Diabetes Mellitus in a Patient With Lafora Disease: Possible Links With Pancreatic β-Cell Dysfunction and Insulin Resistance

Overview

Journal Front Pediatr

Specialty Pediatrics

Date 2019 Feb 1

PMID 30701169

Citations 4

Authors

Ramona C Nicolescu

Sara Al-Khawaga

Berge A Minassian

Khalid Hussain

Affiliations

Soon will be listed here.

Abstract

Lafora disease (LD) is a rare autosomal recessive disorder characterized by progressive myoclonic epilepsy followed by continuous neurological decline, culminating in death within 10 years. LD leads to accumulation of insoluble, abnormal, glycogen-like structures called Lafora bodies (LBs). It is caused by mutations in the gene encoding glycogen phosphatase ( or the E3 ubiquitin ligase malin (. These two proteins are involved in an intricate, however, incompletely elucidated pathway governing glycogen metabolism. The formation of EPM2A and malin signaling complex promotes the ubiquitination of proteins participating in glycogen metabolism, where dysfunctional mutations lead to the formation of LBs. Herein, we describe a 13-years-old child with LD due to a (c.386C > A, p.Pro129His) mutation, who has developed diabetes mellitus and was treated with metformin. We discuss how basic mechanisms of LD could be linked to β-cell dysfunction and insulin resistance.

Citing Articles

Time-regulated transcripts with the potential to modulate human pluripotent stem cell-derived cardiomyocyte differentiation.

Munoz J, Dariolli R, da Silva C, Neri E, Valadao I, Turaca L Stem Cell Res Ther. 2022; 13(1):437.

PMID: 36056380 PMC: 9438174. DOI: 10.1186/s13287-022-03138-x.

Natural history of Lafora disease: a prognostic systematic review and individual participant data meta-analysis.

Pondrelli F, Muccioli L, Licchetta L, Mostacci B, Zenesini C, Tinuper P Orphanet J Rare Dis. 2021; 16(1):362.

PMID: 34399803 PMC: 8365996. DOI: 10.1186/s13023-021-01989-w.

Genotypes and phenotypes of patients with Lafora disease living in Germany.

Brenner D, Baumgartner T, von Spiczak S, Lewerenz J, Weis R, Grimmer A Neurol Res Pract. 2020; 1.

PMID: 32587944 PMC: 7316188. DOI: 10.1186/s42466-019-0040-2.

Insulin and Autophagy in Neurodegeneration.

Prudente de Mello N, Orellana A, Mazucanti C, Lima G, Scavone C, Kawamoto E Front Neurosci. 2019; 13:491.

PMID: 31231176 PMC: 6558407. DOI: 10.3389/fnins.2019.00491.

References

Delibegovic M, Armstrong C, Dobbie L, W Watt P, Smith A, Cohen P . Disruption of the striated muscle glycogen targeting subunit PPP1R3A of protein phosphatase 1 leads to increased weight gain, fat deposition, and development of insulin resistance. Diabetes. 2003; 52(3):596-604. DOI: 10.2337/diabetes.52.3.596. View

Crosson S, Khan A, Printen J, Pessin J, Saltiel A . PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance. J Clin Invest. 2003; 111(9):1423-32. PMC: 154451. DOI: 10.1172/JCI17975. View

Ceulemans H, Bollen M . Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004; 84(1):1-39. DOI: 10.1152/physrev.00013.2003. View

Gomez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari C . Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology. 2005; 64(6):982-6. DOI: 10.1212/01.WNL.0000154519.10805.F7. View

Ganesh S, Puri R, Singh S, Mittal S, Dubey D . Recent advances in the molecular basis of Lafora's progressive myoclonus epilepsy. J Hum Genet. 2005; 51(1):1-8. DOI: 10.1007/s10038-005-0321-1. View

Singh S, Sethi I, Francheschetti S, Riggio C, Avanzini G, Yamakawa K . Novel NHLRC1 mutations and genotype-phenotype correlations in patients with Lafora's progressive myoclonic epilepsy. J Med Genet. 2006; 43(9):e48. PMC: 2564581. DOI: 10.1136/jmg.2005.039479. View

Delgado-Escueta A . Advances in lafora progressive myoclonus epilepsy. Curr Neurol Neurosci Rep. 2007; 7(5):428-33. DOI: 10.1007/s11910-007-0066-7. View

Solaz-Fuster M, Gimeno-Alcaniz J, Ros S, Fernandez-Sanchez M, Garcia-Fojeda B, Criado Garcia O . Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. Hum Mol Genet. 2007; 17(5):667-78. DOI: 10.1093/hmg/ddm339. View

Tagliabracci V, Turnbull J, Wang W, Girard J, Zhao X, Skurat A . Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. Proc Natl Acad Sci U S A. 2007; 104(49):19262-6. PMC: 2148278. DOI: 10.1073/pnas.0707952104. View

10.

DePaoli-Roach A, Tagliabracci V, Segvich D, Meyer C, Irimia J, Roach P . Genetic depletion of the malin E3 ubiquitin ligase in mice leads to lafora bodies and the accumulation of insoluble laforin. J Biol Chem. 2010; 285(33):25372-81. PMC: 2919100. DOI: 10.1074/jbc.M110.148668. View

11.

Lesca G, Boutry-Kryza N, De Toffol B, Milh M, Steschenko D, Lemesle-Martin M . Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease. Epilepsia. 2010; 51(9):1691-8. DOI: 10.1111/j.1528-1167.2010.02692.x. View

12.

Turnbull J, Wang P, Girard J, Ruggieri A, Wang T, Draginov A . Glycogen hyperphosphorylation underlies lafora body formation. Ann Neurol. 2010; 68(6):925-33. DOI: 10.1002/ana.22156. View

13.

Singh P, Singh S, Ganesh S . The laforin-malin complex negatively regulates glycogen synthesis by modulating cellular glucose uptake via glucose transporters. Mol Cell Biol. 2011; 32(3):652-63. PMC: 3266598. DOI: 10.1128/MCB.06353-11. View

14.

Roach P, DePaoli-Roach A, Hurley T, Tagliabracci V . Glycogen and its metabolism: some new developments and old themes. Biochem J. 2012; 441(3):763-87. PMC: 4945249. DOI: 10.1042/BJ20111416. View

15.

Turnbull J, Girard J, Lohi H, Chan E, Wang P, Tiberia E . Early-onset Lafora body disease. Brain. 2012; 135(Pt 9):2684-98. PMC: 3437029. DOI: 10.1093/brain/aws205. View

16.

Duran J, Gruart A, Garcia-Rocha M, Delgado-Garcia J, Guinovart J . Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum Mol Genet. 2014; 23(12):3147-56. DOI: 10.1093/hmg/ddu024. View

17.

Corcia L, Hohensee S, Olivero A, Wong J . Lafora disease with novel autopsy findings: a case report with endocrine involvement and literature review. Pediatr Neurol. 2014; 51(5):713-6. DOI: 10.1016/j.pediatrneurol.2014.07.034. View

18.

Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley C . Lafora disease. Epileptic Disord. 2016; 18(S2):38-62. PMC: 5777303. DOI: 10.1684/epd.2016.0842. View

19.

Brereton M, Rohm M, Shimomura K, Holland C, Tornovsky-Babeay S, Dadon D . Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells. Nat Commun. 2016; 7:13496. PMC: 5123088. DOI: 10.1038/ncomms13496. View

20.

Irimia J, Meyer C, Segvich D, Surendran S, DePaoli-Roach A, Morral N . Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem. 2017; 292(25):10455-10464. PMC: 5481557. DOI: 10.1074/jbc.M117.786525. View