A Novel Deletion Mutation in Underlies Progressive Myoclonic Epilepsy (Lafora Body Disease) in a Pakistani Family

Overview

Journal Neurol Asia

Date 2021 Nov 4

PMID 34733372

Citations 1

Authors

Fizza Orooj

Umm-E-Kalsoom

Xiaochu Zhao

Arsalan Ahmad

Imran Nazir Ahmed

Muhammad Faheem

Muhammad Jawad Hassan

Berge A Minasian

Affiliations

Soon will be listed here.

Abstract

Lafora body disease (MIM-254780), a glycogen storage disease, characterized by Lafora bodies (deformed glycogen molecules) accumulating in multiple organs, is a rare form of myoclonic epilepsy. It manifests in early adolescent years, initially with seizures and myoclonus, followed by dementia and progressive cognitive decline, ultimately culminating in death within 10 years. In Pakistan so far 5 cases have been reported. Here, we report a new case of Lafora body disease belonging to a consanguineous family from Pakistan. Histopathological analysis confirmed presence of lafora bodies in the patient`s skin. Sanger sequencing revealed novel homozygous 5bp deletion mutation (NM_005670.4; c.359_363delGTGTG) in exon 2 of the gene, which was truly segregated in the family. These results will increase our understanding regarding the aetiology of this disorder and will further add to the mutation spectrum of gene.

Citing Articles

MRI characteristics due to gene mutations in a Chinese pedigree with Lafora disease.

Sun Y, Zhou Z, Wang Q, Yan J, Zhang Z, Cui T Mol Genet Genomic Med. 2023; 11(10):e2228.

PMID: 37455597 PMC: 10568394. DOI: 10.1002/mgg3.2228.

References

Gentry M, Afawi Z, Armstrong D, Delgado-Escueta A, Goldberg Y, Grossman T . The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic. Epilepsy Behav. 2020; 103(Pt A):106839. PMC: 7024738. DOI: 10.1016/j.yebeh.2019.106839. View

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

Desdentado L, Espert R, Sanz P, Tirapu-Ustarroz J . [Lafora disease: a review of the literature]. Rev Neurol. 2019; 68(2):66-74. PMC: 6531605. View

Baykan B, Striano P, Gianotti S, Bebek N, Gennaro E, Gurses C . Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. Epilepsia. 2005; 46(10):1695-7. DOI: 10.1111/j.1528-1167.2005.00272.x. View

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

Gregersen N, Bross P, Vang S, Christensen J . Protein misfolding and human disease. Annu Rev Genomics Hum Genet. 2006; 7:103-24. DOI: 10.1146/annurev.genom.7.080505.115737. View

Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B . Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci. 2007; 10(11):1407-13. DOI: 10.1038/nn1998. View

Martin S, Strzelczyk A, Lindlar S, Krause K, Reif P, Menzler K . Drug-Resistant Juvenile Myoclonic Epilepsy: Misdiagnosis of Progressive Myoclonus Epilepsy. Front Neurol. 2019; 10:946. PMC: 6746890. DOI: 10.3389/fneur.2019.00946. View

Chinnaiyan S, Narayana S, Nanjappa V . Adherence to Antiepileptic Therapy in Adults. J Neurosci Rural Pract. 2017; 8(3):417-420. PMC: 5488564. DOI: 10.4103/jnrp.jnrp_392_16. View

10.

Hipp M, Park S, Hartl F . Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol. 2014; 24(9):506-14. DOI: 10.1016/j.tcb.2014.05.003. View

11.

Brewer M, Uittenbogaard A, Austin G, Segvich D, DePaoli-Roach A, Roach P . Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion. Cell Metab. 2019; 30(4):689-705.e6. PMC: 6774808. DOI: 10.1016/j.cmet.2019.07.002. View

12.

Worby C, Gentry M, Dixon J . Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem. 2007; 283(7):4069-76. PMC: 2251628. DOI: 10.1074/jbc.M708712200. View

13.

Nitschke F, Ahonen S, Nitschke S, Mitra S, Minassian B . Lafora disease - from pathogenesis to treatment strategies. Nat Rev Neurol. 2018; 14(10):606-617. PMC: 6317072. DOI: 10.1038/s41582-018-0057-0. View

14.

Kecmanovic M, Keckarevic-Markovic M, Keckarevic D, Stevanovic G, Jovic N, Romac S . Genetics of Lafora progressive myoclonic epilepsy: current perspectives. Appl Clin Genet. 2016; 9:49-53. PMC: 4859416. DOI: 10.2147/TACG.S57890. View

15.

Ahmad A, Dad R, Ullah M, Baig T, Ahmad I, Nasir A . Clinical and genetic studies in patients with Lafora disease from Pakistan. J Neurol Sci. 2017; 373:263-267. DOI: 10.1016/j.jns.2017.01.010. View

16.

Aslam Z, Lee E, Badshah M, Naeem M, Kang C . Whole exome sequencing identified a novel missense mutation in EPM2A underlying Lafora disease in a Pakistani family. Seizure. 2017; 51:200-203. DOI: 10.1016/j.seizure.2017.08.012. View

17.

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

18.

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

19.

Worby C, Gentry M, Dixon J . Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem. 2006; 281(41):30412-8. PMC: 2774450. DOI: 10.1074/jbc.M606117200. View

20.

Singh S, Ganesh S . Lafora progressive myoclonus epilepsy: a meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Hum Mutat. 2009; 30(5):715-23. DOI: 10.1002/humu.20954. View