Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes
Authors: Bowman Pamela , Mathews Frances , Barbetti Fabrizio , Shepherd Maggie H. , Sanchez Janine , Piccini Barbara , Beltrand Jacques , Letourneau-Freiberg Lisa R. , Polak Michel , Greeley Siri Atma W. , Rawlins Eamon , Babiker Tarig , Thomas Nicholas J. , De Franco Elisa , Ellard Sian , Flanagan Sarah E. , Hattersley Andrew T. ,   Neonatal Diabetes International Collaborative Group, Mohsin Fauzia , Cummings Elizabeth , LeGault Laurent , Punthakee Zubin , Van Der Meulen John , Codner Ethel , Gallardo Vivian , Rafiq Meena , Houghton Jayne , Amratlal Patel Kashyap , Ford Tamsin , Kumaraguru Pillai Janani , Finn Roisin , Chakera Ali , Raile Klemens , Schebek Martin , Werner Andrea , Jain Vandana , Heffernan Emmeline , Iovane Brunella , Russo Lucia , De Galan Bastiaan , Voorhoeve Paul , Njolstad Pal , Sulen Asta , Dankovcikova Adriana , Gasperikova Daniela , Stanik Juraj , Aydin Banu , Bas Firdevs , Bundak Ruveyde , Darendeliler Feyza , Raceala-Motoc Stanca , Sanchez Juan C. , Bauer Katherine E. , Greeley Kara W. 
Published: November 2020

OBJECTIVE
ABCC8 mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous studies suggested that people with ABCC8-PNDM require lower sulfonylurea doses and have milder neurological features than those with KCNJ11-PNDM. However, these studies were short-term and included combinations of ABCC8-PNDM and ABCC8-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated ABCC8-PNDM.

RESEARCH DESIGN AND METHODS
We studied all 24 individuals with ABCC8-PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.

RESULTS
Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 [range 4.1–13.2] years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA1c 7.2% vs. 5.7%, P = 0.0004) and remained excellent long-term (1-year vs. 10-year HbA1c 5.7% vs. 6.5%, P = 0.04), n = 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide, P = 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).

CONCLUSIONS
Sulfonylurea treatment of ABCC8-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.