Permanent neonatal diabetes
المؤلف:
Holt, Richard IG, and Allan Flyvbjerg
المصدر:
Textbook of diabetes (2024)
الجزء والصفحة:
6th ed , page283-285
2025-12-21
28
Approximately half of PNDM is caused by variants in the genes KCNJ11 and ABCC8, which encode the Kir6.2 and SUR1 subunits, respectively, of the β- cell adenosine triphosphate (ATP)- sensitive potassium channel (KATP channel). This channel is constitutively open and regulates insulin secretion by closing in response to the raised intracellular ATP levels that occur as a con sequence of hyperglycaemia. Channel closure triggers depolarization of the β- cell membrane, which leads to insulin secretion. Activating variants in KCNJ11 and ABCC8 prevent closure of the potassium channel in response to increased ATP, so the β cell remains hyperpolarized and unable to secrete insulin. Sulfonylureas close the β- cell KATP channel by an ATP- independent route and have been used successfully in the management of individuals with neonatal diabetes resulting from KCNJ11 and ABCC8 variants. In offspring of unrelated parents the majority of PNDM resulting from KATP channel variants arise spontaneously from de novo heterozygous variants. The remaining cases are inherited mainly in an autosomal dominant pattern.
The KATP channel is also present in the brain, nerves, and muscles. Reflecting this distribution of channels, 20% of children with KCNJ11 variants (and occasionally those with ABCC8 variants) have severe neurological features. Recent data suggest that after thorough assessment the rate of psychological and neurological features is much higher in both KCNJ11 and ABCC8 PNDM than previously suggested. In- depth testing of 27 individuals with KATP channel gene variants (KCNJ11 and ABCC8) found that all the participants had neuropsychological dysfunction. In long- term follow- up studies, neurological features were found to persist into adulthood in all KCNJ11 participants. In individuals with ABCC8- related PNDM, 62% had persistent, long- term psychiatric or neurological features.
Heterozygous variants in the insulin gene (INS) have been identified in ~12% of cases of isolated PNDM and insulin treatment is required. Other genetic causes appear to be relatively rare, as outlined in Table1. Parental consanguinity is more likely to result in autosomal recessive inheritance. In children born to consanguineous parents, the commonest cause of PNDM is a homozygous variant in the EIF2AK3 gene, causing Wolcott–Rallison syndrome.
Table1. Causes of neonatal diabetes.
Clinical features
Diabetes caused by KCNJ11 variants typically present in the first 26 weeks of life (median 4–6 weeks) with marked hyperglycaemia often accompanied by ketosis. C- peptide is usually undetectable and pancreatic auto- antibodies negative. As with all neonatal diabetes subtypes, infants are often small for gestational age as a result of reduced fetal insulin secretion with consequent decreased insulin- mediated growth.
Neonatal diabetes caused by an ABCC8 variant has a similar phenotype but leads to TNDM more commonly than PNDM. Children with neonatal diabetes due to INS variants present at a median age of 9 weeks and are also often small for gestational age, but do not have extra- pancreatic features.
The most common neurological features identified in individuals with PNDM resulting from KCNJ11 and ABCC8 variants are developmental delay and learning difficulties. Neurological features persist into adulthood, despite sulfonylurea therapy, as a result of the limited function of the KATP channel in the brain and not as a consequence of long- standing diabetes. The most severe form where neonatal diabetes is accompanied by developmental delay and epilepsy has been named developmental delay, epilepsy, and neonatal diabetes (DEND). Intermediate DEND (iDEND) refers to neonatal diabetes with less severe developmental delay and no epilepsy. The severity of the clinical condition relates closely to the underlying variant and its effect on KATP channel ATP sensitivity.
Management
Although insulin therapy is commonly used in the initial period after diagnosis, the majority of those with KCNJ11 and ABCC8 variants can successfully transfer from insulin to sulfonylurea therapy, usually with significant improvements in glycaemic levels. Of those with KCNJ11 variants 90% can discontinue insulin, while HbA1c appears to improve in all, with a mean drop from 65 to 46 mmol/mol (8.1% to 6.4%) after 12 weeks. Glibenclamide was initially chosen as it is non- selective and widely available; it has been used in the majority of cases and may be more effective than other sulfonylurea agents. The doses needed are often higher than those needed for the treatment of type 2 diabetes: a median dose of 0.45 mg/kg/day is required, with doses up to 1.5 mg/kg/day [101, 111]. Doses up to 2 mg/kg/day have been reported, but doses of 1 mg/kg/day or less are usually sufficient. Reports of side effects are mild and comprise transient gastrointestinal disturbances, the most common being diarrhoea, and tooth discoloration. In individuals with PNDM caused by KCNJ11 and ABCC8 variants, sulfonylurea therapy is a safe and effective long- term treatment, maintaining excellent glycaemic levels for over 10 years without severe hypoglycaemia or serious side effects, even in high doses. Initiation of sulfonylurea therapy immediately after KNCJ11 or ABCC8 variants are confirmed appears to improve neurological outcomes and sulfonylurea therapy may result in some improvement in neurological features, particularly in higher doses. Earlier age at initiation of sulfonylurea therapy, ideally in the first six months of life, appears to correlate with better dose response. Further information on transferring these individuals from insulin to sulfonylureas can be found at www.diabetesgenes.org. Neonatal diabetes resulting from INS variants requires insulin treatment.
Affected individuals with a heterozygous KCNJ11 or ABCC8 variant contemplating parenthood should be counselled that they have a 50% chance of passing on the variant to their offspring. Where unaffected parents, with a child affected by a heterozygous variant, are planning further pregnancies, the risk of further affected children is low because the possibility of a germline variant is approximately 5–10%. Where parents have a child with neonatal diabetes caused by a recessive ABCC8 variant, there is a 25% chance of each further offspring being affected, but the risk is low for subsequent generations. In pregnancy, if the fetus inherits a KATP neonatal diabetes variant (KCNJ11 or ABCC8) from their mother, fetal insulin secretion will be greatly reduced in utero, resulting in reduced fetal growth by ~900 g. If the fetus and the mother both have KATP neonatal diabetes, maternal glibenclamide treatment is recommended as it will cross the placenta and provide in utero treatment to the affected fetus and normalize fetal growth. If the fetus is unaffected, maternal glibenclamide treatment is not recommended in the third trimester as it will exacerbate neonatal hypoglycaemia and excessive fetal growth. Awareness of fetal genotype through the use of cffDNA testing is an important addition to guide management of KATP neonatal diabetes pregnancies.
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