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Genetic Testing in Neonatal Diabetes
Genetic testing for neonatal diabetes has valuable prognostic and therapeutic implications.
By Bassem Dekelbab, MD
In the last few years, different mutations causing pancreatic beta-cell dysfunction and subsequent diabetes have been identified. This genetic subtype of diabetes will include individuals previously described as having Mature Onset Diabetes of the Youth (MODY), permanent neonatal diabetes mellitus (PNDM), and transient neonatal diabetes mellitus (TNDM). The timely diagnosis of genetic diabetes will predict the clinical course, explain associated features, and guide therapy of the index case as well as other diabetic family members.1
Activating mutation of the KCNJ11 gene encoding Kir6.2 subunit of the KATP channels was described recently as a common cause of PNDM and TNDM. The KATP channels are present in pancreatic beta-cells as well as other tissues including brain, nerve, and muscle. This leads to neurological manifestations in some children with neonatal diabetes as seen in Developmental Delay, Epilepsy, and Neonatal Diabetes (DEND) syndrome. When epilepsy is not encountered, it is classified as intermediate DEND.
The ability to diagnose KCNJ11 gene mutation has a major clinical therapeutic implication, as most patients previously treated with insulin injections can switch successfully to oral sulfonylurea. Recent evidence has shown better long-term gylcemic control with such a switch, and improvement of neurological manifestations of DEND syndrome. The following case illustrates the importance of considering genetic testing for KCNJ11 mutation in children with PNDM, TNDM, and DEND syndrome.2,3
CASE DISCUSSION
A 3-month-old white male infant presented with irritability, polyphagia, polyuria, respiratory distress, and weight loss. He was found to have diabetes ketoacidosis with initial blood glucose of 910 mg/dL and venous PH of 7. Past medical history was unremarkable. Family history was positive for type 2 diabetes. Islet cell, glutamic acid decarboxylase, and insulin autoantibodies were negative. He was started on subcutaneous insulin therapy with multiple daily injections. There was difficulty in achieving good gylcemic control with frequent hypoglycemia and A1C ranging from 7.9 to 9.9%. No severe hypoglycemia, seizure, or recurrent episodes of ketoacidosis were reported.
His development and motor skills were normal at diagnosis but delayed at age 1 year. Magnetic resonance imaging of the brain was normal and extensive neurological evaluation did not reveal a clear etiology for his delay. The child was diagnosed with mild cerebral palsy, cognitive impairment, speech delay, and attention deficit hyperactivity disorder.
He underwent genetic testing (Athena Diagnostics, Worcester, MA) at age 8 years, and heterozygous V59M mutation in the KCNJ11 gene was identified. Based on current data regarding potential response of such patients to oral sulfonylurea, he was started on oral glyburide with close monitoring of blood glucose, frequent contact with the family, and gradual weaning of insulin administration. Within
6 weeks, he was completely off insulin and taking oral glyburide three times daily at a total dose of 0.4 mg/kg daily. After 3 months, A1C decreased from 9.2% to 6.9%. At age
9 years, the child's A1C was 6.4% and the family was thrilled with his improvement of cognitive abilities as he started to learn to read.
The availability of genetic testing for neonatal diabetes has valuable prognostic and therapeutic implications. This case illustrates how testing saved a child years of psychological, physical, and economic burden of insulin injections, significantly improved his glycemic control, and led to positive effects on neurological function.
Bassem Dekelbab, MD, is in the Department of Pediatric Endocrinology at St. John Hospital & Medical Center, Detroit. Dr. Dekelbab disclosed that he is a paid consultant to Athena Diagnostics. He may be reached at Dekelbab@pol.net
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