Relapsed 6q24-related Transient Neonatal Diabetes Mellitus Successfully Treated with Sulfonylurea

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Relapsed 6q24-related Transient Neonatal Diabetes Mellitus Successfully Treated with Sulfonylurea

Did you know diabetes diagnosed within 6 months of birth—called neonatal diabetes mellitus (NDM)—affects about 1 in 90,000 to 160,000 live births? Most cases (80%) have a known genetic cause, and one of the most common types is transient neonatal diabetes mellitus (TNDM). TNDM is marked by low birth weight and a unique “remission-relapse” pattern: babies improve with treatment but may develop diabetes again later in childhood or adolescence.

The most frequent cause of TNDM (about 70% of cases) is overexpression of genes on chromosome 6q24. This happens when the father’s gene copies are too active—either through paternal uniparental disomy (inheriting two copies from Dad), duplicated paternal alleles, or hypomethylation (lost chemical “tags” that silence the mother’s gene). While insulin is standard for newborn TNDM, there’s no agreed-upon treatment for relapsed cases. A team of researchers from Peking Union Medical College Hospital in Beijing recently shared a breakthrough: a relapsed 6q24-related TNDM patient successfully treated with a low-dose sulfonylurea drug.

The Patient’s Story

The patient, a 15-year-old Chinese male, was born prematurely at 36+2 weeks (due to premature membrane rupture) to healthy parents. His birth weight was just 1700g—small for his gestational age. At 45 days old, he developed classic diabetes symptoms: excessive urination, thirst, and hunger. Tests revealed a fasting glucose of 30.6 mmol/L (normal for newborns is ~3.3–5.5 mmol/L) and a glycated hemoglobin (HbA1c) of 12.4% (normal is <5.7%). He was treated with intravenous insulin, and by 3 months old, his diabetes went into remission—he no longer needed insulin.

For 14 years, he had no signs of diabetes. But at 14, his fasting glucose spiked to 11.3 mmol/L, and his HbA1c reached 8.2%. A 2-hour oral glucose tolerance test (OGTT) confirmed relapse: his blood glucose was 6.64 mmol/L fasting and 13.47 mmol/L 2 hours after a meal (normal 2-hour glucose is <7.8 mmol/L). Insulin and C-peptide levels (markers of pancreatic beta cell function) were normal, and he tested negative for antibodies linked to type 1 diabetes (GAD, IAA, IA2). He had no other conditions causing secondary diabetes, and whole exome sequencing (a test for genetic mutations) found no abnormalities.

Initial treatment included daily insulin (8 units of Lantus) and lifestyle changes (diet and exercise). While his glucose levels improved—fasting 7–8 mmol/L, postprandial 10–11 mmol/L—his HbA1c stayed between 7.5% and 8.0%, above the target for most people with diabetes.

Confirming the Cause

To find out why he relapsed, doctors used two specialized tests: methylation-specific multiplex-ligation-dependent probe amplification (MS-MLPA) and a global screening array (GSA). The MS-MLPA test checks for epigenetic changes (like methylation) on chromosome 6q24. Results showed hypomethylation of the maternal allele—the mother’s gene copy had lost a chemical “tag” that normally keeps it silent, letting the father’s active gene copy cause overexpression. The GSA test ruled out paternal uniparental disomy (inheriting two copies of chromosome 6 from Dad). Together, these tests confirmed his relapse was due to 6q24-related TNDM.

A New Treatment Path

With this diagnosis, doctors switched his treatment to glimepiride, a sulfonylurea drug, at a low dose (1mg once daily). Sulfonylureas work by stimulating the pancreas to release more insulin—they’re common for type 2 diabetes but aren’t standard for TNDM relapse.

The results were striking: his fasting glucose dropped to 6–7 mmol/L, and postprandial glucose (after meals) fell to 8–10 mmol/L. After 3 months, his HbA1c dropped by ~1% (to around 6.5–7.0%) and stayed stable for over 6 months—with no episodes of hypoglycemia (low blood sugar), a key risk of sulfonylureas.

Why This Works for 6q24 TNDM

6q24-related TNDM is driven by overexpression of two paternal genes: PLAGL1 (pleiomorphic adenoma gene-like 1) and HYMAI (hydatidiform mole associated and imprinted). While the exact way PLAGL1 causes diabetes isn’t fully clear, rodent studies offer clues: too much Plagl1 disrupts two pathways critical for insulin secretion—mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)—and reduces beta cell mass at birth.

Sulfonylureas make sense for relapsed 6q24 TNDM because:

  1. Patients still have intact sulfonylurea receptors on their beta cells (so the drug can stimulate insulin release).
  2. Their beta cells have reduced sensitivity to glucose—sulfonylureas bypass this to trigger insulin release.

Low doses minimize the risk of hypoglycemia, the most common side effect. Other risks (like diarrhea or weight gain) are rare and mild.

What This Means for Other Patients

This case adds to growing evidence that sulfonylureas are a safe, effective option for relapsed 6q24-related TNDM. A 2015 Chinese study reported the first successful sulfonylurea treatment for a 6q24 TNDM patient, and a 2018 study by Garcin et al reviewed 14 patients (including 3 new cases) treated with low-dose sulfonylureas—13 had successful glucose control (5 before remission, 8 after relapse). Only one patient didn’t respond. Another study found dipeptidyl peptidase-4 (DPP-4) inhibitors can also help, but sulfonylureas are more widely available.

Conclusion

For patients with 6q24-related TNDM who relapse, low-dose sulfonylureas offer a viable alternative to insulin—with fewer daily injections and better long-term glucose control. This case shows that personalized care, based on genetic and epigenetic testing, can improve outcomes for rare diabetes types.

Of course, more research is needed. Larger studies with longer follow-up will confirm sulfonylureas’ long-term safety and efficacy. But for now, this breakthrough gives doctors and patients hope for managing a challenging condition.

The original study was published by Jun-Ling Fu, Tong Wang, and Xin-Hua Xiao from the Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing.

References:

  1. Greeley SA, Tucker SE, Naylor RN, Bell GI, Philipson LH. Neonatal diabetes mellitus: a model for personalized medicine. Trends in Endocrinology & Metabolism 2010;21(8):464–472. https://doi.org/10.1016/j.tem.2010.03.004
  2. Yorifuji T, Higuchi S, Hosokawa Y, Kawakita R. Chromosome 6q24-related diabetes mellitus. Clinical Pediatric Endocrinology 2018;27(2):59–65. https://doi.org/10.1297/cpe.27.59
  3. Zhang M, Chen X, Shen S, Li T, Chen L, Hu M, et al. Sulfonylurea in the treatment of neonatal diabetes mellitus children with heterogeneous genetic backgrounds. Journal of Pediatric Endocrinology & Metabolism 2015;28(7–8):877–884. https://doi.org/10.1515/jpem-2014-0429
  4. Garcin L, Kariyawasam D, Busiah K, Fauret-Amsellem AL, Le Bourgeois F, Vaivre-Douret L, et al. Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities. Pediatric Diabetes 2018;19(4):663–669. https://doi.org/10.1111/pedi.12635
  5. Yorifuji T, Hashimoto Y, Kawakita R, Hosokawa Y, Fujimaru R, Hatake K, et al. Relapsing 6q24-related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase-4 inhibitor: a case report. Pediatric Diabetes 2014;15(5):606–610. https://doi.org/10.1111/pedi.12123
  6. Fu JL, Wang T, Xiao XH. Relapsed 6q24-related transient neonatal diabetes mellitus successfully treated with sulfonylurea. Chinese Medical Journal 2019;132(7):846–848. https://doi.org/10.1097/CM9.0000000000000147

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