KCNJ11 – Intermediate DEND Syndrome

Intermediate DEND syndrome is a form of permanent neonatal diabetes mellitus characterized by neonatal onset of hyperglycemia accompanied by developmental delay but without epilepsy. Heterozygous activating mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel, underlie this condition. This association supports genetic testing for KCNJ11 variants in infants diagnosed with diabetes up to 12 months of age, particularly when neurodevelopmental features are present.

Genetic evidence includes four unrelated probands harboring heterozygous missense variants in KCNJ11. A 15-year-old boy with a de novo c.175G>A (p.Val59Met) variant successfully transitioned from insulin to sulfonylurea therapy and exhibited stable glycemic control with neurological improvements (PMID:19686306). A 12-year-old Portuguese girl with a maternally inherited c.601C>T (p.Arg201Cys) variant presented with intermediate DEND phenotype and partial response to sulfonylureas (PMID:22768671). A male infant with c.175G>A (p.Val59Met) exhibited neonatal diabetes and developmental delay with limited neurological recovery despite sulfonylurea treatment (PMID:36937531). Additionally, a patient with c.136C>T (p.His46Leu) showed marked motor and cognitive improvement upon glibenclamide administration (PMID:17982434). One mother–child pair demonstrates familial segregation of a KCNJ11 variant in a PNDM and iDEND spectrum.

All reported variants are missense and result in gain-of-function channel activity, with reduced ATP inhibition and enhanced whole-cell KATP currents in heterologous systems. The recurrent c.175G>A (p.Val59Met) variant exemplifies this mechanism. Functional studies in Xenopus oocytes reveal that these mutations decrease ATP sensitivity directly or via stabilization of the open state, correlating with phenotypic severity (PMID:15583126).

A neuron-specific nV59M mouse model recapitulates the neurobehavioral phenotype of intermediate DEND, displaying hyperactivity, reduced anxiety, and motor coordination deficits (PMID:24582665). Sulfonylurea treatment in patients and tolbutamide rescue in vitro confirm the therapeutic potential of channel inhibition.

No conflicting studies have undermined this gene–disease relationship. The consistency of genetic and functional data across multiple variants and models establishes a robust link between KCNJ11 and intermediate DEND syndrome. Extending genetic screening to include infants up to 12 months of age and early trial of sulfonylurea therapy can improve both metabolic and neurological outcomes.

Key Take-home: Heterozygous activating KCNJ11 variants cause intermediate DEND syndrome, and early identification enables precision therapy with sulfonylureas to ameliorate both glycemic and developmental impairments.

References

• Pediatric diabetes • 2010 • Medical and developmental impact of transition from subcutaneous insulin to oral glyburide in a 15-yr-old boy with neonatal diabetes mellitus and intermediate DEND syndrome PMID:19686306
• Journal of pediatric endocrinology & metabolism • 2012 • Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas PMID:22768671
• Frontiers in neurology • 2023 • Case report: Neonatal diabetes mellitus caused by KCNJ11 mutation presenting with intracranial hemorrhage PMID:36937531
• Nature clinical practice. Neurology • 2007 • Sulfonylurea improves CNS function in a case of intermediate DEND syndrome caused by a mutation in KCNJ11 PMID:17982434
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features PMID:15583126
• Physiology & behavior • 2014 • A mutation causing increased KATP channel activity leads to reduced anxiety in mice PMID:24582665

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