Case 1 (N.NE)
A 52-day-old Iranian girl was referred to us due to lethargy, fever, and poor feeding, which had started 5 days earlier. She was the first child of unrelated healthy parents. There was no family history of diabetes before 25 years of age in three generations. She was born on March 21, 2011, full term by cesarean section (CS), with birth weight of 2.600 kg and height of 48 cm. On physical examination, she was conscious but had drowsiness, dehydration, tachycardia, tachypnea, and sighing Kussmaul respiration. Her weight was 3.700 kg, with height of 52 cm (at the third percentile of the Centers for Disease Control and Prevention [CDC] 2000 clinical growth chart curves), respiratory rate 40 breaths/minute, pulse rate 197/minute, body temperature 38.2 °C, and blood pressure 97/49 mmHg.
Laboratory data showed severe DKA (Table
1). Fluid therapy and low-dose insulin infusion improved DKA, after which maintenance therapy with insulin was commenced. Eleven days later, we decreased the amount of insulin so that blood glucose was maintained between 200 and 300 mg/dL, and glibenclamide was administered to test its effect. It was effective in lowering blood glucose, so it was gradually substituted for insulin. Blood glucose was monitored before and 2 hours after every meal. She received glibenclamide until 2.4 years of age, but frequent monitoring of blood glucose showed some hypoglycemia before meals (minimum = 50 mg), while postprandial glucose was normal or high. Treatment was therefore switched to repaglinide (Novonorm, Novo Nordisk, Denmark), which is short-acting and is claimed to have no effect on insulin release at low blood glucose levels. The time course of treatment and follow-up is shown in Table
2.
Table 1
Laboratory tests at entry
Case 1 | 750 | 6.88 | < 3 | 162 | 4.3 | +2 | 11 | 0.4 |
Case 2 | 500 | 6.98 | 3.9 | 150.4 | 4.8 | +2 | 26 | 1 |
Table 2
Age at appearance of signs and start of different treatments
Case # 1 N.NE | 47 days | Signs appeared |
52 days | Came to hospital with DKA; treatment: low-dose insulin infusion, fluid therapy, then maintenance insulin therapy |
58 days | Glibenclamide |
2.4 years | Repaglinide |
10 years | Repaglinide; no adverse events |
Case # 2 I.M. | 3 months and 5 days | Signs appeared |
3 months and 15 days | Came to hospital with DKA; low-dose insulin infusion, fluid therapy, then maintenance insulin therapy |
3 months and 20 days | Glibenclamide |
4 months and 20 days | Repaglinide |
9 years | Repaglinide; no adverse events |
Because one tablet of repaglinide is 0.5 mg, compared to 5 mg glibenclamide, and the dosage of glibenclamide is 0.4 mg/kg/day [
1], repaglinide dosage was calculated according to its potency as 0.04 mg/kg/day divided into three or more doses before each meal based on the patient’s age and frequency of meals. Preparations of the medicine were made by dissolving one tablet in 10 ml of water and calculating the dosage by volume of solution in every administration and spill-out of the extra. Adjustment of the dosage with weight was done during the follow-up period, which was effective for normal glucose maintenance.
Genetic analysis was done in the molecular genetics laboratory of the Medical School of the University of Exeter in the UK. Sequence analysis of the ABCC8, KCNJ11, and INS genes was performed. Analysis of coding and flanking intronic regions of the KCNJ11, INS, and ABCC8 genes (NM_000525.3, NM_000207.2, NM_001287174.1) was done by Sanger sequencing. A heterozygous missense mutation was identified, with details as follows: gene: KCNJ11; location: exon 1; DNA description: c.602G>A; protein description: p.Arg201His (p.R201H). Therefore, a diagnosis was PNDM was made.
At the last visit, she was 10 years old, with height of 143 cm (75th percentile) and weight of 50 kg (97% of the CDC 2000 curves). Hemoglobin A1C (HbA1C) was measured every 3 months during the follow-up period, with mean ± SD of all of the measurements calculated as 4.6 ± 0.7 (range 3.6–6.4). The blood glucose level from 59 recent self-monitored measurements was 123.36 ± 18 mg/dL (90–173). Neurodevelopmental assays were normal by both physical examination and questions of the parents. Ophthalmic examination was done and found to be normal.
Case 2 (I.M.)
A 3.5-month-old Iranian girl was referred due to vomiting, respiratory distress, fever, and lethargy. She had some of the signs since 10 days before presentation. She was the second child of a family with two children, and the other sibling was healthy. Both parents were healthy and first cousins. There was no family history of diabetes before 25 years of age in three generations. She was born on May 12, 2012, full term by elective CS, with birth weight of 2.500 kg. At the time of admission, she was in a light coma and dehydrated. Her weight was 5 kg (10th percentile) and height 53 cm (under the fifth percentile). Respiratory rate was 50, and pulse rate 170, with normal blood pressure and temperature. She had severe DKA (Table
1). DKA improved after 26 hours of fluid therapy and low-dose insulin infusion. Glibenclamide was substituted for insulin after 5 days, with a dosage of 0.4 mg/kg once daily. The treatment was changed to repaglinide 1 month later because some hypoglycemia (minimum = 52 mg/dL) occurred, in an effort to keep 2-hour postprandial blood glucose at normal levels. The daily dosage was 0.04 mg/kg, and the method of preparation was the same as in the first case. It was divided into eight separate doses before each milk feeding, and when she became older, the daily dose was divided before every meal. During the last visit, she was 9 years old, with weight of 22.5 kg and height of 122 cm. The time course of treatment and follow-up is shown in Table
2.
Weight and height were always in the third percentile of the CDC 2000 curves during follow-up. HbA1C was measured every 3 months, with a mean ± SD of 4.7 ± 0.5 (4.2–6.3). The blood glucose level from 93 recent self-monitored measurements was 118.7 ± 16.4 mg/dL (88–167). Genetic analysis was done in the genes mentioned above and also on the EIF2AK3 gene in the same center. The result was the same as in the first case. The patient showed normal neurological and ophthalmological examination results.
Diabetic complications
Routine physical examination and laboratory tests for diabetic care were done for both patients in different periods: Measurement of HbA1C and physical examination was done every 3 months; lipid profile, biochemical profile, thyroid, liver, and renal function tests were assayed every year. There were no diabetic complications in any organ of the body in either patient, and they had normal neurodevelopment and body growth during 9 and 10 years of follow-up. Annual ophthalmic examination results were also normal, with no retinopathy. Tolerability to the medicine has been very good, with no adverse effects.