Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge. Several proposed disease mechanisms are discussed, as well as the time of damage and potential treatment options. Furthermore, we combine data from longitudinal, cross-sectional and retrospective studies with the observations of specialist teams treating this disease to depict the brain disease course over time. Based on current data and insights, the majority of patients do not exhibit cognitive decline. A subset of patients, often with early onset cerebral and cerebellar volume loss, can nevertheless experience neurological worsening. While a large number of patients with CG suffer from anxiety and depression, the increased complaints about memory loss, anxiety and depression at an older age are likely multifactorial in origin.

Molecular characterization of novel and rare DNA variants in patients with galactosemia.

Introduction: Galactosemia is an inherited disorder caused by mutations in the three genes that encode enzymes implicated in galactose catabolism. Currently, the only available treatment for galactosemia is life-long dietary restriction of galactose/lactose, and despite treatment, it might result in long-term complications. Methods: Here, we present five cases of newborn patients with elevated galactose levels, identified in the context of the newborn screening program. Genetic analysis concerned a next generation sequencing (NGS) methodology covering the exons and adjacent splice regions of the GALT, GALK1, and GALE genes. Results: Our approach led to the identification of eight rare nonsynonymous DNA variants. Four of these variants, namely, p.Arg204Gln and p.Met298Ile in GALT, p.Arg68Leu in GALK1, and p.Ala180Thr in GALE, were already recorded in relevant databases, yet their clinical significance is uncertain. The other four variants, namely, p.Phe245Leu in GALT, p.Gly193Glu in GALK1, and p.Ile266Leu and p.Ala216Thr in the GALE gene, were novel. In silico analysis of the possible effect of these variants in terms of protein function and stability was performed using a series of bioinformatics tools, followed by visualization of the substituted amino acids within the protein molecule. The analysis revealed a deleterious and/or destabilizing effect for all the variants, supported by multiple tools in each case. Discussion: These results, given the extreme rarity of the variants and the specific phenotype of the respective cases, support a pathogenic effect for each individual variant. Altogether, our study shows that targeted NGS methodologies may offer a time- and cost-effective approach for the genetic investigation of galactosemia and can assist in elucidating the complex genetic background of this disorder.

Infections in Children With Cancer: The Role of the Presence or Absence of Neutropenia.

BACKGROUND: Infections in patients with cancer are a major cause of morbidity and mortality. In most cases, the presence of neutropenia renders them prone to infections to either common or opportunistic pathogens. A wide spectrum of bacterial, viral, or fungal agents is encountered in these patients. AIM: The aim of this study was to evaluate infection types and pathogens in pediatric patients with cancer with and without neutropenia. METHODS: A total of 37 pediatric patients with cancer (median age ± 25% quartile, 6.0 ± 2.0% years) with 70 febrile episodes were evaluated at fever's onset and 48 hours later with complete blood count, C-reactive protein, cultures of biological fluids, polymerase chain reaction, and antibody titers. RESULTS: Of 70 infections, 30 (42.85%) were bacterial, 13 (18.57%) were viral, 3 (4.28%) were fungal, 16 (22.85%) were fever of unknown origin, 18 (25.71%) were opportunistic, and 12 (17.14%) were mixed infections. Neutropenia was detected in 42 (60.0%) of 70 febrile episodes, mainly in patients with hematological malignancies [odds ratio, 2.81 (0.96-8.22); P = 0.059]. Neutropenic patients had higher prevalence of mucocutaneous infections (47.6% vs 7.14%; P = 0.004). Herpes simplex virus 1 infections occurred only in the neutropenic group (14.3%). CONCLUSIONS: Patients with cancer exhibited a high prevalence of bacterial (42.85%), opportunistic (25.7%), and mixed infections (17.14%). Patients with hematological malignancies and neutropenia presented higher frequency of mucocutaneous and herpes simplex virus 1 infections than the nonneutropenic ones.

Immune response to influenza vaccination in children with cancer.

The aim of this study was to evaluate the ability of influenza immunization to evoke a protective immune response among children with cancer. We evaluated 75 children with cancer who received influenza vaccination. Hemagglutination Inhibition Antibody titers were determined before and after vaccination. The protective rates after vaccination were 79% for H1N1, 75% for H3N2 and 59% for influenza B virus whereas the seroconversion rates were 54%, 44% and 43% respectively. The differences pre- and post-vaccination were significant regardless the method which was used: seroprotection changes, seroconversion and geometric mean titers analyses. Variables such as the pre-vaccination antibody titers, the time when the responses were measured after the vaccination, the age and the type of malignancy as well as the absolute lymphocyte count were found to be correlated with the immune response but the findings were different for each vaccine subunit. In conclusion, influenza vaccination provides protection in a remarkable proportion of pediatric cancer patients whereas this protection is more obvious against H1N1 and H3N2 compared to influenza B. The immune response after vaccination is significant and seems to be influenced by a variety of factors.

Insulin resistance and cardiometabolic risk factors in obese children and adolescents: a hierarchical approach.

BACKGROUND: This study aims to globally assess the network of insulin resistance (IR)-related factors in a sample of overweight and obese Greek youths. METHODS: A total of 185 subjects were examined, and IR was quantified by homeostasis model assessment (HOMA-IR). Multivariate hierarchical approach was performed, and five distinct levels were recognized, namely, immutable demographic features and early life parameters, current anthropometric measures, IR, unfavorable clinical conditions, and social parameters. Two analyses were performed based on HOMA-IR cut-off values (3.16 and, as an alternative, 3.99). RESULTS: Obesity was associated with IR (adjusted OR=3.19, 95% CI: 1.12-9.09). IR steadily predicted low HDL (adjusted OR=5.75, 95% CI: 1.58-20.87), hypertriglyceridemia (adjusted OR=10.28, 95% CI: 1.18-89.55), and systolic hypertension. At the alternative analysis, IR was also associated with older age, older age at menarche, hyperuricemia, and low school grades. CONCLUSION: Emerging on the grounds of obesity, IR confers risks for dyslipidemia and hypertension at a relatively early age. Along with weight loss, interventions targeted at IR are required to prevent cardiometabolic risk in adolescence.

Immunoassay-based serum hepcidin reference range measurements in healthy children: differences among age groups.

BACKGROUND: Hepcidin is a peptide hormone that plays a key role in regulating iron absorption from the small intestine and body iron distribution. Alterations in hepcidin concentrations have been associated with chronic inflammatory conditions or inherited diseases of iron metabolism. The aim of our study was to evaluate healthy children in order to define normal reference range of serum hepcidin concentrations. The universal use of a reliable commercial ELISA kit gives the ability to compare our results with those from previous studies. METHODS: We evaluated 180 healthy children (88 boys, mean age: 67.55 ± 39.26 months, median: 60, range: 24-156 months) aged 2-12 years, using an immunoassay kit. RESULTS: Hepcidin median values were 46.94 ng/ml for boys and 46.79 ng/ml for girls. No significant differences were observed between boys and girls. There seem to be significantly higher values of hepcidin in older children (10-12 years old). This trend was constant and statistically significant in boys after gender and age group stratification. Although this trend was more prominent in girls, it was not statistically significant. CONCLUSIONS: This study aims at setting up reference values for serum hepcidin concentrations in healthy pediatric population by using a well-established laboratory kit. The difference in hepcidin concentrations in older children could be attributed to different growth rates. Additionally, differences between values in adults and children could reflect alterations in iron metabolism between those two age groups.

Multiple autoimmunity, type 1 diabetes (T1DM), autoimmune thyroiditis and thyroid cancer: is there an association? A case report and literature review.

Type 1 diabetes mellitus (T1DM) is characterized by selective autoimmune destruction of pancreatic b-cells, resulting in insulin deficiency. Associated autoimmune disorders, such as celiac disease, autoimmune thyroiditis, and gastritis, can coexist in patients with T1DM. These disorders are characterized by the presence of antibodies against tissue transglutaminase (anti-tTG-IgA), thyroglobulin, and thyroid peroxidase (anti-TG, anti-TPO), as well as antibodies against gastric parietal cells. Children with T1DM may also develop organ-specific multiple autoimmunity, with the coexistence of one or more autoimmune disorders. Furthermore, there is a lot of controversy regarding the role of thyroid autoimmunity in the pathogenesis of thyroid cancer. We present a child with T1DM and multiple autoimmunity including autoimmune Hashimoto's thyroiditis (HT), who developed thyroid cancer. The literature on the prevalence of associated autoimmunity in children with T1DM and the prevalence, pathogenesis, and timely diagnosis of thyroid cancer among patients with HT is also reviewed.

Deep vein thrombosis and pulmonary embolism in a child with diabetic ketoacidosis and protein s deficiency: a case report.

INTRODUCTION: Diabetic ketoacidosis (DKA) is considered a hypercoagulable state, which may be exacerbated in patients with thrombophilia and lead to thrombosis. CASE REPORT: We report on a 5.5-year-old boy, who was admitted to the pediatric department with DKA due to newly diagnosed type 1 diabetes. Low-grade fever was reported for 6 days prior to admission and continued during DKA management, with negative septic screening. After DKA management, the child developed symptoms of iliofemoral deep vein thrombosis (DVT). A family history of protein S (PS) deficiency was revealed. He was initially treated intravenously with antibiotics and unfractionated heparin, which, after 2 days, was switched to low-molecular-weight heparin and vitamin K antagonist (VKA) due to poor anticoagulant response. On the 6th day of anticoagulant treatment, the patient presented with pulmonary embolism (PE); he continued with VKA and antibiotics, with significant clinical improvement. Prolonged fever was attributed to DVT and PE. The patient was discharged on oral anticoagulants and insulin. CONCLUSION: We report on a child with congenital PS deficiency and DKA who developed DVT and PE despite anticoagulant treatment. It is important in children presenting with DKA to seek thoroughly for a medical history of thrombophilia and to start early thromboprophylaxis in such cases in order to prevent a possible thrombosis.

Serum hepcidin and ferritin to iron ratio in evaluation of bacterial versus viral infections in children: a single-center study.

BACKGROUND: Differential diagnosis of childhood infections is important. Several biochemical indices steer diagnosis toward bacterial agents, although the data are often not definitive. Hepcidin is a central component of blood iron, and ferritin alterations occur during infections. We measured hepcidin changes and evaluated ferritin to iron ratio (FIR) in patients with suspected infections. METHODS: We studied 69 children with infection and an equal number of matched controls during a 3-year period. A bacterial agent was demonstrated in 17 and a viral pathogen in 52 of the patients. Hematologic and biochemical tests were performed on all children including ferritin, iron and hepcidin. FIR was calculated and receiver operating characteristic curve analysis was performed to evaluate the best FIR cutoff value to discriminate between patients and controls and between patients with bacterial infections and viral infections. RESULTS: Hepcidin, ferritin and FIR were significantly higher and iron values significantly lower in febrile patients than its controls. Patients with bacterial infection had significantly lower iron and higher FIR than those with viral infection. FIR had high accuracy discriminating patients from controls but only moderate accuracy discriminating bacterial from viral infected patients. CONCLUSIONS: If further studies with larger samples confirm these observations, FIR could be used as an inexpensive, rapid and easily performed complementary index for diagnosis of bacterial infections.