Antibody Deficiency in Patients with Biallelic KARS1 Mutations.

Biallelic KARS1 mutations cause KARS-related diseases, a rare syndromic condition encompassing central and peripheral nervous system impairment, heart and liver disease, and deafness. KARS1 encodes the t-RNA synthase of lysine, an aminoacyl-tRNA synthetase, involved in different physiological mechanisms (such as angiogenesis, post-translational modifications, translation initiation, autophagy and mitochondrial function). Although patients with immune-hematological abnormalities have been individually described, results have not been collectively discussed and functional studies investigating how KARS1 mutations affect B cells have not been performed. Here, we describe one patient with severe developmental delay, sensoneurinal deafness, acute disseminated encephalomyelitis, hypogammaglobulinemia and recurrent infections. Pathogenic biallelic KARS1 variants (Phe291Val/ Pro499Leu) were associated with impaired B cell metabolism (decreased mitochondrial numbers and activity). All published cases of KARS-related diseases were identified. The corresponding authors and researchers involved in the diagnosis of inborn errors of immunity or genetic syndromes were contacted to obtain up-to-date clinical and immunological information. Seventeen patients with KARS-related diseases were identified. Recurrent/severe infections (9/17) and B cell abnormalities (either B cell lymphopenia [3/9], hypogammaglobulinemia [either IgG, IgA or IgM; 6/15] or impaired vaccine responses [4/7]) were frequently reported. Immunoglobulin replacement therapy was given in five patients. Full immunological assessment is warranted in these patients, who may require detailed investigation and specific supportive treatment.

Perioperative risk factors for neurological impairment in infants with acute liver failure following liver transplantation.

BACKGROUND: Neurological impairment is not rare in infants with acute liver failure (ALF). This study aimed to investigate the perioperative risk factors for neurological impairment following liver transplantation (LT) in infantile ALF. METHODS: Retrospective analysis was performed in infants who were younger than 1 year with ALF who subsequently underwent LT at our hospital between January 2005 and December 2016. Patients were considered to have neurological impairment if the Pediatric Cerebral Performance Category score was between 2 and 5 at the age of 6 years. A comparison between the groups of infants with and without neurological impairment was performed, and factors with p < .10 in the comparison were analyzed using univariate logistic regression analysis for neurological impairment. RESULTS: Twenty-six infants survived until 6 years of age, and 31% (8/26) of them had neurological impairment. Patients with neurological impairment were significantly younger in age at ALF onset, had significantly higher pre-LT bilirubin and prothrombin time/international normalized ratio, and stayed significantly longer in the intensive care unit than those without neurological impairment. Total bilirubin (odds ratio (OR) = 1.12, 95% confidence interval (CI) 1.02-1.22, p = .012), indirect bilirubin (OR = 1.10, 95% CI 1.01-1.20, p = .025), direct bilirubin (OR = 1.22, 95% CI 1.01-1.47, p = .040), and age in month at ALF (OR = 0.76, 95% CI 0.58-0.999, p = .049) showed significant association with neurological impairment. CONCLUSIONS: High pre-LT peak bilirubin value and younger age at ALF onset can be perioperative risk factors for neurological impairment after LT in infantile ALF.

Acute cerebellar ataxia during acute COVID-19: A case series and review of the literature.

Acute coronavirus disease 2019 (COVID-19)-associated cerebellar ataxia without multisystem inflammatory syndrome in children (MIS-C) or encephalopathy in children has been rarely reported. We reviewed medical records of hospitalized children who had developed cerebellar ataxia during the acute phase of COVID-19 infection, without MIS-C or encephalopathy, in our center. We also conducted a literature review and summarized the clinical characteristics, treatment, and outcomes. We found three cases in our center and additional three cases in the literature. All patients were male and five were preschool children. The cerebellar symptoms started between day 2 and day 10 during the acute phase of the COVID-19 infection. Two cases were complicated by mutism. One patient received therapy for acute cerebellar ataxia with corticosteroids, and others did not receive any specific therapy for acute cerebellar ataxia. The symptoms improved completely in all patients, with the recovery interval ranging from one week to two months. Further studies are warranted to elucidate the pathogenesis of acute cerebellar ataxia during acute COVID-19 in children.

Longstanding overt ventriculomegaly diagnosed in adolescents, not adults: a pediatric case report.

BACKGROUND: Longstanding overt ventriculomegaly in adults (LOVA) is a new form of progressive hydrocephalus characterized by onset in early childhood and gradual progression into adulthood. Patients with LOVA are usually asymptomatic in childhood. The diagnosis of LOVA in adolescence has not been reported. CASE REPORT: A patient with macrocephaly and mild ventriculomegaly from infancy developed headache exacerbation and cognitive dysfunction at the age of 11 years. Brain magnetic resonance imaging showed mild tri-ventriculomegaly with no radiological aggravation compared to imaging at the age of 8 years. No papilledema was observed. Drainage of 15 ml of spinal fluid via a lumbar puncture relieved the headache and cognitive dysfunction. Based on repeated improvements in cognitive function and headaches after spinal fluid drainage, we diagnosed the patient with LOVA with symptom onset in early adolescence. A ventriculoperitoneal shunt was placed, and the headaches disappeared completely. The full-scale intellectual quotient, verbal comprehension, and working memory improved significantly. CONCLUSIONS: LOVA may manifest as early as adolescence. The clinical presentation, age, clinical, radiological features, and management vary, and a spinal tap exam is useful for diagnosing LOVA, even in children. The spinal tap exam may be indicated in children with longstanding ventriculomegaly and deteriorating neurological symptoms to diagnose this "treatable intellectual disability."

Public attitudes in the clinical application of genome editing on human embryos in Japan: a cross-sectional survey across multiple stakeholders.

Recent advances in genome editing technology are accompanied by increasing public expectations on its potential clinical application, but there are still scientific, ethical, and social considerations that require resolution. In Japan, discussions pertaining to the clinical use of genome editing in human embryos are underway. However, understanding of the public's sentiment and attitude towards this technology is limited which is important to help guide the debate for prioritizing policies and regulatory necessities. Thus, we conducted a cross-sectional study and administered an online questionnaire across three stakeholder groups: the general public, patients and their families, and health care providers. We received responses from a total of 3,511 individuals, and the attitudes were summarized and compared among the stakeholders. Based on the distribution of responses, health care providers tended to be cautious and reluctant about the clinical use of genome editing, while patients and families appeared supportive and positive. The majority of the participants were against the use of genome editing for enhancement purposes. Participants expressed the view that clinical use may be acceptable when genome editing is the fundamental treatment, the risks are negligible, and the safety of the technology is demonstrated in human embryos. Our findings suggest differences in attitudes toward the clinical use of genome editing across stakeholder groups. Taking into account the diversity of the public's awareness and incorporating the opinion of the population is important. Further information dissemination and educational efforts are needed to support the formation of the public's opinion.

Ketogenic Diet for KARS-Related Mitochondrial Dysfunction and Progressive Leukodystrophy.

KARS encodes lysyl-tRNA synthetase, which is essential for protein translation. KARS mutations sometimes cause impairment of cytoplasmic and mitochondrial protein synthesis, and sometimes lead to progressive leukodystrophies with mitochondrial signature and psychomotor regression, and follow a rapid regressive course to premature death. There has been no disease-modifying therapy beyond supportive treatment. We present a 5-year-old male patient with an asymmetrical leukodystrophy who showed overt evidence of mitochondrial dysfunction, including elevation of lactate on brain MR spectroscopy and low oxygen consumption rate in fibroblasts. We diagnosed this patient's condition as KARS-related leukodystrophy with cerebral calcification, congenital deafness, and evidence of mitochondrial dysfunction. We employed a ketogenic diet as well as multiple vitamin supplementation with the intention to alleviate mitochondrial dysfunction. The patient showed alleviation of his psychomotor regression and even partial restoration of his abilities within 4 months. This is an early report of a potential disease-modifying therapy for KARS-related progressive leukodystrophy without appreciable adverse effects.

Serum and cerebrospinal fluid acyclovir pharmacokinetics in a neonate with HSV-2 meningoencephalitis.

A neonatal patient with Herpes simplex virus type-2 meningoencephalitis was treated by high-dose intravenous acyclovir therapy. Serum and cerebrospinal fluid (CSF) concentrations were measured retrospectively, showing that the CSF-to-serum concentration ratio was 0.67-0.71, which was higher than the previously reported values in other age groups.

Incidence and aetiology of serious viral infections in young febrile infants.

AIM: While the incidence and aetiology of serious bacterial infections among febrile infants younger than 90 days old are well studied, those concerning viral infection are not. There are severe life-threatening viral infections requiring immediate intense therapy. The objective of the study is to describe the incidence and aetiology of serious viral infections (SVI) among young febrile infants. METHODS: A retrospective audit was performed covering all the febrile infants younger than 90 days old admitted to a paediatric emergency department in Japan from 2011 to 2013. SVI was defined as a viral illness that may result in permanent organ dysfunctions or life-threatening complications. Diagnostic investigation consisted of urine and blood culture for all infants, cerebrospinal fluid cultures for infants who do not fulfil the low-risk criteria, rapid antigen tests for several viruses in infants with specific symptoms and blood and/or cerebrospinal fluid polymerase chain reaction of possible viruses for infants with fever without a localising source. RESULTS: Of 275 cases, 32 and 45 cases were diagnosed as serious viral and bacterial infections, respectively. Intensive care unit admission occurred for three viral and four bacterial infections. Viral aetiology consisted of respiratory syncytial virus (11 cases), aseptic meningitis (9 cases), enterovirus (6 cases), influenza virus (3 cases), rotavirus (2 cases) and herpes simplex virus-1 (1 case). Respiratory (14 cases), central nervous (12 cases) and circulatory (6 cases) systems were affected. CONCLUSION: SVI was observed in 11.6% of febrile young infants in a paediatric emergency department.

Ultrasound-guided peripheral intravenous access placement for children in the emergency department.

The usefulness of ultrasound guidance in peripheral intravenous access placement has yet to be established in children. In this prospective comparative study, we investigated success rates of intravenous access placement with ultrasound guidance in a pediatric emergency department. After a failed first attempt with the conventional technique, the second and third attempts were conducted using either the ultrasound guidance (a real-time, dual operator method) or the conventional technique. The success rates within the two interventional attempts were then compared. From a total of 712 participants, those with a failed first attempt were allocated to the ultrasound guidance (n = 99) and conventional technique (n = 100) groups. The success rate was significantly lower for the ultrasound guidance (65%) than for the conventional technique (84%) group (p = 0.002, chi-square test). This remained significant after adjusting for confounders with multiple logistic regression analysis (odds ratio 2.60, 95% confidence interval 1.26-5.37, p = 0.001). CONCLUSION: Ultrasound-guided intravenous access placement using a real-time, dual operator method led to a significantly lower success rate than the conventional technique in children with one failed conventional attempt in the emergency department. TRIAL REGISTRATION: UMIN000014730 What is Known: • Children experience a low success rate (about 60% with 1 attempt and about 90% with 4 attempts) for IV access placement. • Ultrasound guidance may lead to a decreased number of attempts and shorter procedural time with comparable overall IV success rate. What is New: • Ultrasound-guided IV placement (a real-time, dual operator method) actually led to a significantly lower IV success rate than the conventional technique in children in the emergency department. • Our result warrants further trials to determine the precise population who benefits from ultrasound guidance.

Tachycardia may prognosticate life- or organ-threatening diseases in children with abdominal pain.

BACKGROUND: Abdominal pain is common in children, but expeditious diagnosis of life- or organ-threatening diseases can be challenging. An evidence-based definition of tachycardia in children was established recently, but its diagnostic utility has not yet been studied. OBJECTIVE: To test the hypothesis that abdominal pain with tachycardia may pose a higher likelihood of life- or organ-threatening diseases in children. METHODS: A nested case-control study was conducted in a pediatric emergency department in 2013. Tachycardia was defined as a resting heart rate of more than 3 standard deviations above the average for that age. Life- or organ-threatening diseases were defined as "disorders that might result in permanent morbidity or mortality without appropriate intervention." A triage team recorded vital signs before emergency physicians attended patients. Patients with tachycardia (cases) and without tachycardia (controls) were systematically matched for age, sex, and month of visit. The groups were compared for the presence of life- or organ-threatening diseases. RESULTS: There were 1683 visits for abdominal pain, 1512 of which had vital signs measured at rest. Eighty-three patients experienced tachycardia, while 1429 did not. Fifty-eight cases and 58 controls were matched. Life- or organ-threatening diseases were more common in the case group (19%) than the control group (5%, p=0.043). The relative risk of tachycardia to the presence of the diseases was 3.7 (95% confidence interval 1.2-12.0). CONCLUSION: Tachycardia significantly increased the likelihood of life- or organ-threatening diseases. Tachycardia in children with abdominal pain should alert emergency physicians to the possibility of serious illness.

Neonatal Staphylococcus lugdunensis urinary tract infection.

Staphylococcus lugdunensis is a known pathogen of infective endocarditis, but not of urinary tract infection. We report a previously healthy neonate without congenital anomalies of the kidney and urinary tract who developed urinary tract infection due to Staphylococcus lugdunensis, illustrating that Staphylococcus lugdunensis can cause urinary tract infection even in those with no urinary tract complications.

Diagnostic odyssey of Guillain-Barré syndrome in children.

BACKGROUND AND OBJECTIVES: A gap exists between difficulty in diagnosis and importance of early recognition and intervention in pediatric Guillain-Barré syndrome (GBS). Therefore, this study aimed to establish a diagnostic odyssey plot that allows "at-a-glance" overview of the diagnostic odyssey of GBS in children, including overall diagnostic delay, physician-related and patient-related diagnostic delays, and length and frequency of diagnostic errors. METHODS: In this single-center retrospective cohort study, standardized data were obtained from children with GBS from 2003 to 2020. Overall diagnostic delay (time between symptom onset and diagnosis), physician-related diagnostic delay (time between the first medical visit and diagnosis), and patient-related diagnostic delay (time between symptom onset and the first medical visit) were analyzed. RESULTS: The study examined a total of 21 patients (11 men, median age 4.5 years). Overall, there were 40 misdiagnoses among 17 patients, while four were diagnosed correctly at the first visit. The overall diagnostic delay was 9 days [interquartile range (IQR), 6-17 days]. Physician-related diagnostic delay, but not patient-related diagnostic delay, was correlated with the overall diagnostic delay. Patients in the late-diagnosed group were more frequently misdiagnosed during their diagnostic odyssey than patients in the other groups. Risk factors associated with diagnostic delay included delayed onset of weakness and sensory deficits, absence of swallowing problems, and misdiagnosis as orthopedic disorders or viral infections. DISCUSSION: A unique diagnostic odyssey exists in pedaitric GBS. Several clinical risk factors were associated with the diagnostic delay.

A Case of Acute Necrotizing Encephalopathy With Multiple Organ Failure Following COVID-19.

Neurological complications are frequent non-respiratory complications associated with coronavirus disease 2019 (COVID-19), and acute encephalopathy (AE) has been reported to occur in 2.2% of patients. Among many phenotypes of AEs, acute necrotizing encephalopathy (ANE) is associated with multiple organ failure (MOF), leading to severe neurological morbidity and mortality. A previously healthy seven-year-old girl presented with a one-day history of fever followed by 12 hours of vomiting and altered consciousness. On arrival, the patient was in shock. Blood tests revealed severe acute liver failure and kidney injury, accompanied by coagulopathy. The serum interleukin-6 levels were also elevated. PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive. A head CT scan showed heterogeneous low-density areas in the bilateral thalamus, without brainstem involvement. She was diagnosed as ANE complicated with MOF (ANE severity score = 6). Intravenous methylprednisolone and therapeutic plasma exchange (TPE) were initiated with neurocritical care. After the introduction of TPE, hemodynamics improved rapidly, followed by gradual improvement in neurological manifestations. Upon follow-up after two months, no neurological or systemic sequelae were noted. Although further studies are needed, our case suggests that early immunomodulatory therapy and TPE may have contributed to the improvement in ANE and MOF associated with COVID-19.