Other entities represented in this entry:
ORPHA: 99885;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11p15.1 | Diabetes, permanent neonatal 2, with or without neurologic features | 618856 | Autosomal dominant | 3 | KCNJ11 | 600937 |
A number sign (#) is used with this entry because of evidence that permanent neonatal diabetes mellitus-2 (PNDM2) is caused by heterozygous mutation in the KCNJ11 (600937) gene on chromosome 11p15.
Permanent neonatal diabetes mellitus-2 (PNDM2) is characterized by onset of insulin-requiring hyperglycemia within the first months of life that requires insulin therapy throughout life. Some patients additionally have marked developmental delay, muscle weakness, and epilepsy (Gloyn et al., 2004). The triad of developmental delay, epilepsy, and neonatal diabetes is known as DEND (Shimomura et al., 2007).
Proks et al. (2006) stated that heterozygous activating mutations in KCNJ11 are the most common cause of PNDM and account for 26 to 64% of cases, and that neurologic features are found in 20% of patients with KCNJ11 mutations.
For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (606176).
Permanent diabetes of infancy is primarily characterized by onset of hyperglycemia within the first 6 months of life. Among 12 patients with PNDI and mutation in the KCNJ11 gene, Gloyn et al. (2004) reported a mean age of 7 weeks at diagnosis (range birth to 26 weeks). All affected patients had hyperglycemia (270 to 972 mg/dl), and 3 had ketoacidosis. None of the patients had pancreatic autoantibodies associated with type 1 diabetes. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. All patients had low birth weight. Three of 12 patients had similar neurologic abnormalities, including developmental delay, muscle weakness, and epilepsy. All 3 patients with neurologic abnormalities had dysmorphic features, including prominent metopic suture, a downturned mouth, bilateral ptosis, and limb contractures.
Gloyn et al. (2006) reported 4 unrelated patients with developmental delay, epilepsy, and neonatal diabetes (DEND) associated with mutations in the KCNJ11 gene. All had infantile-onset of diabetes without pancreatic autoantibodies (diagnosed from day 1 of life to 3 months) with hyperglycemia, polydipsia, polyuria, and ketoacidosis in some. The most severely affected child had seizures with hypsarrhythmia, neurologic deterioration with social withdrawal, and mild dysmorphic features, including prominent metopic suture, downturned mouth, and bilateral ptosis. She died from aspiration pneumonia at age 6 months; genetic analysis revealed a novel mutation in the KCNJ11 gene (C166F; 600937.0015). Gloyn et al. (2006) considered the phenotype of this patient a case of DEND. Two other patients had developmental delay and axial hypotonia, but only 1 of these also had dysmorphic features and seizures. The fourth child, who had no dysmorphic or neurologic features, had a diabetic mother who also had no neurologic involvement. Gloyn et al. (2006) noted the phenotypic variability between patients, even between those with the same mutation.
Shimomura et al. (2007) reported a patient with neonatal diabetes who had had persistent hyperglycemia from birth and developed refractory neonatal seizures with hypsarrhythmia. By age 3.5 years, psychomotor retardation was severe, with hypotonia, athetotic movements, inability to roll over or sit without support, decreased eye contact, and inability to speak. Shimomura et al. (2007) stated that this patient was the sixth case of DEND (developmental delay, epilepsy, and neonatal diabetes) reported to that time.
Using a battery of targeted neuropsychological and behavioral assessments, Carmody et al. (2016) evaluated 23 patients with KCNJ11 mutations, 9 with and 14 without global developmental delay, all successfully treated with sulfonylurea, and 20 healthy sib controls, The patients without global developmental delay had significant differences compared with sib controls on a range of assessments, including IQ, measures of academic achievement, and executive function. KCNJ11 patients with global delay exhibited significant differences in behavioral symptoms, with a tendency to avoid social contact, and displayed a reduced ability to adapt to new circumstances. Parents reported more immature behavior, gross mood swings, bizarre thoughts, and other unusual and severe behaviors, and there were also significant deficits in all subdomains of daily living skills.
Landmeier et al. (2017) reported that while 25% of patients with KCNJ11 have obvious neurologic dysfunction, less was known about those with milder problems. They compared 30 probands from one center with 25 sibs and found that 13 (43%) of probands had ADHD versus 2 (8%) of sibs (p less than 0.05). They also noted significant differences in behavior difficulties, social awareness, and academic achievement. Sleep disorders were also much more prevalent among KCNJ11 mutation carriers (p less than 0.01).
The transmission pattern of PNDM in families studied by Gloyn et al. (2004) was consistent with autosomal dominant inheritance. Additionally, de novo occurrence was demonstrated.
Zung et al. (2004) reported an infant with PNDM due to a mutation in the KCNJ11 gene (R201H; 600937.0002) who showed a better response to oral sulfonylurea (glibenclamide) treatment than to insulin pump therapy.
Pearson et al. (2006) assessed glycemic control in 49 diabetic patients with known heterozygous mutations in the KCNJ11 gene; 44 (90%) successfully discontinued insulin after receiving appropriate doses of sulfonylureas. The extent of tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycosylated hemoglobin levels improved significantly in patients who switched to sulfonylurea therapy, and improved glycemic control was sustained at 1 year.
Stanik et al. (2007) also reported patients with PNMD due to mutation in the KCNJ11 gene who were successfully transferred from insulin to sulfonylurea therapy with dramatic improvement in diabetes control and quality of life.
The patient of Shimomura et al. (2007) showed a good response to sulfonylurea treatment, with both improved glycemic control without insulin and neurologic improvement. Shimomura et al. (2007) noted that this was the first report of a child with severe DEND who had clinical improvement of both diabetes as well as neurologic features after sulfonylurea therapy.
In 10 of 29 patients with permanent neonatal diabetes, Gloyn et al. (2004) identified 6 novel, heterozygous missense mutations in the KCNJ11 gene (see, e.g., 600937.0002-600937.0003). In 2 patients the diabetes was familial, and in 8 it arose from a spontaneous mutation. In 4 of the 10 families, the mutation was an arg201-to-his substitution (R201H; 600937.0002). When the most common mutation, R201H, was coexpressed with SUR in Xenopus oocytes, the ability of ATP to block mutant ATP-sensitive potassium channels was greatly reduced.
Edghill et al. (2007) noted that the majority of KCNJ11 mutations resulting in neonatal diabetes mellitus occur de novo. They found that germline mosaicism was indicated by pedigree analysis in 2 of 18 families in which neither parent was affected and in 1 of 12 additional parents tested for somatic mosaicism. Edghill et al. (2007) concluded that de novo KCNJ11 mutations can arise during gametogenesis or embryogenesis, thus increasing the risk of neonatal diabetes for subsequent sibs.
Shimomura et al. (2007) reported an Italian boy with severe neonatal diabetes with neurologic features (DEND) caused by a de novo mutation in the KCNJ11 gene (I167L; 600937.0016).
Mannikko et al. (2010) reported 2 novel mutations on the same haplotype (cis), F60Y (600937.0023) and V64L, in the slide helix of Kir6.2 (KCNJ11) in a patient with neonatal diabetes, developmental delay, and epilepsy. Functional analysis revealed that the F60Y mutation increased the intrinsic channel open probability, thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell potassium-ATP currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same, but not a different, subunit. The authors concluded that F60Y is the pathogenic mutation and that interactions between slide helix residues may influence KATP channel gating.
Of 31 Japanese patients with NDM, including 15 with PNDM and 16 with transient NDM (TNDM), Suzuki et al. (2007) identified a 6q24 abnormality (see 601410) in 11, a KCNJ11 mutation in 9, and an ABCC8 (600509) mutation in 2. Seven patients with a KCNJ11 mutation, including 2 with DEND and the 2 with an ABCC8 mutation, had PNDM. All of the patients with the 6q24 abnormality and 2 patients with a KCNJ11 mutation had TNDM. Suzuki et al. (2007) concluded that the 6q abnormality and KCNJ11 mutations are major causes of NDM in Japanese.
Massa et al. (2005) noted that the diagnostic time limit for PNDM has changed over the years, ranging from onset within 30 days of birth to 3 months of age. However, as patients with the clinical phenotype caused by mutation in the KCNJ11 gene have been identified with onset up to 6 months of age, Massa et al. (2005) suggested that the term 'permanent diabetes mellitus of infancy' (PDMI) replace PNDM as a more accurate description, and include those who present up to 6 months of age. The authors suggested that the new acronym be linked to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion with patients with early-onset, autoimmune type I diabetes.
Carmody, D., Pastore, A. N., Landmeier, K. A., Letourneau, L. R., Martin, R., Hwang, J. L., Naylor, R. N., Hunter, S. J., Msall, M. E., Philipson, L. H., Scott, M. N., Greeley, S. A. Patients with KCNJ11-related diabetes frequently have neuropsychological impairments compared with sibling controls. Diabet. Med. 33: 1380-1386, 2016. [PubMed: 27223594] [Full Text: https://doi.org/10.1111/dme.13159]
Edghill, E. L., Gloyn, A. L., Goriely, A., Harries, L. W., Flanagan, S. E., Rankin, J., Hattersley, A. T., Ellard, S. Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. J. Clin. Endocr. Metab. 92: 1773-1777, 2007. [PubMed: 17327377] [Full Text: https://doi.org/10.1210/jc.2006-2817]
Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanne-Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., Robert, J. J. KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. Europ. J. Hum. Genet. 14: 824-830, 2006. [PubMed: 16670688] [Full Text: https://doi.org/10.1038/sj.ejhg.5201629]
Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004. [PubMed: 15115830] [Full Text: https://doi.org/10.1056/NEJMoa032922]
Landmeier, K. A., Lanning, M., Carmody, D., Greeley, S. A. W., Msall, M. E. ADHD, learning difficulties and sleep disturbances associated with KCNJ11-related neonatal diabetes. Pediat. Diabetes 18: 518-523, 2017. [PubMed: 27555491] [Full Text: https://doi.org/10.1111/pedi.12428]
Mannikko, R., Jefferies, C., Flanagan, S. E., Hattersley, A., Ellard, S., Ashcroft, F. M. Interaction between mutations in the slide helix of Kir6.2 associated with neonatal diabetes and neurological symptoms. Hum. Molec. Genet. 19: 963-972, 2010. [PubMed: 20022885] [Full Text: https://doi.org/10.1093/hmg/ddp554]
Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum. Mutat. 25: 22-27, 2005. [PubMed: 15580558] [Full Text: https://doi.org/10.1002/humu.20124]
Pearson, E. R., Flechtner, I., Njolstad, P. R., Malecki, M. T., Flanagan, S. E., Larkin, B., Ashcroft, F. M., Klimes, I., Codner, E., Iotova, V., Slingerland, A. S., Shield, J., Robert, J.-J., Holst, J. J., Clark, P. M., Ellard, S., Sovik, O., Polak, M., Hattersley, A. T. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. New Eng. J. Med. 355: 467-477, 2006. [PubMed: 16885550] [Full Text: https://doi.org/10.1056/NEJMoa061759]
Proks, P., Arnold, A. L., Bruining, J., Girard, C., Flanagan, S. E., Larkin, B., Colclough, K., Hattersley, A. T., Ashcroft, F. M., Ellard, S. A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes. Hum. Molec. Genet. 15: 1793-1800, 2006. [PubMed: 16613899] [Full Text: https://doi.org/10.1093/hmg/ddl101]
Shimomura, K., Horster, F., de Wet, H., Flanagan, S. E., Ellard, S., Hattersley, A. T., Wolf, N. I., Ashcroft, F., Ebinger, F. A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain. Neurology 69: 1342-1349, 2007. [PubMed: 17652641] [Full Text: https://doi.org/10.1212/01.wnl.0000268488.51776.53]
Stanik, J., Gasperikova, D., Paskova, M., Barak, L., Javorkova, J., Jancova, E., Ciljakova, M., Hlava, P., Michalek, J., Flanagan, S. E., Pearson, E., Hattersley, A. T., Ellard, S., Klimes, I. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J. Clin. Endocr. Metab. 92: 1276-1282, 2007. [PubMed: 17213273] [Full Text: https://doi.org/10.1210/jc.2006-2490]
Suzuki, S., Makita, Y., Mukai, T., Matsuo, K., Ueda, O., Fujieda, K. Molecular basis of neonatal diabetes in Japanese patients. J. Clin. Endocr. Metab. 92: 3979-3985, 2007. Note: Erratum: J. Clin. Endocr. Metab. 93: 153 only, 2008. [PubMed: 17635943] [Full Text: https://doi.org/10.1210/jc.2007-0486]
Zung, A., Glaser, B., Nimri, R., Zadik, Z. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J. Clin. Endocr. Metab. 89: 5504-5507, 2004. [PubMed: 15531505] [Full Text: https://doi.org/10.1210/jc.2004-1241]