title: Switching to sulphonylureas in children with iDEND syndrome caused by KCNJ11 mutations results in improved cerebellar perfusion.
abstract: OBJECTIVE
  Activating mutations in the KCNJ11 gene, encoding the Kir6.2 subunit of the KATP channel, result in permanent neonatal diabetes mellitus. They also may cause neurologic symptoms such as mental retardation and motor problems (iDEND syndrome) and epilepsy (DEND syndrome). Sulphonylurea (SU) treatment is reported to alleviate both the neurologic symptoms and diabetes in such cases. The study aimed to establish the magnitude and functional basis of the effect of SUs on the neurologic phenotype in children with iDEND using neuroimaging before and after insulin replacement with glibenclamide.
  
  
  METHODS
  To localize and quantify the effect of glibenclamide administration, we performed single-photon emission computed tomography in seven patients with different mutations in KCNJ11. In five patients, measurements before and after initiation of SU treatment were performed. RESULTS Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region. Cerebellar perfusion improved for both left (P = 0.006) and right (P = 0.01) hemispheres, with the mean improvement being 26.7 ± 7.1% (n = 5). No patients showed deterioration of cerebellar perfusion on SU therapy. Electrophysiological studies revealed a good correlation between the magnitude of KATP channel dysfunction and the clinical phenotype; mutant channels with the greatest reduction in adenosine 5'-triphosphate inhibition were associated with the most severe neurologic symptoms.
  
  
  CONCLUSIONS
  We conclude it is likely that at least some of the beneficial effects of SU treatment on neurodevelopment in iDEND patients result from improved cerebellar perfusion.
authors: Department of Paediatrics, Oncology, Haematology, and Diabetology, Medical University of Lodz, Lodz, Poland. wojciech.mlynarski@umed.lodz.pl
authors: Wojciech
authors: W
authors: Fendler
authors: Iwona
authors: I
authors: Pietrzak
authors: Melissa F
authors: MF
authors: Brereton
authors: Carolina
authors: C
authors: Lahmann
authors: Mariusz
authors: M
authors: Gadzicki
authors: Malgorzata
authors: M
authors: Bienkiewicz
authors: Izabela
authors: I
authors: Drozdz
authors: Maciej
authors: M
authors: Borowiec
authors: Maciej T
authors: MT
authors: Malecki
authors: Frances M
authors: FM
authors: Ashcroft
authors: Wojciech M
authors: WM
authors: Mlynarski
mesh_terms: D000293:Adolescent; D002531:Cerebellum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000188:drug therapy*; D005260:Female; D005905:Glyburide / Q000627:therapeutic use; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis / Q000235:genetics*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D015899:Tomography, Emission-Computed, Single-Photon; D000099161:Kcnj11 Channel
chemical_list: D005905:Glyburide; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; D000099161:Kcnj11 Channel