Neonatal Diabetes is newly recognized and likely devastating metabolic disorder that is caused by the pancreas’ inability to secrete adequate insulin to the respond of high glucose levels. Hyperglycemia and also low levels of insulin characterize this disorder. Neonatal diabetes is normally diagnosed during the first months after birth as a result of poor weight gain, polyuria, or diabetes ketoacidosis. 1 in 300,000 to 400,000 new born develop Neonatal Diabetes.
Neonatal Diabetes forms two separate forms that vary in the length of insulin dependency in the premature stage of the disease.
|Types of Neonatal Diabetes
|Transient Neonatal Diabetes Mellitus (TNDM)
||Transient Neonatal Diabetes Mellitus is a form of neonatal diabetes that is appears in the first six weeks of life and usually ends by 18 months. Transient Neonatal Diabetes Mellitus is characterized by intrauterine growth retardation, dehydration, and failure to thrive that is normally caused by an over expression of 2 genes: PLAGL1 (ZAC) and HYMA1 that are found on chromosome 6q24.There are also mutations in the KCNJ11 and ABCC8 genes. This disorder makes up 50% to 60% of the neonatal diabetes.
There are 3 known mechanisms that may cause Transient Neonatal Diabetes Mellitus 90% of the cases (gene test):
When testing for Transient Neonatal Diabetes Mellitus certain things occur during this time in the child’s body (genetest):
- Paternal uniperental disomy of chromosome 6: There are 2 chromosome 6 homologues where each homologues acquire a copy of the PLGL1 and HYMAL gene. This is likely inherited from the paternal.
- Duplication of 6q24 on the paternal allele: Duplication of the copies of PLAGL1 and HYMAL for the paternal chromosome 6.
- 6q24 methylamine defect: lack of methylamine in the maternal copy of the promoter that may result to expression of the maternal copy.
- Plasma Insulin concentration are low in the presence of high blood glucose.
- Ketones are usually absent
- Islet cell antibodies are also absent
|Permanent Neonatal Diabetes Mellitus
||Permanent neonatal diabetes mellitus is a form of diabetes caused as a result of insulin secretion failures that occurs in the post-natal period and remains throughout life. Intrauterine growth retardation, hyperglycemia, dehydration, osmotic polyuria, sever dehydration and failure to thrive are all associated with this disorder.
There are also other forms of Permanent Neonatal Diabetes Mellitus from different gene mutations:
||KCNJ11 codes for the Kir6.2 protein subunit of the ATP-sensitive potassium (Katp) of pancreatic beta cells. KATP is an important component in a complex chain of reactions that are relevant to the increase in blood glucose concentration. Mutation in this gene results in the decline of sensitivity of Katp as well as congenital impairment of insulin release. This impairment causes intrauterine growth retardation with birth weight small for the age. 20% of individuals with this mutation have been associated with a neurological findings called DEND syndrome (developmental delay epilepsy and neonatal diabetes mellitus)
|GCK related PNDM
||GCK codes for the glycolytic enzyme glucokinase that catalyzes certain steps of glycolsis. This form is regularly seen with the first week of life. Certain mutations of GCK reduce efficiency that pancreatic beta cells use glucose for its ATP production, which then causes a chain of reaction that lead to the secretion of insulin. This gene can lead to another form of monogenic diabetes (MODY2).
||IPF1 code for the transcription factor insulin promoter factor 1 (IPF-1). It stimulates transcription of the insulin gene that responds to high blood glucose concentration. This mutation prevents proper development of the pancreas that may lead into pancreatic agenesis and other complications. This gene mutation can also cause another form of monogenic diabetes(MODY4).
||PNDM can occur as part of the IPEX (Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked) also known as Wolcott-Rallison Syndrome.