Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant <Emphasis Type="Italic">ABCC8/KCNJ11</Emphasis> mutations

Aims/hypothesis  

Dominantly acting loss-of-function mutations in the ABCC8/KCNJ11 genes can cause mild medically responsive hyperinsulinaemic hypoglycaemia (HH). As controversy exists over whether these mutations predispose to diabetes in adulthood we investigated the prevalence of diabetes in families with dominantly inherited ATP-sensitive potassium (K_ATP) channel mutations causing HH in the proband.     

The Renal Cysts and Diabetes (RCAD) Syndrome in a Child with Deletion of the Hepatocyte Nuclear Factor-1β Gene

The authors describe a 14-yr-old boy who presented with non-ketotic hyperglycemia, elevated serum creatinine levels and deranged liver function. There was no microalbuminuria or proteinuria. He also had mild mental retardation with learning difficulties. Ultrasonography of the abdomen revealed multiple renal cysts of varying sizes in both the kidneys. Dosage analysis of the hepatocyte nuclear factor (HNF)-1β gene by multiplex ligation-dependent probe amplification (MLPA) detected a heterozygous whole gene deletion (p.Met1_Trp557del). This finding is consistent with the diagnosis of renal cysts and diabetes (RCAD) syndrome. This is the first case of the RCAD syndrome reported in an Indian patient. Pediatricians need to be aware of this entity whenever renal disease is seen in a diabetic child in the absence of microalbuminuria or proteinuria.     

Piloting education days for patients with early rheumatoid arthritis and their partners: a multidisciplinary approach

Objectives: To develop, pilot, refine and reassess an education day presented by a rheumatology multidisciplinary team (MDT) for recently diagnosed (less than six months) rheumatoid arthritis (RA) patients and their partners/carers. Methods: A patient education day was developed drawing on an assessment of local patient educational needs and preferences and input from a rheumatology MDT. Feedback from the first education day (2004) (Day 1; 12 patients; age range 19–63 years (median 46); 10 of whom were accompanied by a partner) informed the development of a second education day (2005) (Day 2; 19 patients; age range 36–75 years (median 57.5); 13 of whom were accompanied by a partner). Participants completed evaluation forms on both days and at follow‐up between six and seven weeks later, rating each session on a 5‐point scale on dimensions of ‘informative’, ‘useful’, ‘interesting’ and ‘enjoyable’. A global rating of the day's ‘usefulness’ was completed at the end of each day on a 10‐point scale. Participants were asked to write comments on each session and on aspects of the entire day. RA knowledge, and general and RA‐specific self‐efficacy were also measured on day 2 (and at follow‐up) using the 12‐item Patient Knowledge Questionnaire, the 10‐item generalized self‐efficacy scale and a four‐item RA‐specific self‐efficacy scale. Both qualitative and quantitative methodologies were used in the analysis. Results: Ratings for individual sessions were all high, with no session being rated below 4 out of 5 (1 = ‘totally disagree’ to 5 = ‘totally agree’) on both days. The majority of patients (84%) and their partners (57%) responded to the follow‐up. Many had used the information package distributed on the day. Some patients and their partners reported positive changes in RA management. Although patient knowledge did not increase significantly (medians 11 at both time points, p = 0.054) (Day 2), RA self‐efficacy improved (baseline 11 and 14, respectively), suggesting that patients were more confident in managing their condition (p = 0.010). Conclusions: The development of this ‘local’ education and information intervention was carried out in line with Medical Research Council guidelines, and the lessons learned from Day 1 informed further development for Day 2. A one‐day format for education of early RA involving the rheumatology MDT was rated highly by participants and warrants further examination. Although this study was a small ‘local’ intervention, its strengths are that it informs the possibility of wider developments of this kind using a MDT. Copyright © 2008 John Wiley & Sons, Ltd.     

Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype

Aims/hypothesis Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K_ATP) channel, cause both permanent and transient neonatal diabetes. A minority of patients also have neurological features. The identification of a KCNJ11 mutation has important therapeutic implications, as many patients can replace insulin injections with sulfonylurea tablets. We aimed to determine the age of presentation of patients with KCNJ11 mutations and to examine if there was a relationship between genotype and phenotype.Subjects and methods KCNJ11 was sequenced in 239 unrelated patients from 21 countries, who were diagnosed with permanent diabetes before 2 years of age.Results Thirty-one of the 120 patients (26%) diagnosed in the first 26 weeks of life had a KCNJ11 mutation; no mutations were found in the 119 cases (0%) diagnosed after this age. Fourteen different heterozygous mutations were identified, with the majority resulting from de novo mutations. These include seven novel mutations: H46Y, R50Q, G53D C166Y, K170T, L164P and Y330S. All 11 probands with the most common mutation, R201H, had isolated diabetes. In contrast, developmental delay in addition to diabetes was seen in four of five probands with the V59M mutation and two of four with the R201C mutation. Five patients with developmental delay, epilepsy and neonatal diabetes (DEND) syndrome had unique mutations not associated with other phenotypes.Conclusions/interpretation KCNJ11 mutations are a common cause of permanent diabetes diagnosed in the first 6 months and all patients diagnosed in this age group should be tested. There is a strong genotype–phenotype relationship with the mutation being an important determinant of associated neurological features.     

Rapid and sensitive real-time polymerase chain reaction method for detection and quantification of 3243A>G mitochondrial point mutation

Maternally inherited diabetes and deafness and mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes result from the 3243A>G mitochondrial point mutation. Current methods to detect the presence of the mutation have limited sensitivity and may lead to potential misclassification of patients with low levels of heteroplasmy. Here, we describe development and validation of a rapid real-time polymerase chain reaction (PCR) method for detection and quantification of levels of heteroplasmy in a single assay. Standard curve analysis indicated that the sensitivity of detection was less than 0.1%. Time from sample loading to data analysis was 110 minutes. We tested 293 samples including 23 known positives, 40 known negatives, and 230 samples from patients clinically classified as having type 2 diabetes. All positive samples were correctly detected, and of those samples previously quantified, heteroplasmy levels determined using the real-time assay correlated well (r(2) = 0.88 and 0.93) with results from fluorescently labeled PCR-restriction fragment length polymorphism and pyrosequencing methods. Screening of 230 patients classified as having type 2 diabetes revealed one patient with 0.6% heteroplasmy who had previously tested negative by PCR-restriction fragment length polymorphism. Real-time PCR provides rapid simultaneous detection and quantification of the 3243A>G mutation to a detection limit of less than 0.1%, without post-PCR manipulation.     

Large variation in t(11;14)(q13;q32) and t(14;18)(q32;q21) translocation product size is confirmed by sequence analysis of PCR products

Polymerase chain reaction is commonly used to detect t(11;14)(q13;q32) and t(14;18)(q32;q21) chromosomal translocations associated with mantle cell lymphoma and follicular lymphoma. We tested a total of 482 samples from patients with suspected non-Hodgkin's lymphoma and sequenced unusual-sized t(11;14)(q13;q32) and t(14;18)(q32;q21) products from 33 of these patients. BCL-1 or BCL-2 gene rearrangements were confirmed in 23 of 33 patients (70%). Considerable size variation was observed using t(11;14) primers, with MTCA and MTCB t(11;14) products ranging from 234 to 934 bp and 143 to 560 bp respectively. Less variability was observed for t(14;18) Major Breakpoint Region (MBR) products (100-252 bp) but Minor Cluster Region (MCR) products ranged from 217 to 498 bp. We demonstrate the utility of sequence analysis to confirm unusual-sized translocation products and reduce false-positive results because of nonspecific amplification.