Introduction: Vanishing white matter disease (VWM) is considered as one of the most frequent types of inherited childhood leukoencephalopathies. Various neurological and non-neurological manifestations have been reported in this type of leukodystrophy; however, seizures are rarely described in infantile type of VWM. Case Presentation: To patient is a 12 months old boy who experienced frequent seizures at 4th month of age. The seizures were resistant to anti-epileptic drugs and caused 3 periods of hospitalization. Magnetic resonance imaging (MRI) demonstrated demyeli-nating pattern and whole exome sequencing (WES) reported homozygous mutation (c.922G > A) in EIF2B2 gene in exon 8 leading to an amino-acid substitution (p.Val308Met). Conclusions: Infantile onset of vanishing white matter disease can be considered as one of few childhood leukodystrophies that are associated with early onset seizures. Â© 2018, Iranian Journal of Pediatrics

Alizadeh, H.

Amanat, M.

Ashrafi, M.-R.

Mahdieh, N.

Nikbakht, S.

Rezaei, N.

Rezaei, Z.

Tavasoli, A.R.

eprints Iran University of Medical Sciences

Iran J Pediatr. 2018 April; 28(2):e65620.Published online 2018 March 10.doi: 10.5812/ijp.65620.Case ReportSeizure as the Early and Main Manifestation of Infantile VanishingWhite Matter Disease: A Case ReportNegin Rezaei,1 Sedighe Nikbakht,1 Mahmoud-Reza Ashrafi,1,2 Zahra Rezaei,1 Nejat Mahdieh,3 HoumanAlizadeh,4 Man Amanat,1,5 and Ali Reza Tavasoli1,2,*1Children’s Medical Center, Pediatrics Center of Excellence, Tehran, Iran2Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran3Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran4Department of Radiology, Tehran University of Medical Sciences, Tehran, Iran5Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran*Corresponding author: Dr. Ali Reza Tavasoli, Myelin Disorders Clinic, Pediatric Neurology Division, Children’s Medical Center, Tehran University of Medical Sciences, Tehran,Iran. Tel: +98-2166935848, E-mail: a_tavasoli@sina.tums.ac.irReceived 2017 December 27; Revised 2018 February 05; Accepted 2018 February 16.AbstractIntroduction: Vanishing white matter disease (VWM) is considered as one of the most frequent types of inherited childhoodleukoencephalopathies. Various neurological and non-neurological manifestations have been reported in this type of leukodys-trophy; however, seizures are rarely described in infantile type of VWM.Case Presentation: To patient is a 12 months old boy who experienced frequent seizures at 4th month of age. The seizures wereresistant to anti-epileptic drugs and caused 3 periods of hospitalization. Magnetic resonance imaging (MRI) demonstrated demyeli-nating pattern and whole exome sequencing (WES) reported homozygous mutation (c.922G > A) in EIF2B2 gene in exon 8 leading toan amino-acid substitution (p.Val308Met).Conclusions: Infantile onset of vanishing white matter disease can be considered as one of few childhood leukodystrophies thatare associated with early onset seizures.Keywords: Leukodystrophy, Vanishing White Matter, Seizure, Epilepsy1. IntroductionChildhood leukodystrophies consist of various inher-ited white matter disorders with an incidence rangingfrom 1.2 to 3.01 per 100,000 persons/year (1). Vanishingwhite matter disease (VWM) is an autosomal recessive dis-order and one of the most common types of leukodystro-phies and engages all ages including antenatal, infantile,early childhood, late childhood, and adults (2). No dataexists regarding the exact incidence of VWM; however, itseems that this type of leukodystrophy is more commonin Caucasians. It has also been reported in non-white casesfrom South America and Asia.The molecular basis of the disease has been shown tobe due to mutations in any of the five genes encoding sub-units of eukaryotic translation initiation factor B (eiF2B).These genes are known as EIF2B1-5. EIF2B is considered asan important molecule which plays a significant role in theprotein synthesis and managing the cellular stress condi-tions. To date, more than 110 mutations have been discov-ered in EIF2B genes; mostly recognized in EIF2B5, followedby EIF2B4 and EIF2B2 genes (3).The infantile form of the disease appears before the ageof 2 years and usually is determined by hypotonia, progres-sive neurological deterioration, cerebellar ataxia, early on-set cataracts, spasticity, fever and vomiting (3). Moreover,only few cases of early onset or infantile type of vanishingwhite matter disease with refractory seizures have been re-ported (2, 3).Here, we report the clinical and radiologic findings ofa boy with infantile type of vanishing white matter dis-ease who was presented with early onset serial seizures at4 months of age. Molecular genetic evaluations indicateda mutation in EIF2B2 gene which confirmed the disease.2. Case PresentationThe patient is a 12 month old boy who was born atterm to a consanguinous couple with birth weight of2550 grams and head circumference of 34cm. His parentsbrought him to a primary care physician at 2 months of agedue to his poor weight gain. At 4 months, frequent seizureswith staring, clonic movements of the left side limbs andtruncal hypotonia developed. Therefore, the patient wasCopyright © 2018, Iranian Journal of Pediatrics. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided theoriginal work is properly cited.Rezaei N et al.referred to our hospital (children’s Medical center) for fur-ther evaluation. Neurological examinations did not showspasticity nor exaggerated deep tendon reflexes, but ax-ial hypotonia was present. Neurological deterioration wasnot recognized. Awake electroencephalography (EEG) atage of 4 months showed tonic and focal seizures consistingof flattening of the background preceded by generalizedand multifocal spike waves followed by diffuse slow waves.Brain magnetic resonance imaging (MRI) was performedat the time of seizure onset for further evaluation (Figure1). Brain MRI transverse spin echo (SE) T2 weighted imagesat the level of midbrain and high parietal centrum semi-oval demonstrated diffuse abnormally increased signal ofdeep and subcortical white matter. In addition, bilateralhigher signal of anterior temporal subcortical white mat-ter in T2 weighted image compared to deep white mattersuggested early cystic degeneration in these areas. Coro-nal SE T2 weighted image and T1 fluid attenuated inver-sion recovery (FLAIR) sequences at the level of posteriorlimb of internal capsule and dentate nuclei indicated dif-fuse supra and infratentorial white matter increased sig-nals which were relatively low in T1 FLAIR. Overall find-ings were consistent with severe demyelination of whitematter. We considered a demyelinating type of childhoodleukodystrophy as the probable etiology for the clinicalscenario of this patient regarding to MRI pattern involve-ment, early onset refractory seizures and global develop-mental delay. Seizures of the patient stopped with intra-venous anti-epileptic medications and he was discharged 2weeks later with phenobarbital. Basic metabolic tests wereall normal; therefore performing of molecular study wasdiscussed with parents to establish the diagnosis.In his follow-up, truncal tone was improved with oc-cupational therapy at the age of 6 months; however, heexperienced frequent tonic seizures unresponsive to anti-epileptic drugs at 7 months of age. Therefore, the patientwas admitted to pediatric intensive care unit (PICU) of ourhospital for 1 month for better control of seizures. The pa-tient was discharged from the hospital with oral phenobar-bital, phenytoin and levetiracetam. By obtaining informedconsent from parents blood sample of the patient was sentto laboratory for molecular studies.Two weeks later at the age of 8.5 months the patientwas hospitalized again with decreased level of conscious-ness and 5 to 6 times of tonic seizures per day. Meanwhile,he experienced respiratory failure in PICU. Intubation wasperformed; followed by tracheostomy due to long term in-tubation.And now, at the age of 12 months, the patient is dis-charged from hospital and his seizures are under con-trol by phenobarbital, topiramate, lamotrigine, and oxcar-bazepine. His respiration is supported by mechanical ven-tilation through T-tube and oxygen therapy. The last sys-temic and neurologic examinations showed central hypo-tonia, microcephaly, dense cataract, global developmentaldelay and poor weight gain. The results of molecular stud-ies at age 12 months showed the final diagnosis.2.1. Whole Exome SequencingGenomic DNA was extracted from peripheral bloodusing standard protocols. Coding regions and exon-intron boundaries were enriched using Agilent Sure-Select Human All Exon 50 Mb (Agilent TechnologiesSanta Clara, CA) according to the manufacturer’sstandard protocol. Sequencing was performed bytargeted-next generation sequencing (NGS) analyzeron an Illumina, Hiseq4000 (Illumina, San Diego, Cal-ifornia, USA). Burrows-Wheeler Aligner (BWA), GATK(https://www.broadinstitute.org/gatk/) software pack-age and SAMTools were applied to align the reads us-ing on reference genome (hg19), variant calling andfor annotation. The variants were filtered based ontheir frequency (minor allele frequency < 0.1) in 1000Genome ExAC (http://exac.broadinstitute.org/) anddbSNP and EVS (http://evs.gs.washington.edu/EVS/)databases. Some online software tools includ-ing Combined Annotation Dependent Deple-tion (CADD) (http://cadd.gs.washington.edu/),Polyphen2 (http://genetics.bwh.harvard.edu/pph2/),SIFT (http://sift.jcvi.org/) and MutationTaster(http://www.mutationtaster.org/). The standards andguidelines for the interpretation of sequence variantsbased on consensus recommendation of the Americancollege of Medical genetics and genomics (ACMG) 2015was also used to interpret the variants (4). The proband,his parents and sister were analyzed for the found variantusing Sanger sequencing. Those variants that segre-gated with the phenotype within the entire family wereconsidered pathogenic.A homozygous variant (c.922G > A) (rs372548739) wasdetected in EIF2B2 gene in exon 8 leading to an amino acidsubstitution (p.Val308Met). Sanger sequencing at positionc.922 of his clinically asymptomatic parents revealed a het-erozygous mutation but his sister was normal for this po-sition; the segregation analysis confirmed the result. In ad-dition, above mentioned software tools predicted this vari-ant as disease causing.3. DiscussionFrequent seizures were the main manifestation in thispatient. As seizure occurrs in rare cases of infantile VWM,suspecting this type of leukodystrophy as a potential diag-nosis in the early stage of the disease in this patient wasnot possible. To date, no specific algorithmic approachhas been introduced for diagnosis of leukodystrophies.2 Iran J Pediatr. 2018; 28(2):e65620.Rezaei N et al.Figure 1. A, B, Brain magnetic resonance imaging (MRI) Transverse spin echo (SE) T2 weighted images at the level of midbrain and high parietal centrum semi-ovale demon-strated diffuse abnormal increased signal of deep and subcortical white matter. Note bilateral higher signal of anterior temporal subcortical white matter in T2 weightedimage comparing deep white matter which suggests early cystic degeneration in these areas (white arrows). C, D, Coronal SE T2 weighted image and T1 fluid attenuated inver-sion recovery (FLAIR) sequences at the level of posterior limb of internal capsule and dentate nuclei indicated diffuse supra and infratentorial white matter increased signalin T2 weighted image which is respectively low in T1 FLAIR. Overall findings are consistent with severe demyelination of white matter.However, clinical scenario of individuals, imaging findingsand MRI pattern involvement, and genetic tests are thethree main dimensions for diagnosis. In this study, themost common clinical presentations of VWM were not ob-served in the early stage of the disease, but hypotonia. Ittook about 8 months after the first episodes of seizuresuntil other clinical features; including microcephaly andcataract, were recognized. Up to now features like spastic-ity, ataxia and fever have not been observed. Although theoverall clinical presentations were confusing and couldn’tlead to diagnosis, demyelinating pattern in MRI and re-ported homozygous mutation in EIF2B2 gene make the di-agnosis of VWM definite. It is worth to mention that al-though genetic analysis is the most suitable modality fordiagnosis of VWM and other types of leukodystrophies; itshigh cost and late response are the biggest challenges of itsuse. Therefore, to reduce the economic burden of diagno-sis of leukodystrophies one should focus more on clinicalpresentations and imaging MRI findings as much as possi-ble.To date only few cases of early onset VWD have been re-ported in whom frequent seizures have been prominent asclinical manifestations of the disease. These are listed in Ta-ble 1. In one study epilepsy occurrence coincided with var-ious other manifestations of VWD (5); yet another one re-ported seizure as the only clinical manifestation (6). Likeour study, 2 of these trials reported mutations in EIF2B2gene. However, the DNA levels of mutation were different.Leng et al. (7) reported a patient with a compound het-erozygous mutation in EIF2B2gene that caused by c.254T4A,p. Val85Gly mutation in father and c.922G4A, p.Val308Metmutation in mother; however, homozygosity of the muta-tions in our patient is due to consanguineous marriage ofhis parents.Iran J Pediatr. 2018; 28(2):e65620. 3Rezaei N et al.Table 1. Case Report Studies Reporting Seizure as a Manifestation in Infantile form of Vanishing White Matter DiseaseStudy Identification Clinical Features MutationTakano et al. (2) A 4 month-old girl who developed lethargy, vomiting and seizure aswell as rapid neurological deterioration.Two heterozygous mutations in the EIF2B5 gene (c.584G > A andc.1223T > C).Hata et al. (8) Physical and mental development of a boy began to deteriorate afterconvulsions at 10 months of age. A marked decrease in volume ofwhite matter, with no typical cystic rarefaction was observed.Submicroscopic deletion of 14q24.3, which included EIF2B2 and amissense mutation of EIF2B2 (V85E) of the remaining allele.Shimada et al. (5) A 2-year-old boy with progressive developmental deteriorationassociated with intractable epilepsy at 11 months of age, which wastriggered by recurrent acute infectious diseases. Small palpebralfissures, bushy eyebrows, ear abnormalities, small upturned nose,downturned corners of the mouth, and micrognathia were otheridentified characteristic features.Deletion at 14q24.3 that included EIF2B2.Gungor et al. (6) A 12 months old boy presented with intractable seizures since he was3 months of age. He had intractable and prolonged seizures duringthe course of his disease.Homozygote c.1091G > A mutation at the EIF2B4 geneThe study was approved by ethics committee of chil-dren’s hospital center, pediatric center of excellence.3.1. ConclusionInfantile type of VWD in association with some typesof childhood leukodystrophies including type I Alexanderdisease, Aicardi-Goutieres syndrome, Canavan disease andKrabbe disease (9) can be considered as those leukodystro-phies of pediatric population that are associated with earlyonset seizures in their clinical manifestations.AcknowledgmentsWe thank the patient’s parents for their kind coopera-tion and the nursing personnel of our PICU for altruisticmedical care of the patient.References1. Ashrafi MR, Rezaei Z, Heidari M, Nikbakht S, Malamiri RA, Moham-madi M, et al. The First Report of Relative Incidence of Inherited WhiteMatter Disorders in an Asian Country Based on an Iranian BioregistrySystem. J Child Neurol. 2018;33(4):255–9. doi: 10.1177/0883073817751804.[PubMed: 29333903].2. Takano K, Tsuyusaki Y, Sato M, Takagi M, Anzai R, Okuda M, et al. AJapanese girl with an early-infantile onset vanishing white matter dis-ease resembling Cree leukoencephalopathy.BrainDev. 2015;37(6):638–42. doi: 10.1016/j.braindev.2014.10.002. [PubMed: 25457085].3. van der Knaap MS, Pronk JC, Scheper GC. Vanishing white mat-ter disease. Lancet Neurol. 2006;5(5):413–23. doi: 10.1016/S1474-4422(06)70440-9. [PubMed: 16632312].4. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Stan-dards and guidelines for the interpretation of sequence variants: ajoint consensus recommendation of the American College of Medi-cal Genetics and Genomics and the Association for Molecular Pathol-ogy. Genet Med. 2015;17(5):405–24. doi: 10.1038/gim.2015.30. [PubMed:25741868].5. Shimada S, Miya K, Oda N, Watanabe Y, Kumada T, Sugawara M, etal. An unmasked mutation of EIF2B2 due to submicroscopic dele-tion of 14q24.3 in a patient with vanishing white matter disease. AmJ Med Genet A. 2012;158A(7):1771–7. doi: 10.1002/ajmg.a.35431. [PubMed:22678813].6. Gungor O, Ozkaya AK, Hirfanoglu T, Dilber C, Aydin K. A rare mutationin EIF2B4 gene in an epileptic child with vanishing white matter dis-ease: a case report. Genet Couns. 2015;26(1):41–6. [PubMed: 26043506].7. Leng X, Wu Y, Wang X, Pan Y, Wang J, Li J, et al. Functional analysisof recently identified mutations in eukaryotic translation initiationfactor 2Bvarepsilon (eIF2Bvarepsilon) identified in Chinese patientswith vanishing white matter disease. J Hum Genet. 2011;56(4):300–5.doi: 10.1038/jhg.2011.9. [PubMed: 21307862].8. Hata Y, Kinoshita K, Miya K, Hirono K, Ichida F, Yoshida K, et al. An au-topsy case of infantile-onset vanishing white matter disease relatedto an EIF2B2 mutation (V85E) in a hemizygous region. Int J Clin ExpPathol. 2014;7(6):3355–62. [PubMed: 25031760].9. Ashrafi MR, Tavasoli AR. Childhood leukodystrophies: A litera-ture review of updates on new definitions, classification, diagnos-tic approach and management. Brain Dev. 2017;39(5):369–85. doi:10.1016/j.braindev.2017.01.001. [PubMed: 28117190].4 Iran J Pediatr. 2018; 28(2):e65620.

Seizure as the early and main manifestation of infantile vanishing white matter disease: A case report

http://eprints.iums.ac.ir/7090/1/Seizure-as-the-early-and-main-manifestation-of-infantile-vanishing-white-matter-disease-A-case-report2018Iranian-Journal-of-PediatricsOpen-Access.pdf

Seizure as the early and main manifestation of infantile vanishing white matter disease: A case report

Abstract

Similar works

Full text

Available Versions

eprints Iran University of Medical Sciences