Neonatal diabetes
| Neonatal diabetes | |
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transient neonatal diabetes mellitus (TNDM), a form of diabetes that disappears during the infant stage but may reappear later in life.[1]
Specific genes that can cause NDM have been identified. Signs and symptomsThe first sign of neonatal diabetes is often slowed fetal growth, followed by unusually low birthweight.[4] At some point within the first six months of life, infants with neonatal diabetes tend to experience the classic symptoms of type 1 diabetes: thirst, frequent urination, and signs of dehydration.[4] The timing of symptom onset varies with the type of neonatal diabetes. Those with transient neonatal diabetes tend to have symptoms in the first few days or weeks of life, with affected children showing weight loss and signs of dehydration, along with high levels of sugar in the blood and urine. Some children also have high levels of ketones in the bood and urine, or signs of metabolic acidosis.[5] Permanent neonatal diabetes starts slightly later, typicalaly around six weeks of age. Regardless of type, preterm infants tend to experience symptoms earlier, typically around one week of age.[6] Neonatal diabetes is classified into three subtypes: permanent, transient, and syndromic; each with distinct genetic causes and symptoms.[5] Syndromic neonatal diabetes is the term for diabetes as just one component of any of several complex syndromes that affect neonates, including Wolcott-Rallison syndrome, and Wolfram syndrome. Symptoms vary widely based on the syndrome.[5]
ComplicationsPeople with KATP channel variations are at increased risk of developing attention deficit hyperactivity disorder, sleep disruptions, seizures, and experiencing developmental delay – all due to the presence of KATP channels in the brain.[7] These can range from unnoticeably mild to severe, and can sometimes improve with sulfonylurea treatment.[7] Those with 6q24 overexpression tend to have transient diabetes, with hyperglycemia tending to disappear within the first year of life.[7] Despite the return of euglycemia, people with 6q24 overexpression are at high risk of developing diabetes later in life, as teenagers or adults.[7] Many of the genetic variations that cause neonatal diabetes are inherited in an autosomal dominant manner, i.e. receiving a single copy of the disease-associated variant results in disease. This is the case for the KATP genes KCNJ11 and ABCC8, and paternally inherited 6q24 amplifications, any of which have a 50% chance of being transmitted to each offspring of an affected individual.[7]
CauseNeonatal diabetes is a endoplasmic reticulum stress, preventing β cells from recognizing glucose or secreting insulin, or abnormal expression of the 6q24 region on chromosome 6.[8]
MechanismMost permanent neonatal diabetes cases are caused by variations in the ER stress and β-cell death.[7]
Most transient neonatal diabetes is caused by the over- epigenetic regulation of the locus.[7] The copy of 6q24 inherited from one's father normally has much higher gene expression than the copy inherited from one's mother. Therefore, inheriting two copies of the gene region from one's father (either through uniparental disomy, or receiving two copies from one's father in addition to the copy from one's mother) commonly results in over-expression of the locus. Alternatively, inheriting a maternal copy of 6q24 with defective DNA methylation can result in similar over-expression of the locus.[7]
Variants in several other genes can cause neonatal diabetes, though these cases are much rarer. Two genes in this region that can be associated with TNDM: ZAC and HYMAI genes 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
( insulin secretion regulation.[11] The function of the HYMAI (hydatiform mole-associated and imprinted transcript) is unknown.[11]
Second, chromosome 6 q24 TNDM.
ZFP57 Gene Third, mother's 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.[13][12]
Moreover, half of TNDM patients that contain chromosome 6q24 related TNDM.[11]
DiagnosisDiagnosis of neonatal diabetes is complicated by the fact that hyperglycemia is common in neonates – particularly in preterm infants, 25–75% of whom have hyperglycemia.[6] Neonatal hyperglycemia typically begins in the first ten days of life, and lasts just two to three days.[6] Diagnosis of TNDM and PNDMThe diagnostic evaluations are based upon the following evaluation factors: 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 insulin therapy to sulfonylureas.[citation needed ]
TNDM Diagnosis associated with Chromosome 6q24 MutationsThe 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.
Diagnostic Test of NDM
Genetic Testing of NDM
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.[14] 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[14]. Treatment Neonates with diabetes are initially treated by Treatment options depend on the underlying genetic variations of each person with neonatal diabetes. The most common mutations underlying neonatal diabetes – KCNJ11 and ABCC8 variants – can be treated with sulfonylureas alone, eventually transitioning off of insulin completely.[15] In many cases, neonatal diabetes may be treated with oral glyburide . Physicians may order genetic tests to determine whether or not transitioning from insulin to sulfonylurea drugs is appropriate for a patient.
People whose disease is caused by KATP variants can often be treated with high-dose sulfonylureas, which directly promote the closure of the KATP channel.[7] OutcomesThe 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.[16] 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.[16] The long-term prognosis depends on the person's metabolic control, which effects the presence and complications of diabetes complications.[16] 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.[citation needed] EpidemiologyAbout 1 in 90,000 to 160,000 children born develops neonatal diabetes, with approximately half developing permanent and half transient neonatal diabetes.[17][18] See also
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