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Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their body’s ability to produce or use insulin. NDM is a monogenic (controlled by a single gene) form of diabetes that occurs in the first 6 months of life. Infants do not produce enough insulin, leading to an increase in glucose accumulation. It is a rare disease, occurring in only one in 100,000 to 500,000 live births. NDM can be mistaken for the much more common type 1 diabetes, but type 1 diabetes usually occurs later than the first 6 months of life. There are two types of NDM: permanent neonatal diabetes mellitus (PNDM) is a lifelong condition. Transient neonatal diabetes mellitus (TNDM) is diabetes that disappears during the infant stage but may reappear later in life.
Specific genes that can cause NDM have been identified. The onset of NDM can be caused by abnormal pancreatic development, beta cell dysfunction or accelerated beta cell dysfunction. Individuals with monogenic diabetes can pass it on to their children or future generations. Each gene associated with NDM has a different inheritance pattern.
Common symptoms of NDM includes:
An excessive thirst (also known as polydipsia) and increased urination (also known as polyuria) are common signs of diabetes. An individual with diabetes, have accumulated blood glucose. Their kidneys are working overtime to filter and uptake excess sugar. However, their kidneys cannot keep up, excess sugar is excreted into their urine, and this drag along fluids from the diabetic’s tissues. This may lead to more frequent urination and lead to dehydration. As a diabetic individual drinks more fluids to satisfy their thirst, he or she urinates even more.
Effected areas of the body are the eyes, mouth, kidneys, heart, and pancreas. Other symptoms of dehydration includes headache, thirst and dry mouth, dizziness, tiredness, and dark colored urine. In severe cases of dehydration in diabetics, low blood pressure, sunken eyes, a weak pulse or rapid heart beat, feeling confused or fatigue. Dehydration and high blood glucose for extended period of time, the diabetic’s kidney would try to filter the blood of access glucose and excrete this as urine. As the kidneys are filtering the blood, water is being removed from the blood and would need to be replaced. This leads to an increased thirst when the blood glucose is elevated in a diabetic individual. Water is needed to re-hydrate the body. Therefore, the body would take available from other parts of the body, such as saliva, tears, and from cells of the body. If access water is not available, the body would not be able to pass excess glucose out of the blood by urine and can lead to further dehydration.
Severe symptoms of NDM (Deficiency of insulin):
Is a diabetic complication that occurs when the body produces high levels of acid in the blood (ketones). This effects the pancreas, fat cells, and kidneys. This condition occurs when the body cannot produce enough insulin. In the absence or lack of insulin, the body of an diabetic individual will break down fat as fuel. This process produces a buildup of acids in the bloodstream known as ketones, in which leads to ketoacidosis if left untreated. The symptoms of ketoacidosis develop rapidly or within 24 hours. Symptoms of ketoacidosis are excessive thirst, frequent urination, nausea or vomiting, stomach pain, tiredness, shortness or fruity smell on breath and confusion.
A condition in which the unborn baby is smaller than he or she should be, due to the fact he or she not growing at a normal rate in the womb. Delayed growth puts the baby at risk of certain problems during pregnancy, delivery, and after birth. The problems are as follows: baby’s birth weight is 90% less than normal weight, difficulty handling vaginal delivery, decreased oxygen levels, hypoglycemia (low blood glucose), low resistance to infection, low Apgar scores (a test given after birth to test the baby’s physical condition and evaluate if special medical care is needed), Meconium aspiration (inhaling of stools passed while in the uterus) which causes breathing issues, irregular body temperature and high red blood cell count.
A condition characterized as high blood glucose, which occurs when the body has too little insulin or when the body cannot use insulin properly. Hyperglycemia affects the pancreas, kidneys, and body’s tissues. Characterization of hyperglycemia is high blood glucose, high levels of sugar in the urine, frequent urination and increase thirst.
A condition characterized an extremely low blood glucose, usually less than 70 mg/dL. Areas of the body that are affected, pancreas, kidneys, and mental state.
Causes of NDM
PNDM and TNDM are inherited genetically from the mother or father of the infant. Different genetic inheritance or genetic mutations can lead to different diagnosis of NDM (Permanent or Transient Neonatal Diabetes Mellitus). The following are different types of inheritance or mutations:
TNDM occurs within the first several days to weeks of an infant’s life. Intrauterine growth restriction (IUGR) is commonly seen in affected individuals and defined as poor growth of an unborn baby while in his or her mother’s womb. In comparison, of PNDM, the insulin dose requirement of TNDM is often lower. TNDM resolves on its own at an average age of twelve weeks. Although, individuals will relapse in 50% of cases (usually during childhood or young adulthood). The parts of the body that are mostly affected are the pancreas, central nervous system and various tissues of the body.
An average of 70% of TNDM is caused by defects initiating over-expression of the father genes in the imprinted region (genes whose expression is dependent on the parent that contributed them) of chromosome 6q24 (Chromosome meaning a string-like structure made of nucleic acid and protein that carries genetic material). There are three mechanism that can cause 6q24-related TNDM, which includes the father’s DNA being defected by uniparental isodisomy (UPD) on chromosome 6 and inherited duplication of 6q24 (inherited duplication is a small chromosomal change in which a very little amount of genetic material is copied in chromosome 6). The last possible cause of TNDM, the mother’s genes are affected by DNA methylation (DNA methylation is the process in which methyl groups or CH3- are added to the DNA molecule. When a methyl group is located on a promoter, it stops gene transcription). In previous research, it has been observed the involvement of an imprinted gene within TNDM, is only expressed by the father’s genetic material or chromosome, resulting in an increased expression of the imprinted gene by UPD or inherited duplication that leads to the onset of diabetes. Numerous defects within the genome can lead to over-expression of the father’s defected genes in the chromosome 6q24 region and result in TNDM. However, there are two genes in this region that can be associated with TNDM:
ZAC and HYMAI Genes
ZAC is a zinc-finger protein that controls apoptosis (programmed cell death) and cell cycle arrest (cell division and duplication of DNA stops when the cell detects cell damage or defects) in PLAG1
(pleomorphic adenoma gene-like 1). PLAG1 is a transcription regulator of the type 1 receptor for pituitary adenylated cyclase-activating polypeptide (is a polypeptide that activates adenylate cyclase and increases the cyclic adenosine monophosphate or cAMP. cAMP is a second messenger that is used for neighboring cells to perform signal transduction in targeted cells), which is important for insulin secretion regulation. The function of the HYMAI (hydatiform mole-associated and imprinted transcript) is unknown.
Second, chromosome 6q24-TNDM is caused by over-expression of imprinted genes at 6q24 (PLAGL1 [ZAC] and HYMAI). It was discovered that a differentially methylated region (DMR) is present within the shared promoter of these genes. Generally the expression of the mother’s alleles of PLAGL1 and HYMAI are blocked or not expressed by DMR methylation and only the father’s alleles of PLAG1 and HYMA1 are expressed. The previously listed genetic mechanisms result in twice the normal amount of these two genes and cause chromosome 6q24 TNDM.
Third, mother’s hypomethylation defects (a genetic defect that stops the allele from getting a methyl group, which would inhibit transcription) can occur from an isolated genomic imprinting or occur as a defect called, “hypomethylation imprinted loci” (HIL). HIL is defined as the loss of a methyl group in the 5-methylcytosine nucleotide at a fixed position on a chromosome. Homozygous ( having two of the same alleles) or heterozygous (defined as having one each of two different alleles) ZFP57 pathogenic variant make up almost half of TNDM-HIL, but the other causes of HIL are unknown.
Moreover, half of TNDM patients that contain chromosome 6q24-related TNDM experiencing re-occurrence of diabetes during their childhood or young adulthood. The onset of insulin resistance and increased insulin requirements are associated with puberty and pregnancy initiating the relapse of diabetes. In the event of remission, individuals do not show symptoms or impairment Beta-cell function in the fasting state. Insulin secretory response to intravenous glucose loading might be abnormal in those destined to have a relapse of diabetes. TNDM caused by 6q24 genomic defects are always associated with IGUR. Other contributing factors are umbilical hernia and enlarged tongue, which are present in 9 and 30% of patients with chromosome 6q24 related TNDM.
KCNJ11 and ABCC8 Genes
In addition, TNDM initiated by the genes, KCNJ11 or ABCC8 mutations are similar to mutations in chromosome 6q24-related to TNDM. Normally, the birth weight in infants are lower in chromosome 6q24 TNDM patients and diabetes is initiated at an earlier age (similar to readmission). There may be an overlap between chromosome 6q24 and KCNJ11 and ABCC8-related TNDM, making genetic diagnosis necessary for treatment.
Recessive mutations in the INS gene encoding insulin were discovered to trigger both PNDM and TNDM. Diabetes occurs because there is an decrease insulin biosynthesis as a result of homozygous mutations. Common phenotype is decreased birth weight and average age of diagnosis is one week. Previous studies show relapse of diabetes occurred at an average age of 26 weeks.
PNDM is associated with mutations in the Beta-cell ATP sensitive potassium channel (KATP) initiated by heterozygous leading to mutations in KCNJ11 and ABCC8, which is a result of 31% and 10% of PNDM cases (results based on Exeter experiment series). Twelve percent of mutations in the insulin gene leads to PNDM.
KCNJ11 and ABCC8 Genes association with Beta-cell ATP Sensitive Potassium Channel
KCNJ11 encodes Kir6.2 (a protein coding gene in the potassium channel) and ABCC8 encodes the gene, SUR1 (the type 1 subunit of the sulfonylurea receptor), a member of the ATP-binding cassette transporter family, the two components of the KATP channel. This channel links glucose metabolism to insulin secretion by closing in response to ATP. Blood glucose storage into Beta-cells lead to glycolysis and cause ATP generation. The elevated ATP/adenosine diphosphate ratio causes closure of the KATP channel, and inhibit potassium efflux (a lot of potassium flows out of this channel), that leads to depolarization of the Beta-cell membrane. Depolarization is the loss of the difference in charge between the inner and outer parts of the plasma membrane of a muscle. This occurs because of change in permeability and migration of sodium ions inside the cell. The voltage gated channels then open, allowing calcium (Ca+) to flow inside the channel and cause exocytosis (active transport that moves molecules out of a cell by ejecting them in an energy using process) of insulin-containing granules from the Beta-cells. Activation of defects in KCNJ11 or ABCC8 seems to make the KATP channel less sensitive to ATP, leaving more channels in an open state after high levels of glucose occurs. Resulting in the failure of insulin response to high blood glucose and leading to NDM.
The diagnostic evaluations are based upon current literature and research available on NDM. The following evaluation factors are: patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. TNDM patients are younger at the age of diagnosis of diabetes and have lower insulin requirements, an overlap occurs between the two groups, therefore TNDM cannot be distinguished from PNDM based clinical feature. An early onset of diabetes mellitus is unrelated to autoimmunity in most cases, relapse of diabetes is common with TNDM, and extensive follow ups are important. In addition, molecular analysis of chromosomes 6 defects, KCNJ11 and ABCC8 genes (encoding Kir6.2 and SUR1) provide a way to identify PNDM in the infant stages. Approximately,50% of PNDM are associated with the potassium channel defects which are essential consequences when changing patients from insulin therapy to sulfonylureas.
The uniparental disomy of the chromosome can be used as diagnostic method provide proof by the analysis of polymorphic markers is present on Chromosome 6. Meiotic segregation of the chromosome can be distinguished by comparing allele profiles of polymorphic makers in the child to the child’s parents’ genome. Normally, a total uniparental disomy of the chromosome 6 is evidenced, but partial one can be identified. Therefore, genetic markers that are close to the region of interest in chromosome 6q24 can be selected. Chromosome duplication can found by that technique also.
Samples from fetus or child and both parents are needed for analysis. Chromosome of interest must be specified on request form. For prenatal samples (only): if the amniotic fluid (non-confluent culture cells) are provided. Amniotic fluid is added and charged separately. Also, if chorionic villus sample is provided, a genetic test will be added and charged separately. Microsatellites markers and polymerase chain reaction are used on the chromosomes of interest to test the DNA of the parent and child to identify the presence of uniparental disomy.
Apgar score is a test given after birth to test the baby’s physical condition and evaluate if special medical care is needed.
In many cases, neonatal diabetes may be treated with oral sulfonylureas such as glyburide. Physicians may order genetic tests to determine whether or not transitioning from insulin to sulfonylurea drugs is appropriate for a patient.
The transfer from insulin injections to oral glibenclamide therapy seems highly effective for most patients and safe. This illuminates how the molecular understanding of some monogenic form of diabetes may lead to an unexpected change of the treatment in children. This is a spectacular example of how the pharmacogenomic approach improves in a tremendous way the quality of life of the young diabetic patients.
The outcome for infants or adults with NDM have different outcomes among carriers of the disease. Among affected babies, some have PNDM while others have relapse of their diabetes and other patients may experience permanent remission. Diabetes may reoccur in the patient’s childhood or adulthood. It was estimated that neonatal diabetes mellitus will be TNDM in about 50% are half of the cases.
During the Neonatal stage, the prognosis is determined by the severity of the disease (dehydration and acidosis), also based on how rapidly the disease is diagnosed and treated. Associated abnormalities (e.g. irregular growth in the womb or enlarged tongue) can effect a person’s prognosis. The long-term prognosis depends on the person’s metabolic control, which effects the presence and complications of diabetes complications. The prognosis can be confirmed with genetic analysis to find the genetic cause of the disease. WIth proper management, the prognosis for overall health and normal brain development is normally good. It is highly advised people living with NDM seek prognosis from their health care provider.