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 mellitus, permanent neonatal 3, with or without neurologic features | 618857 | Autosomal dominant; Autosomal recessive | 3 | ABCC8 | 600509 |
A number sign (#) is used with this entry because of evidence that permanent neonatal diabetes mellitus-3 (PNDM3) is caused by heterozygous or homozygous mutation in the ABCC8 (600509) gene on chromosome 11p15.
Permanent neonatal diabetes mellitus-3 (PNDM3) is characterized by the onset of mild to severe hyperglycemia within the first months of life, and requires lifelong therapy (summary by Babenko et al., 2006). Some patients also have neurologic features, including developmental delay and epilepsy (Proks et al., 2006; Babenko et al., 2006). The triad of developmental delay, epilepsy, and neonatal diabetes is known as DEND.
For a discussion of genetic heterogeneity of permanent neonatal diabetes mellitus, see PNDM1 (606176).
Proks et al. (2006) described a patient with PNDM3 in whom the first indication of hyperglycemia was mild glycosuria without ketonuria on the seventh day of life. Birth weight was 2200 g. Hyperglycemia gradually increased until it was 20g/24h at the age of 13 weeks. At that time a formal diagnosis of diabetes was made on the basis of an oral glucose tolerance test, on which insulin values were less than the detection limits of the assay. Other laboratory values were normal. At age 13 weeks the patient weighed 3400 g (less than -2 SD), with a length of 53 cm (less than -2 SD) and a head circumference of 34.2 cm (less than -2 SD). Insulin treatment was started at age 15 weeks in single or multiple dosages of 0.7 U/kg/day, using mixtures of short- and intermediate-acting insulin; glycemic control was poor. The patient showed marked motor and social developmental delay, with muscle weakness with hypotonia apparent by 1 year. During his second year, there were intermittent fine distal and athetoid involuntary movements with the later development of severe muscle spasms. Electroencephalography revealed nonspecific generalized epileptiform activity. Brain CT scan was normal. At age 27 years the patient remained on insulin treatment and high doses of anticonvulsive medication, had never achieved speech, and had difficulty standing unaided owing to muscle spasms in his limbs.
Stanik et al. (2007) studied a patient with PNDM3 who was born at 40 weeks' gestation at a normal weight. He developed diabetes in his second month of life as manifested with polyuria, polydipsia, and failure to thrive during a respiratory tract infection. Hyperglycemia reached 28 mmol/liter without changes in acidobasic balance. Axial hypotonus required rehabilitation lasting for 36 months.
Stanik et al. (2007) reported a patient with PNDM due to mutation in the ABCC8 gene who was successfully transferred from insulin to sulfonylurea therapy, with achievement of normoglycemia.
The transmission pattern of PNDM3 in families studied by Ellard et al. (2007) was consistent with autosomal dominant or autosomal recessive inheritance. In other cases, de novo occurrence was demonstrated.
In a 27-year-old man who had permanent neonatal diabetes, severe developmental delay, and generalized epileptiform activity on EEG, Proks et al. (2006) identified heterozygosity for a de novo missense mutation (F132L; 600509.0016) in the ABCC8 gene. Functional studies showed that F132L markedly reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, thereby increasing the whole-cell K(ATP) current; the authors noted that the functional consequence of the F132L mutation mirrors that of mutations in KCNJ11 (600937) causing neonatal diabetes.
From a group of 73 patients with neonatal diabetes, Babenko et al. (2006) screened the ABCC8 gene in 34 who did not have alterations in chromosome 6q or mutations in the KCNJ11 or GCK genes. In 2 PNDM patients, they identified heterozygosity for a mutation (600509.0017 and 600509.0018, respectively). They also identified heterozygosity for 5 different mutations (see, e.g., 600509.0019 and 600509.0020) in 7 patients with transient neonatal diabetes (TNDM2; 610374). Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had markedly higher activity than did wildtype channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The mutation-positive fathers of 5 of the probands with transient neonatal diabetes developed type II diabetes mellitus (125853) in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. The authors noted that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group.
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 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.
Babenko, A. P., Polak, M., Cave, H., Busiah, K., Czernichow, P., Scharfmann, R., Bryan, J., Aguilar-Bryan, L., Vaxillaire, M., Froguel, P. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. New Eng. J. Med. 355: 456-466, 2006. [PubMed: 16885549] [Full Text: https://doi.org/10.1056/NEJMoa055068]
Ellard, S., Flanagan, S. E., Girard, C. A., Patch, A.-M., Harries, L. W., Parrish, A., Edghill, E. L., Mackay, D. J. G., Proks, P., Shimomura, K., Haberland, H., Carson, D. J., Shield, J. P. H., Hattersley, A. T., Ashcroft, F. M. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am. J. Hum. Genet. 81: 375-382, 2007. [PubMed: 17668386] [Full Text: https://doi.org/10.1086/519174]
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]
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]