Sulfonylrea Treatment in Permanent Neonatal Diabetes Due to G53D Mutation in the KCNJ11 Gene

Abstract

Improvement in glycemic control and neurological function P revious studies have reported the successful switch from insulin to sulfonylrea therapy in some patients who have neonatal diabetes due to KCNJ11 mutations (1); however, data on adults are limited (2,3). Also, it has not yet been determined whether neurological symptoms can be improved by the action of sulfonylrea therapy.Here, we report the glycemic and neurological responses in an adult patient with the G53D mutation in the KCNJ11 gene who was transferred from insulin to sulfonylurea.A 26-year-old male patient was diagnosed with diabetes in the third month of life, and insulin treatment was initiated. Islet cell antibodies were negative. He showed severe learning difficulties and very poor attention. Crisis of generalized seizures started at age 5 years during episodes of hypoglycemia; his electroencephalogram was normal.In 2006, the proband was found to have a heterozygous G53D mutation in the KCNJ11 gene. In an attempt to switch from insulin to sulfonylrea therapy, glibenclamide was introduced. After 4 weeks, the patient no longer required insulin and was using 0.8 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 glibenclamide; subsequently, the dose was reduced to 0.68 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 . Capillary glucose measurements showed that 3 months after starting glibenclamide therapy, mean glucose levels before lunch and dinner reduced from 185 Ϯ 100 to 107 Ϯ 45 mg/dl (P ϭ 0.036) and from 225 Ϯ 110 to 111 Ϯ 41 mg/dl (P ϭ 0.006), respectively. A 72-h continuous glucose monitoring showed that 76% of glycemic values were between 71 and 199 mg/dl. Postprandial Cpeptide level was Ͻ0.05 ng/ml before sulfonylrea therapy and increased to 1.3 ng/ml during glibenclamide treatment.The patient was given an identical battery of neuropsychological tests before and after initiating sulfonylrea therapy. At baseline, the patient showed low intellectual level (IQ: 52) and global impairment on cognitive functions. Retesting 3 months after initiating glibenclamide showed an important improvement in verbal performance, such as episodic verbal memory, visual naming ability, verbal learning, and long-term memory.Here, we showed the effectiveness of sulfonylrea therapy in an adult patient carrying the G53D mutation in the KCNJ11 gene. The change to sulfonylrea resulted in a marked improvement in diabetes control and quality of life. Also, an improvement on verbal performance was observed. It is very likely that the improvement observed in our patients' neurological status is related to the action of glibenclamide on sulfonylrea receptor 1 present in the neurons. However, we cannot exclude the possibility that the reduction of hypoglycemia may also have contributed.In summary, this case illustrates that sulfonylrea treatment can be effective even in adult patients with neonatal diabetes due to KCNJ11 mutations. Besides improvements on metabolic control and quality of life, sulfonylrea therapy also showed beneficial effect on neurological functions.

Long-term response to sulfonylurea in a patient with diabetes due to mutation in the KCNJ11 gene

“…Following the identification of the mutation the patient was transferred from insulin to glibenclamide. The initial response to SU therapy was previously reported (13). After 4 weeks the patient was independent of insulin and using 0.8 mg/kg/day of glibenclamide divided into three doses.…”

Glibenclamide unresponsiveness in a Brazilian child with permanent neonatal diabetes mellitus and DEND syndrome due to a C166Y mutation in KCNJ11 (Kir6.2) gene

“…Several mutations related to severe DEND syndrome (Q52R, G53R, V59G, I296L, G334D) are insensitive to glibenclamide (4,12,19,20); nevertheless in some forms of intermediate DEND syndrome (I167L, G53D, H46L, V59M), characterized by less severe developmental delay and without epilepsy, glibenclamide therapy has improved metabolic control, neuromuscular symptoms (17,(21)(22)(23)(24) and even cognition (V59M) (25). Evidence that sulfonylurea could change CNS blood fl ow and function was provided by the use of Figure 1.…”

Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11

“…Although transfer is less likely to be successful for patients with DEND syndrome [34] there are at least two cases where this was not the case. One patient's epilepsy and psychomotor development improved [59] and the second case showed better verbal performance, visual naming ability, verbal learning and long term memory [60].…”