Relapsed 6q24-Related Transient Neonatal Diabetes Mellitus Successfully Treated with Sulfonylurea
Neonatal diabetes mellitus (NDM) is a rare condition characterized by diabetes diagnosed within the first six months of life, occurring in approximately one in every 90,000 to 160,000 live births. Approximately 80% of NDM cases have a known genetic cause. NDM can be classified into three categories: transient (TNDM), permanent (PNDM), and syndromic. Among these, TNDM accounts for about 45% of all NDM cases. The most common cause of TNDM is the overexpression of genes on chromosome 6q24, which is responsible for approximately 70% of TNDM cases. This overexpression can occur through one of three mechanisms: paternal uniparental disomy (41%), duplication of paternal alleles (33%), or hypomethylation of the maternal allele (26%).
TNDM is often associated with being small for gestational age and follows a natural history of “Diabetes-Remission-Relapse.” Insulin is typically the first-line treatment during the neonatal period. However, there is no standardized treatment for patients who experience a relapse of TNDM. This report discusses a case of a Chinese male patient with a history of 6q24-related TNDM who relapsed at 14 years of age and was successfully treated with a low dose of the sulfonylurea glimepiride.
The patient was a 15-year-old male who had been diagnosed with TNDM shortly after birth. He was born prematurely at 36 weeks and 2 days due to premature rupture of membranes, with a birth weight of 1700 grams. At 45 days old, he presented with symptoms of polyuria, polydipsia, and polyphagia. Laboratory tests revealed a fasting glucose level of 30.6 mmol/L and a glycated hemoglobin A1c (HbA1c) level of 12.4%. He was initially treated with an intravenous insulin infusion at a dose of 0.02 to 0.05 U/kg per hour. Over the following days, his insulin requirement gradually decreased, and treatment was discontinued by three months of age. Annual biochemical examinations showed no glucometabolic abnormalities during his childhood.
At 14 years old, the patient experienced a relapse of diabetes, with a fasting glucose level of 11.3 mmol/L and an HbA1c level of 8.2%. A 2-hour oral glucose tolerance test (2h-OGTT) with a standard meal was conducted. The results showed a glucose level of 6.64 mmol/L at 0 hours and 13.47 mmol/L at 2 hours. Insulin levels were 9.29 mU/mL at 0 hours and 36.2 mU/mL at 2 hours, while C-peptide levels were 1.98 ng/mL at 0 hours and 5.82 ng/mL at 2 hours. At this time, the patient’s height was 176 cm, and his weight was 52.5 kg. He tested negative for antibodies associated with type 1 diabetes (GAD, IAA, IA-2) and displayed normal islet function. His detailed history and endocrinological testing ruled out secondary diabetes. Whole exome sequencing revealed no mutations.
The patient was initially treated with Lantus (8 U/day) along with lifestyle modifications. His fasting and postprandial capillary glucose levels were 7 to 8 mmol/L and 10 to 11 mmol/L, respectively, as measured by a home glucometer. His HbA1c levels ranged from 7.5% to 8.0%. To confirm the diagnosis, a methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) assay was performed using a SALSA MS-MLPA kit ME033. The kit contains eight probes specific for sequences in or near the TNDM critical region of chromosome 6q24, along with two blank control probes (IGF2R and RB1). The threshold for chromosomal abnormalities was set at 0.7 for deletions and 1.3 for duplications. Abnormal values were colored red and plotted outside the threshold line. Three probes in the PLAGL1 gene revealed a maternal peak reduction or paternal uniparental disomy (patUPD6).
Additionally, a global screening array (GSA) microchip, which includes 660,000 single nucleotide polymorphisms (SNPs) of the whole genome, was used to detect possible paternal uniparental disomy. The GSA analysis showed no evidence of paternal uniparental disomy in the region of chromosome 6q24, confirming that the patient had hypomethylation of the maternal allele in this region.
After confirming the diagnosis and obtaining informed consent, the patient was treated with glimepiride at a dose of 1 mg once daily. His fasting and postprandial capillary glucose levels improved to 6–7 mmol/L and 8–10 mmol/L, respectively. After three months of treatment, his HbA1c levels dropped by approximately 1% and remained stable for over six months without any episodes of hypoglycemia.
The overexpression of paternal genes on chromosome 6q24 is believed to be the underlying cause of 6q24-related TNDM. This region includes two genes: pleiomorphic adenoma gene-like 1 (PLAGL1, also known as ZAC1) and hydatidiform mole associated and imprinted (HYMAI). The exact mechanism by which PLAGL1 causes TNDM remains unclear. In rodent models, overexpression of Plagl1 disrupts the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways in beta cells at birth. These pathways are crucial for glucose-induced insulin secretion, and overexpression of PLAGL1 is thought to reduce beta cell mass at birth.
Insulin is widely considered the first-line therapy for 6q24-related TNDM during the neonatal period. However, given that patients with 6q24-related TNDM typically have relatively healthy beta cell function during remission, sulfonylurea treatment has a biological rationale. Sulfonylureas work by binding to sulfonylurea receptors on pancreatic beta cells, which are presumed to be intact in patients with 6q24-related TNDM. Additionally, these patients have decreased sensitivity to glucose, and sulfonylureas can help improve insulin release. The most common side effect of sulfonylureas is hypoglycemia, which can be managed through dose adjustment. Other side effects, such as diarrhea and weight gain, are relatively rare and less severe.
This case is consistent with previous reports of successful sulfonylurea treatment in patients with 6q24-related TNDM. In 2015, the first Chinese patient with 6q24-related TNDM was successfully treated with sulfonylurea. Similar to the current case, that patient had a low birth weight, early-onset diabetes, and high blood glucose and HbA1c levels. Both patients were treated with low-dose sulfonylurea and achieved stable glucose control without side effects. Additionally, a review of 11 patients with 6q24-related TNDM treated with low-dose sulfonylurea showed that 13 out of 14 patients were successfully treated, including five before remission and eight after relapse. Only one case did not respond to sulfonylurea treatment. A recent study also found that the dipeptidyl peptidase-4 inhibitor, another antidiabetic agent, could be a useful alternative for relapsed 6q24-related TNDM.
In conclusion, the evidence from this case and previous studies supports the efficacy and safety of sulfonylurea therapy in 6q24-related TNDM, particularly after relapse. Sulfonylurea treatment provides a viable alternative to insulin, offering stable glucose control with minimal side effects. Further studies involving larger numbers of patients with 6q24-related TNDM are necessary to confirm these findings and optimize treatment protocols.
doi.org/10.1097/CM9.0000000000000147
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