Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations

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Passone , C D G B , Vermillac , G , Staels , W , Besancon , A , Kariyawasam , D , Godot , C , Lambe , C , Talbotec , C , Girard , M , Chardot , C , Berteloot , L , Hachem , T , Lapillonne , A , Poidvin , A , Storey , C , Neve , M , Stan , C , Dugelay , E , Fauret-Amsellem , A-L , Capri , Y , Cave , H , Ybarra , M , Chandra , V , Scharfmann , R , Bismuth , E , Polak , M , Carel , J C , Pigneur , B & Beltrand , J 2022 , ' Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations ' , Frontiers in Endocrinology , vol. 13 , 802351 . https://doi.org/10.3389/fendo.2022.802351

Title: Mitchell-Riley Syndrome : Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations
Author: Passone, Caroline de Gouveia Buff; Vermillac, Gaelle; Staels, Willem; Besancon, Alix; Kariyawasam, Dulanjalee; Godot, Cecile; Lambe, Cecile; Talbotec, Cecile; Girard, Muriel; Chardot, Christophe; Berteloot, Laureline; Hachem, Taymme; Lapillonne, Alexandre; Poidvin, Amelie; Storey, Caroline; Neve, Mathieu; Stan, Cosmina; Dugelay, Emmanuelle; Fauret-Amsellem, Anne-Laure; Capri, Yline; Cave, Helene; Ybarra, Marina; Chandra, Vikash; Scharfmann, Raphael; Bismuth, Elise; Polak, Michel; Carel, Jean Claude; Pigneur, Benedicte; Beltrand, Jacques
Contributor organization: Centre of Excellence in Stem Cell Metabolism
STEMM - Stem Cells and Metabolism Research Program
University of Helsinki
Faculty of Medicine
Date: 2022-06-22
Language: eng
Number of pages: 12
Belongs to series: Frontiers in Endocrinology
ISSN: 1664-2392
DOI: https://doi.org/10.3389/fendo.2022.802351
URI: http://hdl.handle.net/10138/346549
Abstract: Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function. MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6(R181W) and RFX6(V506G) variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function. ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6(V506G) and RFX6(R181W) mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function. Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.
Subject: neonatal diabetes mellitus
RFX6
Mitchell-Riley syndrome
diabetes technology
beta-cell function
parenteral nutrition
INTESTINAL ATRESIA
VARIANTS
ONSET
CELLS
GENE
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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