Alternative titles; symbols
ORPHA: 79134, 99885; DO: 0060639;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p13 | Diabetes mellitus, permanent neonatal 1 | 606176 | Autosomal recessive | 3 | GCK | 138079 |
A number sign (#) is used with this entry because of evidence that permanent neonatal diabetes mellitus-1 (PNDM1) is caused by homozygous mutation in the glucokinase gene (GCK; 138079) on chromosome 7p13.
Permanent neonatal diabetes mellitus-1 (PNDM1) is a rare autosomal recessive disorder characterized by severe hyperglycemia which requires insulin treatment soon after birth. The disorder results from a complete lack of glucokinase; total absence of basal insulin release was observed as well (Njolstad et al., 2001).
PNDM is distinct from transient neonatal diabetes mellitus (TNDM; see 601410) and childhood-onset autoimmune diabetes mellitus type I (IDDM; 222100).
Genetic Heterogeneity of Permanent Neonatal Diabetes Mellitus
PNDM2 (618856) is caused by heterozygous mutation in the KCNJ11 (600937) gene on chromosome 11p15.1.
PNDM3 (618857) is caused by heterozygous or homozygous mutation in the ABCC8 (600509) gene on chromosome 11p15.1.
PNDM4 (618858) is caused by heterozygous or homozygous mutation in the INS (176730) gene on chromosome 11p15.5.
Pancreatic agenesis, which results in exocrine pancreatic deficiency as well as permanent neonatal-onset diabetes mellitus, can be caused by mutation in the PDX1 gene (600733). Pancreatic agenesis associated with cerebellar agenesis (609069) can be caused by mutation in the PTF1A gene (607194). Pancreatic agenesis associated with congenital cardiac defects (600001) can be caused by mutation in the GATA6 gene (601656).
Njolstad et al. (2001) described 2 patients with permanent neonatal diabetes mellitus and complete deficiency of glucokinase. The first patient was a Norwegian girl, the child of first-cousin parents, who was delivered by cesarean section at 36 weeks' gestation due to poor fetal growth. In addition to being small for gestational age, she had total situs inversus. On the first day of life, her blood glucose concentration was 145 mg/deciliter (8.1 mmol/liter), and on day 2 it was 300 mg/deciliter (17 mmol/liter), at which time treatment with insulin was started. Glycemic control was difficult to achieve, but there was no ketosis. Basal and glucagon-stimulated serum C-peptide concentrations were nearly undetectable on several occasions. Epilepsy developed at age 5 years, probably due to a neonatal brain abscess, and she subsequently had mild learning and behavioral difficulties. At age 15 years her glycemic response to glucagon was normal. Her sister developed typical type 1 diabetes at the age of 7 years. Both of her parents had glucose intolerance. The second patient was an Italian girl who had hyperglycemia and marked growth retardation at birth and who had been treated with insulin since birth. Basal serum C-peptide concentrations were low at birth, declined further with age, and did not increase in response to glucagon. Her mother had impaired fasting glycemia, and her father had impaired glucose tolerance.
Njolstad et al. (2003) described 3 additional cases of glucokinase-related permanent neonatal diabetes. All had intrauterine growth retardation (birth weight less than 1,900 g) and insulin-treated diabetes from birth. All of the mothers had been diagnosed with gestational diabetes and later diagnosed with either fasting hyperglycemia or diabetes treated with diet. The father in family 1 had mild diabetes treated with diet and the father in family 2 was discovered to have diabetes during the investigation of his affected son. The authors concluded that glucokinase deficiency may be regarded as a recessively inherited inborn error of metabolism, with heterozygous carriers having a mild phenotype (see MODY2, 125851) and homozygous carriers associated with PNDM1 having a particularly severe phenotype.
The transmission pattern of PNDM1 in the families reported by Njolstad et al. (2001) was consistent with autosomal recessive inheritance.
Turkkahraman et al. (2008) evaluated the clinical response to sulfonylurea treatment in a 4-year-old Turkish boy with a homozygous T168A mutation in the GCK gene causing PNDM1. Oral glibenclamide was given over a 3-month period and was shown to be beneficial with a 12-fold increase of both basal and stimulated insulin secretion. Hemoglobin A1C levels were reduced from 9.4% to 8.1% on a reduced insulin dose (0.85 to 0.60 U/kg/day). During glibenclamide therapy, the mean fasting blood glucose (FBG) decreased compared to the FBG before initiation of the drug (189 mg/dl +/- 92 on treatment vs 227 mg/dl +/- 97 before treatment; p less than 0.05). However, postprandial glucose did not change significantly (184 mg/dl +/- 97 on treatment vs 192 mg/dl +/- 96; p = 0.79). The authors suggested that basal insulin secretion is improved with sulfonylurea therapy, but that as glucose levels increase during the postprandial period, the ATP generated by metabolism is insufficient for continued insulin granule docking and exocytosis, a situation in contrast with patients with PNDM2 (618856) caused by mutations in the KCNJ11 gene (600937). Turkkahraman et al. (2008) concluded that it is possible that patients with GCK mutations causing a less severe phenotype may respond better to sulfonylureas than do those with mutations causing a more severe phenotype.
Njolstad et al. (2001) described 2 patients in whom complete deficiency of glucokinase caused permanent neonatal-onset diabetes mellitus. Both patients showed total absence of basal insulin release, and both had homozygous missense mutations in the GCK gene (138079.0010 and 138079.0011).
Gloyn et al. (2002) concluded that complete glucokinase deficiency is not a common cause of permanent neonatal diabetes.
Gloyn, A. L., Ellard, S., Shield, J. P., Temple, I. K., Mackay, D. J., Polak, M., Barrett, T., Hattersley, A. T. Complete glucokinase deficiency is not a common cause of permanent neonatal diabetes. Diabetologia 45: 290 only, 2002. [PubMed: 11942315] [Full Text: https://doi.org/10.1007/s00125-001-0746-9]
Njolstad, P. R., Sagen, J. V., Bjorkhaug, L., Odili, S., Shehadeh N., Bakry, D., Sarici, S. U., Alpay, F., Molnes, J., Molven, A., Sovik, O., Matschinsky, F. M. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes 52: 2854-2860, 2003. [PubMed: 14578306] [Full Text: https://doi.org/10.2337/diabetes.52.11.2854]
Njolstad, P. R., Sovik, O., Cuesta-Munoz, A., Bjorkhaug, L., Massa, O., Barbetti, F., Undlien, D. E., Shiota, C., Magnuson, M. A., Molven, A., Matschinsky, F. M., Bell, G. I. Neonatal diabetes mellitus due to complete glucokinase deficiency. New Eng. J. Med. 344: 1588-1592, 2001. [PubMed: 11372010] [Full Text: https://doi.org/10.1056/NEJM200105243442104]
Shield, J. P. H. Neonatal diabetes: new insights into aetiology and implications. Horm. Res. 53 (suppl. 1): 7-11, 2000. [PubMed: 10895036] [Full Text: https://doi.org/10.1159/000053198]
Turkkahraman, D., Bircan, I., Tribble, N. D., Akcurin, S., Ellard, S., Gloyn, A. L. Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy. J. Pediat. 153: 122-126, 2008. [PubMed: 18571549] [Full Text: https://doi.org/10.1016/j.jpeds.2007.12.037]