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GeNeViSTA
Gene/ Chromosome | Locus | Clinical features
|
Chr 6 | 6q24 |
|
ABCC8/ KCNJ11 | 11p15.1 |
|
INS | 11p15.5 |
|
GCK | 7p15.3- p15.1 |
|
PDX1 | 13q12.1 |
|
NDM- Neonatal diabetes mellitus; IUGR- Intrauterine growth retardation; SGA- Small for gestational age; MODY- Maturity-onset diabetes of the young
KATP channels consist of the ion transporting Kir6.2 subunits (coded by the KCNJ11 gene) and regulator subunit SUR1 (sulfonylurea receptor coded by the ABCC8 gene). Activating heterozygous variants cause membrane hyperpolarisation, and prevent calcium influx and thereby insulin secretion. Since these channels are also present in the brain, neurological symptoms may be seen. Oral sulfonylureas can bind to the SUR1 subunit and induce closure of potassium channels, thereby reestablishing the normal physiology.
Heterozygous variants in the insulin (INS) gene affect the structure of preproinsulin. Abnormal protein accumulates, causing severe endoplasmic reticulum stress and β cell death. This variant usually causes permanent NDM. However, certain rare, recessive mutations are also reported, which alter the protein expression and can cause transient or permanent DM. These respond well to insulin therapy.
The first step in glucose metabolism inside β cell is catalysed by the glucokinase enzyme (coded by the GCK gene). It is a “sensor” of blood glucose and controls insulin secretion. Nonsense mutations cause neonatal diabetes when homozygous as glucokinase is completely deficient. Similar heterozygous mutations can cause glucose intolerance (MODY 2) and hence parents of those with homozygous mutations can have fasting hyperglycemia.
Homozygous mutations of PDX1 gene can present with pancreatic agenesis or hypoplasia. Table 2 lists the other significant pathogenic variants.
Insulin being an anabolic hormone plays a critical role in fetal and extrauterine growth. In this context of insulin deficiency, many patients present with intrauterine growth retardation and low birth weight. Postnatal faltering of growth manifests when untreated. Clinical differentiation of transient from permanent NDM is difficult, except for the rapid fall in insulin requirement over 12-14 weeks. However, findings such as macroglossia and umbilical hernia have been described in 6q24-associated phenotypes. Fifty to sixty percent of TNDM cases can present with relapse of diabetes around puberty and in adulthood, which resembles early onset type 2 diabetes mellitus (Temple and Shield, 2002). This is proposed to be due to insulin resistance and could be prevented with lifestyle modifications and avoiding the potential risk factors (fast-food, smoking, lack of exercise). Neurological features like developmental delay and epilepsy (DEND syndrome), attention-deficit hyperactivity disorder (ADHD) or sleep disruptions are suggestive of KATP channel mutations. Ketoacidosis is rare at presentation and almost unlikely in transient NDM. Around 30% of individuals with INS mutations present with diabetic ketoacidosis (DKA) (Letourneau et al., 2017). The specific gene-related clinical features are listed in Tables 1 and 2.
Hyperglycemia in the neonatal period may be caused by prematurity, extremely low birthweight, sepsis, necrotising enterocolitis, parenteral nutrition, use of drugs (such as glucocorticoids, catecholamine, caffeine, etc.) and any forms of stress such as mechanical ventilation or surgery. Neonatal DM is a rare cause, but there should be a strong suspicion when persistent (>150-200 mg/dL and insulin dependent more than seven days) or acute extreme hyperglycaemia (>1000mg/dL) is noted. Low or undetectable plasma insulin and C-peptide levels relative to hyperglycemia can confirm the diagnosis of NDM. Hyperketonaemia and ketonuria are not usually seen in initial presentation. An abdominal ultrasonogram must be done to look for presence or absence of pancreas. Further delineation of pancreatic morphology is done with computed tomography (CT) or magnetic resonance imaging (MRI) of the pancreas, whenever indicated. Stool fat examination and fecal elastase is tested in those with pancreatic agenesis/ hypoplasia to rule out exocrine deficiency.
Molecular genetic testing is recommended for all diabetes mellitus detected in less than 6 months of age. Additionally, those presenting between 6 months and 1 year should be tested if any extra-pancreatic features, negative autoantibodies, unusual family history, associated congenital defects or multiple autoimmune disorders are noted (ISPAD Clinical Practice Consensus Guidelines, 2022). Different testing strategies are used (Figure 2), such as serial single gene testing, multigene panel including the most common genes like ABCC8, KCNJ11, INS, GCK and PDX1, or a comprehensive genomic testing with whole exome or whole genome sequencing. Syndrome specific clinical phenotypes should be tested for the corresponding gene as per Table 2. Serial testing of single genes is a time consuming and expensive procedure with a high chance to miss rare genetic variants, except when clinical phenotypes specific to certain genes are identified. Whole exome sequencing is a cost-effective approach in a country like India, enabling detection of both common and uncommon pathogenic variants.
Initial management consists of emergency stabilisation by rehydration and intravenous insulin infusion to control hyperglycemia. Once the child is stable and tolerates oral feeds, an appropriate regimen of subcutaneous insulin must be started. Infants requires very minimal doses of insulin only and hypoglycemia is more dangerous to the growing brain. Any inappropriate dose of rapid and short acting insulin can cause severe hypoglycemia and should be avoided. Longer acting insulin analogues such as Glargine or Detemir are preferred, as it maintains a basal insulin level without significant hypoglycemia. Intermediate acting insulins are not as effective but may be used in low-income settings.
Continuous subcutaneous insulin infusion (CSII) can deliver accurate insulin doses corresponding to blood glucose levels. This is more physiologic, safer, and reduces HbA1c better when compared to other regimens.
Sulfonylurea therapy is beneficial in KCNJ11 and ABCC8 mutations and some pathogenic variants of GCK. Around 90-95% of these patients achieve glycemic control with oral sulfonylureas when weaned off insulin therapy. It also improves the neurological symptoms. Various transfer protocols are available online for insulin to sulfonylurea transition. High doses (0.4-1.0 mg/kg/day of Glibenclamide) may be required. Crushed tablets are poorly soluble in water. Recently, a sulfonylurea suspension (AmglidiaR) has been approved by the European Medicines Agency (EMA). Common side effects are transitory diarrhoea and nausea.
Diet modification is better than diet restriction in children. A high calorie diet is recommended to maintain adequate weight gain. Pancreatic enzyme replacement must be provided for those with exocrine insufficiency.
Relapse of transient neonatal DM can respond to diet alone or needs addition of oral hypoglycemic agents with occasional insulin requirement.
Confirmation of pathogenic variants can help in several aspects such as provision of targeted gene specific therapeutic modalities, early prediction of other associated system involvement, and for counselling and testing other family members. In transient NDM due to 6q24 mutations, paternal duplications are autosomal dominant, and hence carry a 50% transmission risk if inherited from the father (Temple and Shield, 2002). UPD6 is usually sporadic with a low recurrence risk. Maternal hypomethylation can be theoretically transmitted to 50% offspring of affected female individuals, but only de-novo and non-recurrent cases have been detected till now. Pathogenic variants of KCNJ11 have autosomal dominant inheritance when familial, but 90% are de novo heterozygous mutations (ISPAD CPCG 2022). Phenotypes related to ABCC8 and INS variants are either autosomal dominant or recessive and GCK and PDX1- related NDM follows an autosomal recessive pattern of inheritance.
Clinical phenotype | Genes affected | OMIM Phenotype
|
Pancreatic exocrine insufficiency or agenesis and cardiac abnormalities | GATA6 | Neonatal and childhood Onset diabetes/ Pancreatic agenesis and congenital heart defects (OMIM # 600001)
|
Enteropathy and dermatitis | FOXP3 | Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX syndrome) (OMIM # 304790)
|
Cerebellar involvement | PTF1A | Pancreatic agenesis 2/ Pancreatic and cerebellar agenesis (OMIM # 609069)
|
Congenital hypothyroidism, hepatic fibrosis, cystic renal dysplasia, congenital glaucoma | GLIS3 | Diabetes mellitus, neonatal, with congenital hypothyroidism (OMIM # 610199)
|
Cerebellar hypoplasia, sensorineural deafness, and visual impairment | NEUROD1 | Maturity-Onset Diabetes of the Young 6 (MODY 6) (OMIM # 606394)
|
Pancreatic hypoplasia, intestinal atresia, and gall bladder hypoplasia | RFX6 | Mitchell-Riley syndrome (OMIM # 615710)
|
Congenital malabsorptive diarrhoea | NEUROG3 | Diarrhea 4, malabsorptive, congenital (OMIM # 610370)
|
Skeletal abnormalities (epiphyseal dysplasia) and liver dysfunction | EIF2AK3 | Wolcott-Rallison syndrome (OMIM # 226980)
|
Megaloblastic anemia and deafness | SLC19A2 | Thiamine-responsive megaloblastic anemia (TRMA) syndrome (OMIM # 249270)
|
Renal and genital abnormalities | HNF1B | Renal cysts and diabetes syndrome (OMIM # 137920)
|
Optic atrophy, diabetes insipidus and deafness | WFS1 | Wolfram syndrome 1 (OMIM # 222300)
|
Genetic counselling begins with identification of the variant(s) in the proband. There are several methods available to determine the pathogenicity of the variant such as database searches, in silico modelling with web-based applications, in-vitro functional studies of the protein product and clinical studies such as familial co-segregation studies. The mode of inheritance is communicated, and recurrence risk of parents and siblings are predicted. Pathogenic variants of GCK, INS, PDX1, RFX6, etc. can present with neonatal diabetes when homozygous and milder forms of diabetes such as Maturity Onset Diabetes of Young (MODY) when heterozygous. In these cases, heterozygous parents and siblings should undergo a screening blood glucose test even if asymptomatic. Prenatal counselling is advised for those with a known pathogenic variant in a family member. Option of prenatal/ preimplantation genetic testing can be suggested for the identified variant in the proband.
Periodic daily blood glucose monitoring with conventional glucometers or continuous glucose monitoring systems (CGMS) is done to assess therapeutic adequacy. Target HbA1c should be less than 7.5. ISPAD suggests yearly HbA1c monitoring for transient NDM patients after remission for early identification of relapse. Long term follow-up should include metabolic work-up and socio-education. Periodic developmental assessment is needed, especially in KCNJ11 and ABCC8 pathogenic variants. Yearly screening for microalbuminuria and retinopathy should start from 10 years of age.
Neonatal diabetes mellitus is a rare cause of hyperglycemia in neonates, with a predominant monogenic origin. After confirming the diagnosis, genetic testing is recommended for prognostication and management. Pancreatic malformations and extra-pancreatic features should be specifically looked for. Initial therapy is with insulin replacement, but a transition to oral sulfonylureas must be attempted as soon as a favourable pathogenic variant (KCNJ11 and ABCC8) is identified. Lifestyle modifications and periodic follow-up are the key to disease control.
1. Beltrand J, et al. Neonatal Diabetes Mellitus. Front Pediatr. 2020; 8:540718.
2. Castillero AB, Simmons R. Hypoglycemia and Hyperglycemia. Cloherty and Stark’s manual of neonatal care. Ninth edition; Eichenwald EC, Hansen AR, Martin C, Stark AR, editors; 2023. p.318-332.
3. De Franco E, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. The Lancet. 2015; 386(9997):957–963.
4. De Leon DD, Stanley CA. Permanent Neonatal Diabetes Mellitus. 2008 Feb 8 [Updated 2016 Jul 29]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1447/
5. Hattersley AT, et al. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatric Diabetes. 2018;19(S27):47–63.
6. Lemelman MB, et al. Neonatal Diabetes Mellitus: An Update on Diagnosis and Management. Clin Perinatol. 2018; 45(1):41–59.
7. Letourneau LR, et al. Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis. Diabetes Care. 2017; 40(10):e147–148.
8. Misra S, Owen KR. Genetics of Monogenic Diabetes: Present Clinical Challenges. Curr Diab Rep. 2018; 18(12):141.
9. Polak M, Cave H. Neonatal diabetes mellitus: a disease linked to multiple mechanisms. Orphanet J Rare Dis. 2007; 2(1):12.
10. Temple IK, Mackay DJG. Diabetes Mellitus, 6q24-Related Transient Neonatal. 2005 Oct 10 [Updated 2018 Sep 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1534/.
11. Temple I, Shield J. Transient neonatal diabetes, a disorder of imprinting. J Med Genet. 2002; 39(12): 872–875.
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