Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Novel variants causing megalencephalic leukodystrophy in Sudanese families

Abstract

Mutations in MLC1 cause megalencephalic leukoencephalopathy with subcortical cysts (MLC), a rare form of leukodystrophy characterized by macrocephaly, epilepsy, spasticity, and slow mental deterioration. Genetic studies of MLC are lacking from many parts of the world, especially in Sub-Saharan Africa. Genomic DNA was extracted for 67 leukodystrophic patients from 43 Sudanese families. Mutations were screened using the NGS panel testing 139 leukodystrophies and leukoencephalopathies causing genes (NextSeq500 Illumina). Five homozygous MLC1 variants were discovered in seven patients from five distinct families, including three consanguineous families from the same region of Sudan. Three variants were missense (c.971 T > G, p.Ile324Ser; c.344 T > C, p.Phe115Ser; and c.881 C > T, p.Pro294Leu), one duplication (c.831_838dupATATCTGT, p.Ser280Tyrfs*8), and one synonymous/splicing-site mutation (c.762 C > T, p.Ser254). The segregation pattern was consistent with autosomal recessive inheritance. The clinical presentation and brain MRI of the seven affected patients were consistent with the diagnosis of MLC1. Due to the high frequency of distinct MLC1 mutations found in our leukodystrophic Sudanese families, we analyzed the coding sequence of MLC1 gene in 124 individuals from the Sudanese genome project in comparison with the 1000-genome project. We found that Sudan has the highest proportion of deleterious variants in MLC1 gene compared with other populations from the 1000-genome project.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Stylianos E. Antonarakis, Brian G. Skotko, … Roger H. Reeves

References

  1. Bajaj SK, Misra R, Gupta R, Chandra R, Malik A. Megalencephalic leukoencephalopathy with sub cortical cysts: an inherited dysmyelinating disorder. J Pediatr Neurosci. 2013;8:77–80.

    Article  Google Scholar 

  2. van der Knaap MS, Abbink TE, Min R Megalencephalic leukoencephalopathy with subcortical cysts. GeneReviews®. University of Washington, Seattle; 1993.

  3. Hamilton EMC, Tekturk P, Cialdella F, Rappard DF, van, Wolf NI, Yalcinkaya C. et al. Megalencephalic leukoencephalopathy with subcortical cysts. Neurology. 2018;90:e1395–e1403.

    Article  Google Scholar 

  4. López-Hernández T, Sirisi S, Capdevila-Nortes X, Montolio M, Fernández-Dueñas V, Scheper GC, et al. Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Hum Mol Genet. 2011;20:3266–77. https://doi.org/10.1093/hmg/ddr238.

    Article  Google Scholar 

  5. López-Hernández T, Ridder MC, Montolio M, Capdevila-Nortes X, Polder E, Sirisi S. et al. Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 2011;88:422–32.

    Article  Google Scholar 

  6. van der Knaap MS, Lai V, Köhler W, Salih MA, Fonseca M-J, Benke TA, et al. Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann Neurol . 2010;67:834–7. https://doi.org/10.1002/ana.21980.

    PubMed  Google Scholar 

  7. Dubey M, Bugiani M, Ridder MC, Postma NL, Brouwers E, Polder E, et al. Mice with megalencephalic leukoencephalopathy with cysts: a developmental angle. Ann Neurol. 2015;77:114–31.

    Article  CAS  Google Scholar 

  8. Capdevila-Nortes X, López-Hernández T, Apaja PM, López de Heredia M, Sirisi S, Callejo G, et al. Insights into MLC pathogenesis: GlialCAM is an MLC1 chaperone required for proper activation of volume-regulated anion currents. Hum Mol Genet. 2013;22:4405–16.

    Article  CAS  Google Scholar 

  9. Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8.

    Article  CAS  Google Scholar 

  10. Amin M, Elsayed L, Ahmed AE. Clinical and genetic characteristics of leukodystrophies in Africa. J Neurosci Rural Pract. 2017;8:S89–93.

    Article  Google Scholar 

  11. Duarri A, Lopez de Heredia M, Capdevila-Nortes X, Ridder MC, Montolio M, López-Hernández T, et al. Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model. Neurobiol Dis. 2011;43:228–38.

    Article  CAS  Google Scholar 

  12. Cao B, Yan H, Guo M, Xie H, Wu Y, Gu Q, et al. Ten novel mutations in Chinese patients with megalencephalic leukoencephalopathy with subcortical cysts and a long-term follow-up research. PLoS One. 2016;11:e0157258. https://doi.org/10.1371/journal.pone.0157258.

  13. Leegwater PA, Yuan BQ, van der Steen J, Mulders J, Könst AA, Boor PK, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8.

    Article  CAS  Google Scholar 

  14. Wang J-M, Jiang Y-W, Wu X-R. [Effects on astrocytic function from MLC1 gene mutation with megalencephalic leukoencephalopathy with subcortical cysts]. Sheng Li Ke Xue Jin Zhan. 2010;41:69–71.

    CAS  PubMed  Google Scholar 

  15. Zhu L-N, Ma X-W, Zheng T, He F, Feng Z-C. [Analysis of MLC1 gene mutation in a Chinese family with megalencephalic leukoencephalopathy with subcortical cysts]. Zhongguo Dang Dai Er Ke Za Zhi. 2015;17:367–70.

    CAS  PubMed  Google Scholar 

  16. Yüzbaşioğlu A, Topçu M, Cetin Kocaefe Y, Ozgüç M. Novel mutations of the MLC1 gene in Turkish patients. Eur J Med Genet. 2011;54:281–3.

    Article  Google Scholar 

  17. Shimada S, Shimojima K, Masuda T, Nakayama Y, Kohji T, Tsukamoto H, et al. MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts. Hum Genome Var. 2014;1:14019.

    Article  Google Scholar 

  18. Mancini C, Vaula G, Scalzitti L, Cavalieri S, Bertini E, Aiello C, et al. Megalencephalic leukoencephalopathy with subcortical cysts type 1 (MLC1) due to a homozygous deep intronic splicing mutation (c.895-226T>G) abrogated in vitro using an antisense morpholino oligonucleotide. Neurogenet. 2012;13:205–14.

    Article  Google Scholar 

  19. Chen X, Qu H, Yu T, Luo R. [Identification of a novel MLC1 mutation in a Chinese patient affected with megalencephalic leukoencephalopathy with subcortical cysts]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2016;33:316–9.

    CAS  PubMed  Google Scholar 

  20. Montagna G, Teijido O, Eymard-Pierre E, Muraki K, Cohen B, Loizzo A, et al. Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1. Hum Mutat. 2006;27:292.

    Article  Google Scholar 

  21. Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, et al. Indian Agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurol. 2004;62:878–82.

    Article  CAS  Google Scholar 

  22. Ben-Zeev B, Levy-Nissenbaum E, Lahat H, Anikster Y, Shinar Y, Brand N, et al. Megalencephalic leukoencephalopathy with subcortical cysts; A founder effect in Israeli patients and a higher than expected carrier rate among Libyan Jews. Hum Genet. 2002;111:214–8.

    Article  CAS  Google Scholar 

  23. Leegwater PAJ, Yuan BQ, Van der Steen J, Mulders J, Könst AAM, Boor PKI, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet. 2001;68:831–8.

    Article  CAS  Google Scholar 

  24. Shimada S, Shimojima K, Masuda T, Nakayama Y, Kohji T, Tsukamoto H, et al. MLC1 mutations in Japanese patients with megalencephalic leukoencephalopathy with subcortical cysts. Hum Genome Var. 2014;1:14019.

  25. Choi SA, Kim SY, Yoon J, Choi J, Park SS, Seong MW, et al. A unique mutational spectrum of MLC1 in Korean patients with megalencephalic leukoencephalopathy with subcortical cysts: P.Ala275Asp founder mutation and maternal uniparental disomy of chromosome 22. Ann Lab Med. 2017;37:516–21.

    Article  CAS  Google Scholar 

  26. Yüzbaşioğlu A, Topçu M, Kocaefe YÇ, Özgüç M. Novel mutations of the MLC1 gene in Turkish patients. Eur J Med Genet. 2011;54:281–3.

    Article  Google Scholar 

  27. Gorospe JR, Singhal BS, Kainu T, Wu F, Stephan D, Trent J, et al. Indian agarwal megalencephalic leukodystrophy with cysts is caused by a common MLC1 mutation. Neurol. 2004;62:878–82.

    Article  CAS  Google Scholar 

  28. van der Knaap MS, Boor I, Estévez R. Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. Lancet Neurol. 2012;11:973–85.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Imen Dorboz.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amin, M., Vignal, C., Hamed, A.A.A. et al. Novel variants causing megalencephalic leukodystrophy in Sudanese families. J Hum Genet 67, 127–132 (2022). https://doi.org/10.1038/s10038-021-00945-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-021-00945-7

This article is cited by

Search

Quick links