Agnieszka Gach

Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11

Background A 12-week-old female presented with neonatal diabetes. Insulin therapy alleviated the diabetes, but the patient showed marked motor and mental developmental delay. The patient underwent genetic evaluation at the age of 6 years, prompted by reports that mutations in the KCNJ11 gene caused neonatal diabetes.Investigations Genomic sequencing of the ATP-sensitive potassium (KATP) channel gene KCNJ11 and in vitro functional analysis of the channel defect, and single-photon emission CT imaging before and after glibenclamide therapy.Diagnosis Genetic evaluation revealed a missense mutation (His46Leu) in KCNJ11, which encodes the Kir6.2 subunit of the KATP channel, conferring reduced ATP sensitivity. Functional studies demonstrated that the mutant channels were strongly inhibited by the sulfonylurea tolbutamide.Management Sulfonylurea (glibenclamide) treatment led to both improved glucose homeostasis and an increase in mental and motor function.

The cross-reactivity of anti-asparaginase antibodies against different L-asparaginase preparations.

Repeated administration of l-asparaginase leads to the development of specific antibodies and hypersensitivity reactions. The aim of the study was to evaluate a possible cross-reaction of anti-asparaginase antibodies, developed against the native E. colil-asparaginase (Asparaginase Medac), with other preparations of the enzyme. Sixteen patients with acute lymphoblastic leukemia, in whom in the reinduction phase of treatment hypersensitivity against l-asparaginase was observed and/or the presence of anti-asparaginase antibodies was established were recruited for the present study. Ten out of 16 tested sera showed cross-immunoreactivity to PEG-asparaginase, while no reactivity to l-asparaginase derived from Erwinia chrysantemi was observed. Since cross-reacting antibodies were also found in sera of patients with no overt allergic reaction, l-asparaginase may undergo silent inactivation during the reinduction phase of therapy. This finding is of clinical importance with regard to appropriate dosage and necessitates careful enzyme activity monitoring in all patients undergoing repeated treatment with various l-asparaginase preparations.

Transfer to Sulphonylurea Therapy in Adult Subjects With Permanent Neonatal Diabetes Due to KCNJ11-Activating Mutations Evidence for improvement in insulin sensitivity

A ctivating mutations in the KCJN11 gene encoding in the ATP-sensitive K channel (KATP channel) subunit Kir6.2 were reported (1) as the most common cause of permanent neonatal diabetes (PND). Recently, it has been shown that most subjects with Kir6.2 mutations could be switched from insulin to sulfonylurea and that such treatment is both safe and highly effective, at least in the short term (2,3). Notably, the majority of reported successfully transferred patients were children. Data on adults are very scarce, and there are few mutation carriers transferred off insulin (2,4). Moreover, some adult subjects are unable to switch from insulin to sulfonylurea (2). We have recently identified four adult carriers of a Kir6.2 mutation and provided evidence that they, before the sulfonylurea exposure, were characterized by decreased insulin sensitivity (5). Here, we report their successful transfer to sulfonylurea.

Efficacy and Safety of Sulfonylurea Use in Permanent Neonatal Diabetes Due to KCNJ11 Gene Mutations: 34-Month Median Follow-Up

BACKGROUND Recently, many patients with Kir6.2-related permanent neonatal diabetes mellitus (PNDM) have been successfully transferred from insulin therapy to sulfonylurea (SU) treatment. The long-term efficacy and safety of SU treatment in PNDM patients, however, have not yet been determined. METHODS We monitored glycemic control and the occurrence of potential side effects in 14 Kir6.2-related PNDM patients from Poland (median age, 12.0 years; range, 5-50 years) who were transferred to SU therapy at least 2 years ago. Three of the 14 patients were lost to follow-up, whereas for the remaining 11 individuals the median follow-up was 34 months (range, 27-51 months). RESULTS The initial reduction of glycated hemoglobin (HbA1c) after the switch to SU (approximately 3-6 months post-transfer) was 1.68% (range, 0.3-3.7%), and good metabolic control was maintained over the entire period of observation with an average HbA1c level of 6.0% (range, 5.3-6.7%) at the last visit. This was accompanied by a substantial drop in SU dose by 0.24 mg/kg, which constituted a 38.0% decrease. A rapid progression of retinal changes was observed in one patient, a 34-year-old woman at the beginning of the observation, with preexisting proliferative diabetic retinopathy. No causal relationship between these changes and SU treatment could be proven. Neither serious side effects nor progression of diabetes complications was observed in any other patients. No detrimental effect on growth in the observed minors was recorded. CONCLUSIONS In summary, the switch from insulin therapy to SU treatment in PNDM related to KCNJ11 mutations was found to be an efficient and safe therapeutic method over a period of 34-month median follow-up. Although no serious side effects were associated with SU treatment, their use in Kir6.2 PNDM requires further attention, particularly in children, adolescents, and patients with advanced chronic diabetes complications.

Assessment of insulin sensitivity in adults with permanent neonatal diabetes mellitus due to mutations in the KCNJ11 gene encoding Kir6.2.

Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of ATP-sensitive potassium channel have been described in patients with permanent neonatal diabetes mellitus (PNDM). The main pathophysiological feature of PNDM associated with Kir6.2 mutations is a profound defect in insulin secretion. However, the expression of Kir6.2 protein is not limited to beta-cells; it also includes skeletal muscles, heart, brain, and peripheral nerves. Thus, the hypothesis that Kir6.2 mutations may influence insulin sensitivity in humans seems justified. Moreover, this notion is additionally supported by an animal model of Kir6.2 knock-out mice. Four adult carriers of a Kir6.2 mutation from the Polish population (mean age 31.5 years, range 20-50) were available for this study that aimed to evaluate their insulin sensitivity by the hyperinsulinemic euglycemic clamp technique. Three subjects carried the R201H mutation and one patient was a carrier of the K170N mutation. In addition, eight healthy volunteers with normal glucose tolerance were examined for comparison (mean age 31.0 years, range 20-41). The mean M value, i.e. the amount of metabolized glucose, for PNDM cases equaled 4.49 mg/(kg x min) (range 2.76-6.66) and was significantly lower than in the control group (9.64 mg/(kg x min), range 4.59-18.00). This observation suggests that impaired insulin sensitivity, in addition to profoundly decreased insulin secretion, contributes to the clinical picture of PNDM resulting from mutations in the Kir6.2 gene. An additional factor that might influence insulin sensitivity in our diabetes patients is glucose toxicity that may have appeared due to poor metabolic control prior to the examination (mean HbA1c = 8.95%). The intriguing question to be answered in the future is whether an improvement in insulin action could be seen following the transfer of Kir6.2 mutation carriers to sulphonylurea compounds.

Association of Maternal and Fetal Single-Nucleotide Polymorphisms in Metalloproteinase (MMP1, MMP2, MMP3, and MMP9) Genes with Preeclampsia

Background Metalloproteinases (MMPs) play a pivotal role during the process of trophoblast invasion and placentation. The appearance of five functional single-nucleotide polymorphisms (SNP) in the genes of the metalloproteinases most commonly implicated in the implantation process may influence the development of preeclampsia. Methods Blood samples were collected from 86 mothers and 86 children after preeclampsia and 85 mothers and 85 children with uncomplicated pregnancies. The distribution of genotypes for −1607 1G/2G MMP1, −735 C/T MMP2, −1306 C/T MMP2, −1171 5A/6A MMP3, and −1562C/T MMP9 polymorphisms was determined by RFLP-PCR. Results The occurrence of 1G/1G MMP1 or 5A/5A MMP3 genotype in the mother or 1G/1G MMP1 or 5A/6A MMP3 genotype in the child is associated with preeclampsia development. Moreover, simultaneous maternal and fetal 1G/1G homozygosity increases the risk of preeclampsia development 2.39-fold and the set of maternal 5A/5A and fetal 5A/6A MMP3 genotypes by over 4.5 times. No association between the carriage of studied MMP2 or MMP9 polymorphisms and the predisposition to preeclampsia was found. Conclusion The maternal 1G/1G MMP1 and 5A/5A MMP3 and fetal 1G/1G MMP1 and 5A/6A MMP3 gene polymorphisms may be strong genetic markers of preeclampsia, occurring either individually or together.

Folate status, regulatory T cells and MTHFR C677T polymorphism study in allergic children.

PURPOSE This study aimed to investigate early-life folate serum concentrations in children with food, inhalant or mixed type allergy. The influence of folate levels on the FoxP3 expression in Treg (regulatory T) cells in the studied children, taking into account the MTHFR (5,10-methylenetetrahydrofolate reductase) genotypes was also analyzed. MATERIAL AND METHODS The study was performed in 83 allergic children (study group) and 49 healthy children (control group), aged 2-72 months. Medical history of each child was obtained and laboratory tests (serum folic acid concentrations and MTHFR C677T polymorphism) were carried out. The percentage of Treg cells was evaluated in almost a half of the examined subjects (48.5%). RESULTS Significantly higher serum folate levels in the group of children with food allergy than in those with inhalant allergy was confirmed (P=0.037). In the study group the TT homozygotes were characterized by significantly lower folate concentrations than CC homozygotes (P=0.045). A negative correlation was demonstrated between the FoxP3 expression in CD4+CD25highFoxP3+ peripheral blood lymphocytes and serum folic acid concentrations. The correlation was more pronounced in the group of allergic children and it was statistically significant (r=-0.339, P<0.05). CONCLUSIONS The results of the study indicate a possibility of some effects of folate status on Treg cells, thus suggesting their potential role in the development and course of allergy in children.