Developmental Delay, Epilepsy And Neonatal Diabetes Syndrome Research Articles

Cognitive deficits and impaired hippocampal long-term potentiation in KATP-induced DEND syndrome

ATP-sensitive potassium (KATP) gain-of-function (GOF) mutations cause neonatal diabetes, with some individuals exhibiting developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. Mice expressing KATP-GOF mutations pan-neuronally (nKATP-GOF) demonstrated sensorimotor and cognitive deficits, whereas hippocampus-specific hKATP-GOF mice exhibited mostly learning and memory deficiencies. Both nKATP-GOF and hKATP-GOF mice showed altered neuronal excitability and reduced hippocampal long-term potentiation (LTP). Sulfonylurea therapy, which inhibits KATP, mildly improved sensorimotor but not cognitive deficits in KATP-GOF mice. Mice expressing KATP-GOF mutations in pancreatic β-cells developed severe diabetes but did not show learning and memory deficits, suggesting neuronal KATP-GOF as promoting these features. These findings suggest a possible origin of cognitive dysfunction in DEND and the need for novel drugs to treat neurological features induced by neuronal KATP-GOF.

Structure based analysis of KATP channel with a DEND syndrome mutation in murine skeletal muscle

Developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, the most severe end of neonatal diabetes mellitus, is caused by mutation in the ATP-sensitive potassium (KATP) channel. In addition to diabetes, DEND patients present muscle weakness as one of the symptoms, and although the muscle weakness is considered to originate in the brain, the pathological effects of mutated KATP channels in skeletal muscle remain elusive. Here, we describe the local effects of the KATP channel on muscle by expressing the mutation present in the KATP channels of the DEND syndrome in the murine skeletal muscle cell line C2C12 in combination with computer simulation. The present study revealed that the DEND mutation can lead to a hyperpolarized state of the muscle cell membrane, and molecular dynamics simulations based on a recently reported high-resolution structure provide an explanation as to why the mutation reduces ATP sensitivity and reveal the changes in the local interactions between ATP molecules and the channel.

Severe Developmental Delay, Epilepsy and Neonatal Diabetes (DEND) Syndrome: A Case Report

Developmental delay, Epilepsy and Neonatal Diabetes (DEND) syndrome is the most severe form of Permanent Neonatal Diabetes with KCNJ11 gene mutation which accounts for most of the cases. We report the first DEND syndrome in Malaysia with heterozygous missense mutation Q52R at KCNJ11 (Kir6.2) gene with delayed presentation beyond 6 months of age and failure to transition to glibenclamide. This report signifies the phenotypical variability among patients with the same genetic mutation and the different response to treatment.

Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas

Permanent neonatal diabetes mellitus (PNDM) is a rare form of diabetes diagnosed within the first 6 months of life. Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM. The majority of the patients represent isolated cases resulting from de novo mutations. Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay, is called developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome and the milder form, with less severe developmental delay and without epilepsy, is designated intermediate DEND syndrome. Individuals with KCNJ11 mutations have been successfully transitioned from insulin to sulfonylurea (SU) therapy. Furthermore, there have been cases reported with variable improvement in neurological function following a successful switching. We describe a 12-year-old Portuguese girl with PNDM due to the previously reported R201C mutation in the KCNJ11 gene. Her medical history includes prematurity and moderate developmental delay. The mutation was inherited from her mother who has isolated PNDM. The patient was successfully transferred from insulin to SU, whereas her mother showed SU resistance. Despite good glycemic control, no improvements in the cognitive performance were verified. We present our experience in switching treatment from insulin to oral SUs in this family, and also discuss whether or not the girl's developmental delay is related with the Kir6.2 mutation. To our knowledge, this is the first Portuguese patient reported with successful transition to SU treatment.

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

Successful transfer to sulfonylurea therapy in an infant with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome and a novel ABCC8 gene mutation

What does the membrane KATP channel really do in skeletal muscle?

In this issue of The Journal of Physiology, Boudreault et al. (2010) present an interesting phenomenon resulting from inactivation or absence of the skeletal muscle surface membrane KATP channel. Muscles with non-functional KATP channels were subjected to two fatigue protocols separated by at least 15 min. During the second fatigue protocol compared to the first, tetanic force was maintained at a higher level, and the concentration of free myoplasmic Ca2+ ([Ca2+]i) and force during the inter-tetanic intervals showed only modest increases. The reason for the improved performance in the second fatigue protocol remains unclear. The KATP channel is abundant in the sarcolemma of striated muscle. It consists of four Kir6.x subunits that form the pore and four SURx ATP binding subunits (for recent review see Flagg et al. 2010). As the name suggests, ATP is the controller of the channel keeping it closed when [ATP] is above 1 mm (Spruce et al. 1985). Other modulators of the KATP channel, e.g. H+, PIP2, and phosphorylation, have also been described but at normal [ATP]i, their effect is modest. Interestingly, electrophysiological, pharmacological and gene analysis data indicate that while the predominant form of the striated muscle KATP channel is composed of Kir6.2 and SUR2A complexes, there can also be significant levels of Kir6.1, SUR2B and SUR1 in some muscles. The Kir6.1 and Kir6.2 pores have widely different conductances (35 and 80 pS, repectively) and this together with the heterogeneity of the SUR subunits underlies the maximal KATP current density seen in different mouse muscles, ranging from 10 pA μm−2 in the slow soleus to 80 pA μm−2 in the fast tibialis anterior (Tricario et al. 2006). The striking behaviour of the channel in opening at low levels of ATP led to its examination as a factor in muscle fatigue. A decline in muscle force or power output (commonly called fatigue) occurs when muscles are repeatedly contracted. Exercise involves a huge increase in ATP consumption and an attractive hypothesis advanced was that as [ATP]i declines, muscle KATP channels would open, partially depolarise the membrane and impair action potential activated release of Ca2+ from the sarcoplasmic reticulum. Thus, there would be a beneficial effect in that muscle energy consumption would be reduced. Despite the fact that [ATP]i rarely falls by more than 25% even during intensive exercise, the concept of ATP compartmentalisation and possibility of far greater declines in [ATP] close to the surface membrane KATP channel allowed this hypothesis to thrive. Pharmacological manipulations of the membrane KATP channel have yielded equivocal results. Opening the channel accelerated the loss of force but so too, in many but not all experiments, did blockers of the membrane KATP channel. When Kir6.2 knockout mice were tested, it was obvious that tetanic force production was markedly less than in wild-type mice. Fatigue developed more rapidly in muscles from Kir6.2 knockout mice than in those from wild-type mice (Cifelli et al. 2007). Boudreault et al. show in the present study that this rapid development of fatigue could be largely prevented by an earlier fatigue run. Thus, the role of KATP channels in fatigue is dubious. If the membrane KATP channel is not important in fatigue, then what is its role? One clue comes from the finding in the present paper of Boudreault et al. that muscles with non-functional membrane KATP channels have a slower recovery of force after the end of the fatiguing exercise. This slower recovery of force after exercise was preceded by a marked elevation in inter-tetanic concentration of internal Ca2+, which entered the muscle cells through verapamil sensitive channels, presumably L-type channels. It is well known that prolonged elevated [Ca2+]i leads to impaired force production and locally activates Ca2+-dependent proteases (Murphy & Lamb, 2009). Thus, the presence of functional membrane KATP channels may assist in limiting the influx of Ca2+ during sustained contractile activity. But for the fortunate individual without a mutation of Kir6.2 or the SUR subunits of the KATP channel, this is not a factor that will limit exercise capacity. Mutations of the subunits in the membrane KATP channel that lead to clinical manifestations are fortunately rare. One of the better known is the developmental delay, epilepsy and neonatal diabetes (DEND) syndrome which is accompanied by muscle flaccidity and motor impairment. Recently, a mouse model carrying a human mutation known to produce the DEND syndrome was developed. When expressed only in the muscles, no muscle or motor deficit was observed. However, when expressed in neurons, clear muscle and motor impairments were found (Clark et al. 2010). These results again reiterate the point that under normal daily activities, non-functional KATP channels in the membrane of skeletal muscle have little consequence but when the isolated muscle is fatigued to the extreme in vitro, some impairment may be seen.

A novel mutation causing DEND syndrome

Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome. We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant K(ATP) channels heterologously expressed in Xenopus oocytes. We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell K(ATP) currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities. We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.

New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features

Activating mutations in the ABCC8 gene that encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the pancreatic islet ATP-sensitive K(+) channel (K(ATP) channel) cause both permanent and transient neonatal diabetes. Recently, we have described the novel mechanism where basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore is increased. In our present study, we identified six new heterozygous ABCC8 mutations, mainly in patients presenting the transient form of neonatal diabetes (six of eight), with a median duration of initial insulin therapy of 17 months (range 0.5-38.0). Most of these mutations map to key functional domains of SUR1. Whereas Kir6.2 mutations are a common cause of permanent neonatal diabetes and in a few cases associate with the DEND (developmental delay, epilepsy, and neonatal diabetes) syndrome, SUR1 mutations are more frequent in transient (52%) compared with permanent (14%) neonatal diabetes cases screened for ABCC8 in our series. Although ketoacidosis is frequent at presentation, SUR1 mutations associate mainly with transient hyperglycemia, with possible recurrence later in life. One-half of the SUR1 neonatal diabetic patients presented with de novo mutations. In some familial cases, diabetes is not always present in the adult carriers of SUR1 mutations, supporting variability in their clinical expressivity that remains to be fully explained.

KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features

Heterozygous activating mutations in the gene encoding for the ATP-sensitive potassium channel subunit Kir6.2 (KCNJ11) have recently been shown to be a common cause of permanent neonatal diabetes. Kir6.2 is expressed in muscle, neuron and brain as well as the pancreatic beta-cell, so patients with KCNJ11 mutations could have a neurological phenotype in addition to their diabetes. It is proposed that some patients with KCNJ11 mutations have neurological features that are part of a discrete neurological syndrome termed developmental Delay, Epilepsy and Neonatal Diabetes (DEND), but there are also neurological consequences of chronic or acute diabetes. We identified KCNJ11 mutations in four of 10 probands with permanent neonatal diabetes and one affected parent; this included the novel C166F mutation and the previously described V59M and R201H. Four of the five patients with mutations had neurological features: the patient with the C166F mutation had marked developmental delay, severe generalised epilepsy, hypotonia and muscle weakness; mild developmental delay was present in the patient with the V59M mutation; one patient with the R201H mutation had acute and chronic neurological consequences of cerebral oedema and another had diabetic neuropathy from chronic hyperglycaemia. In conclusion, the clinical features in these patients support the existence of a discrete neurological syndrome with KCNJ11 mutations. The severe DEND syndrome was seen with the novel C166F mutation and mild developmental delay with the V59M mutation. These features differ markedly from the neurological consequences of acute or chronic diabetes.

Activating Mutations in Kir6.2 and Neonatal Diabetes

Closure of ATP-sensitive K(+) channels (K(ATP) channels) in response to metabolically generated ATP or binding of sulfonylurea drugs stimulates insulin release from pancreatic beta-cells. Heterozygous gain-of-function mutations in the KCJN11 gene encoding the Kir6.2 subunit of this channel are found in approximately 47% of patients diagnosed with permanent diabetes at <6 months of age. There is a striking genotype-phenotype relationship with specific Kir6.2 mutations being associated with transient neonatal diabetes, permanent neonatal diabetes alone, and a novel syndrome characterized by developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. All mutations appear to cause neonatal diabetes by reducing K(ATP) channel ATP sensitivity and increasing the K(ATP) current, which inhibits beta-cell electrical activity and insulin secretion. The severity of the clinical symptoms is reflected in the ATP sensitivity of heterozygous channels in vitro with wild type > transient neonatal diabetes > permanent neonatal diabetes > DEND syndrome channels. Sulfonylureas still close mutated K(ATP) channels, and many patients can discontinue insulin injections and show improved glycemic control when treated with high-dose sulfonylurea tablets. In conclusion, the finding that Kir6.2 mutations can cause neonatal diabetes has enabled a new therapeutic approach and shed new light on the structure and function of the Kir6.2 subunit of the K(ATP) channel.