Neonatal diabetes

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Neonatal diabetes
Newborn infant.jpg
Neonatal infant

Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their body's ability to produce or use insulin. NDM is a kind of diabetes that is monogenic (regulated by a single gene) and arises 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. [1] 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), a lifelong condition, and transient neonatal diabetes mellitus (TNDM), a form of diabetes that disappears during the infant stage but may reappear later in life. [1]

Contents

Specific genes that can cause NDM have been identified. [2] The onset of NDM can be caused by abnormal pancreatic development, beta cell dysfunction or accelerated beta cell dysfunction. [3] Along with maturity-onset diabetes of the young (MODY), NDM is a form of monogenic diabetes. Individuals with monogenic diabetes can pass it on to their children or future generations. Each gene associated with NDM has a different inheritance pattern.

Signs and symptoms

The 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 IPEX syndrome, Wolcott-Rallison syndrome, and Wolfram syndrome. Symptoms vary widely based on the syndrome. [5]

Complications

People 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]

Cause

Neonatal diabetes is a genetic disease, caused by genetic variations that were either spontaneously acquired or inherited from one's parents. At least 30 distinct genetic variants can result in neonatal diabetes. [8] The development and treatment of neonatal diabetes will vary based on the particular genetic cause. Known genetic variants cause neonatal diabetes by five major mechanisms: Preventing the development of the pancreas or β cells, promoting β-cell death by autoimmunity or endoplasmic reticulum stress, preventing β cells from recognizing glucose or secreting insulin, or abnormal expression of the 6q24 region on chromosome 6. [8]

Mechanism

Most permanent neonatal diabetes cases are caused by variations in the ATP-sensitive potassium channel, KATP. [7] Disease-associated variants of either subunit of KATP, KCNJ11 and ABCC8 , can result in a channel that is "stuck open", rendering the β cell unable to secrete insulin in response to high blood glucose. [7] Children born with disease-associated KATP variants often have intrauterine growth restriction and resulting low birthweight. [7] Similarly, the second most common cause of permanent neonatal diabetes is alterations to the gene that encodes insulin. Mutations associated with neonatal diabetes tend to cause misfolding of the insulin protein; misfolded insulin accumulates in the endoplasmic reticulum (ER), leading to ER stress and β-cell death. [7]

Most transient neonatal diabetes is caused by the over-expression of a cluster of genes on chromosome 6, a region called 6q24. [7] Over-expression of 6q24 is often caused by anomylous 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. [7] Genetic changes that disable the transcription factors CNOT1 , GATA4 , GATA6 , PDX1 , PTF1A , or RFX6 – all involved in the development of the pancreas – result in a shrunken or missing pancreas. [7] [9] Similarly, variations in the transcription factors GLIS3 , NEUROD1 , NEUROG3 , NKX2-2 , or MNX1 can result in malformed or absent β cells that do not secrete insulin. [10] EIF2AK3 variants can exacerbate ER stress causing β-cell death, skeletal issues, and liver dysfunction. [7] Some variations in immune gene FOXP3 can cause IPEX syndrome, a severe and multifaceted disease that includes neonatal diabetes among its symptoms. [7]

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 [ citation needed ]

(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. [11] The function of the HYMAI (hydatiform mole-associated and imprinted transcript) is unknown. [11]

Second, chromosome 6 q24-TNDM is caused by over-expression of imprinted genes at 6q24 (PLAGL1 [ZAC] and HYMAI). [12] 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 6 q24 TNDM.[ citation needed ]

ZFP57 Gene

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. [12] 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. [13] [12]

Moreover, half of TNDM patients that contain chromosome 6 q24-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. [11] 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. [11] TNDM caused by 6q24 genomic defects are always associated with IGUR. [11] Other contributing factors are umbilical hernia and enlarged tongue, which are present in 9 and 30% of patients with chromosome 6 q24 related TNDM. [11]

Diagnosis

Diagnosis 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 PNDM

The 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 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.[ citation needed ]

TNDM Diagnosis associated with Chromosome 6q24 Mutations

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.[ citation needed ]

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

Neonatal Diabetes Mellitus (NDM) Monitores.jpg
Neonatal Diabetes Mellitus (NDM)

Neonates with diabetes are initially treated by intravenous infusion of insulin, with a dose of 0.05 units/kilogram/hour commonly used. [15]

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 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.[ citation needed ]

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]

Outcomes

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. [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 ]

Epidemiology

About 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

Related Research Articles

<span class="mw-page-title-main">Hypoglycemia</span> Decrease in blood sugar

Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose below 70 mg/dL (3.9 mmol/L), symptoms associated with hypoglycemia, and resolution of symptoms when blood sugar returns to normal. Hypoglycemia may result in headache, tiredness, clumsiness, trouble talking, confusion, fast heart rate, sweating, shakiness, nervousness, hunger, loss of consciousness, seizures, or death. Symptoms typically come on quickly.

The following is a glossary of diabetes which explains terms connected with diabetes.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Hyperglycemia</span> Too much blood sugar, usually because of diabetes

Hyperglycemia or Hyperglycaemia is a condition in which an excessive amount of glucose (glucotoxicity) circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even higher values such as 13.9–16.7 mmol/L (~250–300 mg/dL). A subject with a consistent fasting blood glucose range between ~5.6 and ~7 mmol/L is considered slightly hyperglycemic, and above 7 mmol/L is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average, however, chronic levels above 10–12 mmol/L (180–216 mg/dL) can produce noticeable organ damage over time.

<span class="mw-page-title-main">Sulfonylurea</span> Class of organic compounds used in medicine and agriculture

Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea, a dehydrogenated derivative of urea). The side chains R1 and R2 distinguish various sulfonylureas. Sulfonylureas are the most widely used herbicide.

Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. Along with neonatal diabetes, MODY is a form of the conditions known as monogenic diabetes. While the more common types of diabetes involve more complex combinations of causes involving multiple genes and environmental factors, each forms of MODY are caused by changes to a single gene (monogenic). GCK-MODY and HNF1A-MODY are the most common forms.

Hyperinsulinemic hypoglycemia describes the condition and effects of low blood glucose caused by excessive insulin. Hypoglycemia due to excess insulin is the most common type of serious hypoglycemia. It can be due to endogenous or injected insulin.

<span class="mw-page-title-main">Congenital hyperinsulinism</span> Medical condition

Congenital hyperinsulinism (HI or CHI) is a rare condition causing severe hypoglycemia in newborns due to the overproduction of insulin. There are various causes of HI, some of which are known to be the result of a genetic mutation. Sometimes HI occurs on its own (isolated) and more rarely associated with other medical conditions.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that originates when cells that make insulin are destroyed by the immune system. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate glucose levels in the bloodstream. It results in high blood sugar levels in the body prior to treatment. The common symptoms of this elevated blood sugar are frequent urination, increased thirst, increased hunger, weight loss, and other serious complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks if not months.

An ATP-sensitive potassium channel is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. KATP channels are widely distributed in plasma membranes; however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").

In molecular biology, the sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of antidiabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. More specifically, SUR proteins are subunits of the inward-rectifier potassium ion channels Kir6.x. The association of four Kir6.x and four SUR subunits form an ion conducting channel commonly referred to as the KATP channel.

K<sub>ir</sub>6.2 Protein-coding gene in the species Homo sapiens

Kir6.2 is a major subunit of the ATP-sensitive K+ channel, a lipid-gated inward-rectifier potassium ion channel. The gene encoding the channel is called KCNJ11 and mutations in this gene are associated with congenital hyperinsulinism.

<span class="mw-page-title-main">HNF1A</span> Protein-coding gene in the species Homo sapiens

HNF1 homeobox A, also known as HNF1A, is a human gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Mutations in the HNF1A gene have been known to cause diabetes. The HNF1A gene also contains a SNP associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">ABCC8</span> Protein-coding gene in the species Homo sapiens

ATP-binding cassette transporter sub-family C member 8 is a protein that in humans is encoded by the ABCC8 gene. ABCC8 orthologs have been identified in all mammals for which complete genome data are available.

<span class="mw-page-title-main">Wolcott–Rallison syndrome</span> Medical condition

Wolcott–Rallison syndrome,WRS, is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the eukaryotic translation initiation factor 2-alpha kinase 3. Other disease names include multiple epiphyseal dysplasia and early-onset diabetes mellitus. Most patients with this disease do not survive to adulthood. The majority of WRS patients die from fulminant hepatitis during childhood. There are few reported cases for this disease. Of the 54 families worldwide with reported WRS cases, 22.2% of them are from the Kingdom of Saudi Arabia. Of the 23 WRS patients in Saudi Arabia, all but one is the result of consanguineous marriages. Another country where WRS cases have been found is Kosovo. Here, the Albanian population is also known for consanguineous marriages, but there were some cases involving patients from non-consanguineous parents that were carriers for the same mutant allele.

MODY 2 or GCK-MODY is a form of maturity-onset diabetes of the young. It is due to any of several mutations in the GCK gene on human chromosome 7 for glucokinase. Glucokinase serves as the glucose sensor for the pancreatic beta cell. Normal glucokinase triggers insulin secretion as the glucose exceeds about 90 mg/dl. These loss-of-function mutations result in a glucokinase molecule that is less sensitive or less responsive to rising levels of glucose. The beta cells in MODY 2 have a normal ability to make and secrete insulin, but do so only above an abnormally high threshold. This produces a chronic, mild increase in blood sugar, which is usually asymptomatic. It is usually detected by accidental discovery of mildly elevated blood sugar. An oral glucose tolerance test is much less abnormal than would be expected from the impaired (elevated) fasting blood sugar, since insulin secretion is usually normal once the glucose has exceeded the threshold for that specific variant of the glucokinase enzyme.

Permanent neonatal diabetes mellitus (PNDM) is a newly identified and potentially treatable form of monogenic diabetes. This type of neonatal diabetes is caused by activating mutations of the KCNJ11 gene, which codes for the Kir6.2 subunit of the beta cell KATP channel. This disease is considered to be a type of maturity onset diabetes of the young (MODY).

<span class="mw-page-title-main">Transient neonatal diabetes</span> Medical condition

Transient neonatal diabetes mellitus (TNDM) is a form of neonatal diabetes presenting at birth that is not permanent. This disease is considered to be a type of maturity onset diabetes of the young (MODY).

Researcher - Dr. Dinesh Kacha Research Article - Diabetes Reversal Through Ayurvedic Lifestyle

Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.

References

  1. 1 2 "Monogenic Forms of Diabetes | NIDDK". National Institute of Diabetes and Digestive and Kidney Diseases. Archived from the original on 2017-03-12. Retrieved 2017-11-05.
  2. ↑ Monogenic Forms of Diabetes: Neonatal Diabetes Mellitus and Maturity-onset Diabetes of the Young Archived 2015-04-19 at the Wayback Machine at National Diabetes Information Clearinghouse, a service of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NIH Publication No. 07–6141. March 2007. Copyright cite: This publication is not copyrighted.
  3. ↑ "Neonatal diabetes - Other types of diabetes mellitus - Diapedia, The Living Textbook of Diabetes". www.diapedia.org. Archived from the original on 2017-12-13. Retrieved 2017-11-06.
  4. 1 2 Atkinson et al. 2020, "Neonatal Diabetes".
  5. 1 2 3 Garg & Devaskar 2020, "Diabetes Mellitus in the Newborn".
  6. 1 2 3 Lemelman, Letourneau & Greeley 2018, "Hyperglycemia in the Neonatal Period".
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Lemelman, Letourneau & Greeley 2018, "Types of Diabetes".
  8. 1 2 De Franco 2021, "Introduction".
  9. ↑ De Franco 2021, "Neonatal Diabetes Caused by Failure of Pancreatic Development".
  10. ↑ De Franco 2021, "Neonatal Diabetes Caused by Failure of β-Cell Development".
  11. 1 2 3 4 5 6 Naylor, Rochelle N; Greeley, Siri Atma W; Bell, Graeme I; Philipson, Louis H (2011-06-05). "Genetics and pathophysiology of neonatal diabetes mellitus". Journal of Diabetes Investigation . 2 (3): 158–169. doi:10.1111/j.2040-1124.2011.00106.x. ISSN   2040-1116. PMC   4014912 . PMID   24843477.
  12. 1 2 3 Temple, Isabel Karen; Mackay, Deborah J.G.; Docherty, Louise Esther (1993). "Diabetes Mellitus, 6q24-Related Transient Neonatal". In Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E.; Bean, Lora J.H.; Mefford, Heather C.; Stephens, Karen; Amemiya, Anne; Ledbetter, Nikki (eds.). GeneReviews. Seattle (WA): University of Washington, Seattle. PMID   20301706. Archived from the original on 2020-10-21. Retrieved 2018-01-29.
  13. ↑ "What is Homozygous? - Definition, Traits & Example - Video & Lesson Transcript | Study.com". study.com. Archived from the original on 2023-11-17. Retrieved 2017-11-07.
  14. 1 2 "UNIPD - Clinical: Uniparental Disomy". www.mayomedicallaboratories.com. Archived from the original on 2023-11-17. Retrieved 2017-11-07.
  15. 1 2 Lemelman, Letourneau & Greeley 2018, "Management Considerations".
  16. 1 2 3 "Permanent neonatal diabetes mellitus | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2023-09-17. Retrieved 2017-12-13.
  17. ↑ Lemelman, Letourneau & Greeley 2018, "Introduction".
  18. ↑ Katugampola, Gevers & Dattani 2020, "Neonatal Diabetes".

Works cited

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