KIMOTO Yasuhiro

WATANABE Yoshiyuki

YAMAMOTO Toshiyuki

YAMAMOTO-SHIMOJIMA Keiko

Tokyo Women’s Medical University

Two Different MLC1 Variants Compounded with aCommon Variant S93L in Japanese Patients ofMegalencephalic Leukoencephalopathy withSubcortical Cysts著者名 YAMAMOTO-SHIMOJIMA Keiko, KIMOTO Yasuhiro,WATANABE Yoshiyuki, YAMAMOTO Toshiyukijournal orpublication titleTokyo Women's Medical University Journalvolume 4page range 94-97year 2020-12-25URL http://hdl.handle.net/10470/00032753―94―Case ReportTWMUJ 4: 94-97, 2020Two Different MLC1 Variants Compounded with a Common Variant S93L in JapanesePatients of Megalencephalic Leukoencephalopathy with Subcortical CystsKeiko Yamamoto-Shimojima,１Yasuhiro Kimoto,２Yoshiyuki Watanabe,３ and Toshiyuki Yamamoto１１Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan２Department of Pediatrics, Miyazaki University, Miyazaki, Japan３Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan(Accepted August 5, 2020)(Advance Publication by J-STAGE September 25, 2020)Megalencephalic leukoencephalopathy with subcortical cysts (MLC; MIM#604004) is a rare congenital disorder of the cere-bral white matter. Most MLC patients have MLC1 mutations which are inherited in an autosomal recessive manner. Sincethere is no established biomarker for MLC, genetic testing is necessary for a final diagnosis. We identified compound het-erozygous mutations in two different Japanese patients having MLC. Both patients showed a common mutation of c.278C>T(p.Ser93Leu) in a heterozygous status. In addition, two different mutations (c.337_353delinsG and c.423+1G>A) were identi-fied in the homologous alleles of the patients, respectively. Although these two variants were first identified in the Japanesepopulation, they have since been reported in other Asian countries and might be founder mutations of the gene in Asianpopulation.Key Words: Sanger sequencing, leukodystrophy, macrocephalyIntroductionMegalencephalic leukoencephalopathy with subcorticalcysts (MLC; MIM#604004) is a congenital disorder ofthe cerebral white matter.１Patients with MLC typicallyshow megalencepahly since the neonatal period. Thus,patients with MLC are often referred to the hospital by ahealth checkup system for neonates and are radiologi-cally examined. If the patients exhibit cystic-like findingsin the subcortical white matter, presence of MLC wouldbe strongly suggested. White matter involvement andclinical severity often display step-wise progression.Most patients with MLC have MLC1 mutations whichare inherited in an autosomal recessive manner.２Sincethere is no biomarker for MLC, genetic testing is neces-sary for a final diagnosis. Previously, many genetic muta-tions have been reported for MLC.３Here, we report ontwo additional patients with MLC.Case ReportsPatient 1 is a 3-year-old Japanese boy, who was born at39 weeks of gestation, with a birth occipitofrontal cir-cumference (OFC) of 36.0 cm (> 97th centile), indicatingCorresponding Author: Toshiyuki Yamamoto, Institute of Medical Genetics, Tokyo Women’s Medical University, 8-1 Kawada-cho,Shinjuku-ku, Tokyo 162-8666, Japan. yamamoto.toshiyuki@twmu.ac.jpdoi: 10.24488/twmuj.2020007CopyrightⒸ 2020 Society of Tokyo Women’s Medical University. This is an open access article distributed under the terms of CreativeCommons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal source is properly credited.―95―Figure　1　Results of MRI examination. Patient 1 shows cystic-like findings in the subcortical white matter (A; white arrows) and diffuse white matter involvement (B). Patient 2 shows diffuse T1-low (C) and T2-hypointensities (D) in the white matter. A BC Dmacrocephaly. The patient is the only child of his healthyparents who were non-consanguineous. His family his-tory is no-remarkable. His OFC was measured to be 48.0cm (> 97th centile) during a health checkup at 5 months,and macrocephaly became remarkable. Then, he was re-ferred to the hospital, and brain magnetic resonance im-aging (MRI) displayed a high T2 intensity in the whitematter, in association with suspected cystic findings inthe subcortical region, suggesting the presence of MLC.At present, he shows mildly delayed motor development,probably due to macrocephaly with an OFC of 57.3 cm(> 97th centile). Brain MRI clearly demonstrated typicalMLC findings (Figure 1A and B).Patient 2 is a 14-month-old Japanese girl, who wasborn at 36 weeks of gestation, with a birth weight of2,435 g. The patient is the only child of her healthy par-ents who were non-consanguineous. There is no-remarkable family history. During early infancy, the pa-tient showed normal development; however, she demon-strated mildly delayed gross motor development. At 10months, she could not sit upright and macrocephaly wasalso noted. Then, she was referred to the hospital and herbrain MRI displayed a diffuse white matter abnormality(Figure 1C and D).Molecular DiagnosisSince MLC was suspected in both the patients, geneticdiagnosis was performed. This study was approved bythe institutional ethics committee (#338C) and performedin accordance with the Declaration of Helsinki. Writteninformed consent was obtained from the families, and pe-―96―Figure　2　Electropherograms of Sanger sequencing. The c.278C>T is commonly observed (A). Both c.337_353delinsG (B) and c.423+1G>A (C) are shown as heterozygous.  A T C C C C T C G G C A A T T/TI P S A I/LT C A G C A A T A A A C/aS A I Ng t gT T T C A G A T A T T G T T TG G T T T G C T GF Q T L FG L LCBAripheral blood samples were obtained from the patientsand their parents.First, the common mutation, NM_139202(MLC1_v001):c.278C>T (p.Ser93Leu), in exon 4 was confirmedby PCR Sanger sequencing according to a previous re-port.３Since both the patients displayed the mutation in aheterozygous status (Figure 2A), other exons were sub-sequently analyzed. NM_139202(MLC1_v001):c.337_353 delinsG ( p. Ile 113 Glyfs * 4 ) in exon 5 and NM _139202(MLC1_v001):c.423+1G>A in intron 6 wereidentified in patient 1 and patient 2, respectively (Fig-ure 2B and C).In patient 1, the p.Ser93Leu and the p.Ile113Glyfs*4were inherited from the mother and the father, respec-tively. In patient 2, the p.Ser93Leu and the c.423+1G>Awere inherited from the father and the mother, respec-tively. Therefore, both the patients showed MLC1 muta-tions as a compound heterozygous pattern.DiscussionThe p.Ser93Leu mutation was first identified in 2003.４Subsequently, this mutation has been recognized as acommon mutation among Japanese patients with MLC.５Indeed, in our laboratory, all previous patients with MLCdisplayed p.Ser93Leu in at least one allele.３Thus, wefirstly check the existence of p.Ser93Leu in patients withsuspected MLC.In this study, we initially identified p.Ser93Leu in twopatients. Subsequently, we analyzed all exons with confi-dence. As expected, two different mutations were identi-fied in both the patients in combination with p.Ser93Leu.Thus, this supported the fact that our strategy was reason-able.The mutation, c.337_353delinsG (p.Ile113Glyfs*4),identified in patient 1 and his father, is related to aframeshift alteration. Thus, loss-of-function was sus-pected as a consequence. This mutation has only been re-ported in Korea.６The mutation, c.423+1G>A, identifiedin patient 2 and her mother, was located on the splice do-nor site and hence is considered to cause a splicing ab-normality. This splicing mutation has only been reportedin Iran.７Although these two mutations are the first to befound in Japanese population, it is extremely rare that thesame mutations occur independently in the same popula-tion. Therefore, these mutations are considered to befounder mutations in Asian population.Generally, clinical features of the patients with MLCare variable and there is no clear genotype-phenotypecorrelation in MLC. Thus, it is hard to predict futureprognosis or severity of patients with MLC from theirgenotypes.３―97―Anyway, since both the parents in the two familieswere carriers of MLC1 mutations, these two couples haverecurrent risk in future pregnancies. Therefore, geneticinformation identified in this study would be beneficialfor genetic counseling and future prenatal diagnosis.AcknowledgementsWe would like to express our gratitude to the patients andtheir families for their cooperation.Conflicts of Interest: There is no conflicts of interest forany of the authors.References1．van der Knaap MS, Barth PG, Stroink H et al: Leukoen-cephalopathy with swelling and a discrepantly mildclinical course in eight children. Ann Neurol 37: 324―334, 19952．Leegwater PA, Yuan BQ, van der Steen J et al: Muta-tions of MLC1 (KIAA0027), encoding a putative mem-brane protein, cause megalencephalic leukoencephalopa-thy with subcortical cysts. Am J Hum Genet 68: 831―838, 20013．Shimada S, Shimojima K, Masuda T et al: MLC1 muta-tions in Japanese patients with megalencephalic leukoen-cephalopathy with subcortical cysts. Hum Genome Var1: 14019, 20144．Saijo H, Nakayama H, Ezoe T et al: A case of megalen-cephalic leukoencephalopathy with subcortical cysts(van der Knaap disease): molecular genetic study. BrainDev 25: 362―366, 20035．Tsujino S, Kanazawa N, Yoneyama H et al: A commonmutation and a novel mutation in Japanese patients withvan der Knaap disease. J Hum Genet 48: 605―608, 20036．Choi SA, Kim SY, Yoon J et al: A Unique MutationalSpectrum of MLC1 in Korean Patients With Megalen-cephalic Leukoencephalopathy With Subcortical Cysts:p.Ala275Asp Founder Mutation and Maternal Unipa-rental Disomy of Chromosome 22. Ann Lab Med 37:516―521, 20177．Kariminejad A, Rajaee A, Ashrafi MR et al: Eight novelmutations in MLC1 from 18 Iranian patients with mega-lencephalic leukoencephalopathy with subcortical cysts.Eur J Med Genet 58: 71―74, 2015

Two Different MLC1 Variants Compounded with a Common Variant S93L in Japanese Patients of Megalencephalic Leukoencephalopathy with Subcortical Cysts

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Two Different MLC1 Variants Compounded with a Common Variant S93L in Japanese Patients of Megalencephalic Leukoencephalopathy with Subcortical Cysts

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