in more industrialized countries than previously thought.

Nitric oxide synthesis in ornithine transcarbamylase deficiency: possible involvement of low no synthesis in clinical manifestations of urea cycle defect.

Nitric oxide (NO) levels in plasma and urine were determined in 5 girls with ornithine transcarbamylase deficiency (OTCD) of late-onset type, who often developed migraine-like headache or vomiting. The patients were found to have low NO synthesis, suggesting that the low NO synthesis contributes to the clinical manifestations of urea cycle defect.