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Pediatric Neurology 51 (2014) 225e232

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Pediatric Neurology

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Original Article

Vanishing White Matter Disease in French-Canadian PatientsFrom Quebec

Marie-Ève Robinson MDa,*, Elsa Rossignol MD, MSc b,c,Bernard Brais MD, M Phil, PhDd,e, Guy Rouleau MD, PhDd,Jean-François Arbour MD f, Geneviève Bernard MD, MSc d,g,h

aDepartment of Pediatrics, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, CanadabDepartment of Neurosciences, CHU-Sainte-Justine, Université de Montréal, Montreal, Quebec, CanadacDepartment of Pediatrics, CHU-Sainte-Justine, Université de Montréal, Montreal, Quebec, CanadadDepartment of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University Health Center, Montreal, Quebec,CanadaeDepartment of Human Genetics, Montreal Neurological Institute, McGill University Health Center, Montreal, Quebec, CanadafCentre Hospitalier de Trois-Rivières, Trois-Rivières, Quebec, CanadagDepartment of Pediatrics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, CanadahDepartment of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada

Article HistReceived D* Commu

of PediatrOttawa; 40

E-mail a

0887-8994/$http://dx.doi

abstract

BACKGROUND: Vanishing whitematter disease is an autos

omal recessive leukodystrophy caused bymutations in anyof thefive genes encoding the subunits of the eukaryotic translation initiation factor 2B.Most of the reported patientsare of North American and European ancestry. OBJECTIVE: The objective of the study was to review the clinical,radiological, and molecular characteristics of vanishing white matter disease in a cohort of French-Canadian pa-tients. METHODS: Between 2004 and March 2012, five French-Canadian (non-Cree) patients from Quebec wereclinically and genetically diagnosed with vanishing white matter disease within three Montreal Neurogenetics andLeukodystrophy clinics. Their clinical presentation and evolution, demographic characteristics, genetic mutations,and imaging were reviewed and compared with what is known in the literature. RESULTS: Sequencing of the exonsand intronic boundaries of the EIF2B1-5 genes revealed a rare 260C>T (A87V) missense mutation in EIF2B3 in twohomozygous patients and one compound heterozygous patient. This mutation was previously reported in only onepatient in the literature. The carrier frequency is unknown. Also, three of five Quebec patients had an extremelyrare vanishing white matter disease presentation of migraines with transient neurological abnormalities.CONCLUSION: The 260C>T (A87V) mutation in exon 3 of the EIF2B3 gene is likely a founder mutation for vanishingwhite matter disease in Quebec. Transient hemiparesthesia and hemiparesis episodes accompanied by headachesas presenting abnormalities of vanishing white matter disease are usually rare but seemed to be more frequentamong the French-Canadian Quebec patients. They seemed to be preceded by periods of stress.

Keywords: EIF2B3, founder mutation, headaches, Quebec, vanishing white matter disease

Pediatr Neurol 2014; 51: 225-232

� 2014 Elsevier Inc. All rights reserved.

ory:ecember 31, 2013; Accepted in final form May 8, 2014nications should be addressed to: Dr. Robinson; Departmentics; Children’s Hospital of Eastern Ontario; University of1 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.ddress: marie.eve.robinson@gmail.com

- see front matter � 2014 Elsevier Inc. All rights reserved..org/10.1016/j.pediatrneurol.2014.05.006

Introduction

Vanishing white matter disease (VWMD; MIM 603896),1

also known as childhood ataxia with central nervous sys-tem hypomyelination,2 is one of the most common child-hood leukoencephalopathies.3 It was first described asmyelinopathia centralis diffusa in 1993.4 It classically pre-sents between 2 and 5 years of age5 with prominent

M.-È. Robinson et al. / Pediatric Neurology 51 (2014) 225e232226

cerebellar ataxia and spasticity.1,6 The neurological deterio-ration is typically characterized by a chronic progressivecourse with episodes of acute neurological deterioration af-ter minor head trauma or febrile infections.1,5,7,8 Brain mag-netic resonance image (MRI) usually demonstrates diffuseand symmetric abnormalities of the cerebral white matter.These white matter hyperintensities are followed by cerebralwhite matter rarefaction and cystic degeneration,9 in whichthe white matter is replaced by fluid.10 Although MRIs inearly stages usually demonstrate extensive white matterabnormalities,10 Van der Lei et al.9 recently demonstratedthat early imaging can illustrate more patchy changes in thewhite matter without cystic degeneration or rarefaction.

VWMD is an autosomal recessive leukoencephalopathycaused by mutations in any of the five genes (EIF2B1, EIF2B2,EIF2B3, EIF2B4, and EIF2B5) encoding the subunits of theeukaryotic translation initiation factor 2B (eIF2B).11,12 eIF2Bplays an essential role in the regulation of translation of RNAinto proteins, especially under circumstances of stress.11,12

More than 121 mutations in the five EIF2B genes have beenreported.13,14 Mutations in EIF2B5 represent 57-70%15-17 of allpatients with VWMD. Fogli et al.18 evidenced that distinctmutations are specifically associated with milder or more se-verephenotypes. Inaddition, it isnowwell established that theseverity of the disease is inversely proportional to age ofonset.8 Schiffmann et al.19 described a variable VWMD clinicalspectrum consisting of a prenatal, subacute infantile, earlychildhood, late childhood, and adult onset forms, with theadult onset form being the mildest, usually characterized bybehavioral changes, headaches, and dementia.20 Most re-ported patients are Caucasian from North American countriesor Western Europe,11 although patients from China,21,22

Brazil,23 Japan,24 Australia,25 Portugal, Hungary, and Poland16

have also been reported. We hereby report five French-Canadian patients with VWMD originating from Quebec,including threepatientswitha raregeneticmutation inEIF2B3.

Materials and Methods

Between 2004 and March 2012, five French-Canadian patients fromthe province of Quebec were evaluated and diagnosed with VWMD atdifferent Neurogenetics and Leukodystrophy clinics inMontreal. Informedconsent was obtained from all participants with approved research pro-tocols at the Montreal Children’s Hospital (ethics approval number 11-105-PED) and CHU-Notre-Dame (ethics approval numberATX_ND02.045). These patients underwent EIF2B1-5 gene sequencing(PreventionGenetics Laboratory, Marshfield,WI) andwere present to havemutations reported to be causative for VWMD. We evaluated clinicaldisability according to a score developed by Ohlenbusch et al.,6 which hasalso been previously used for VWMD patients. We used this scoring sys-tem because it includes the full spectrum of clinical involvement inVWMD and is easily applicable.6 We also reviewed the clinical presenta-tion and evolution, demographic characteristics, genetic mutations, andavailable imaging of the five patients.

Results

We identified five French-Canadian (non-Cree) patientswith VWMD in Quebec (two men and three women).Table 1 summarizes the demographic characteristics, clin-ical evolution, investigations, and genetic mutations of thefive patients. The average age of presentation was 7 years(range, 2-20 years). Fig 1 represents a map of Quebec withthe geographic origins of the patients’ families.

Patient 1

This boy was first referred to the neurology serviceduring a hospitalization at age 29 months for new onsetataxia and tremor in the context of a febrile illness. He wasthe second child of nonconsanguineous French-Canadianparents from Bas-Saint-Laurent, northeast of Quebec City.A detailed family history revealed that the mother had twofirst trimester spontaneous abortions. He had a single sisterin good health and two cousins with multiple sclerosis. Thepatient was born after a pregnancy complicated by hypo-tensive episodes. His initial psychomotor development wascompletely normal. His past medical history was significantfor recurrent otitis media, pneumonias, bronchiolitis, andmultiple episodes of fever of unknown origin.

During his hospitalization, the investigations included anormal electroencephalograph (EEG) and a head computedtomography (CT) showing diffuse leukoencephalopathy. Theremaining investigations were noncontributory and arepresent inTable1. TheMRI revealeddiffuse T2hyperintensityand T1 hypointensity of the white matter compared withgrey matter structures, with typical involvement of thecentral tegmental tracts at the level of the brain stem andpreservation of the outer rim of the corpus callosum, as wellas white matter rarefaction, best observed on Fluid attenu-ation inversion recovery (FLAIR) images (Fig 2).

He improved significantly in the following weeks, withonly few residual abnormalities, including rare episodes ofright hand tremor and balance difficulties, especially in themorning,without clear gait ataxia. Around the age of 3 years,his tremor became more significant and bilateral. He beganto refuse to eat certain foods with utensils because of thistremor. His gait also deteriorated, and he developed frankataxia and frequent falls. It was noticed that when going upor down the stairs, hewas preferentially using his left leg. Atthat time, his neurological examination was significant formild dysarthria and mild spasticity in all four limbs. Notremor was evident. Deep tendon reflexes were 3, except atthe ankles, where they were 4. Sustained ankle clonus waspresent bilaterally. Cerebellar examination revealed dys-metria and amildlywide-based gait. The patient’s conditiondeteriorated progressively. He became wheelchair bound atthe age of 5 years, with progressive spasticity, severe ataxia,dysarthria, dysmetria, and pronounced limb tremors. Ge-netic testing (PreventionGenetics Laboratory) revealed thatthe patient was homozygous in exon 3 of the EIF2B3 gene forthe 260C>T (A87V) mutation.

Patient 2

This girl first presented at the emergency department atage 25 months after an episode of pharyngitis. Her signsincluded vomiting, refusal to walk, ataxia, aphasia, andheadaches unspecified for 2 weeks. She is the only daughterof distantly related parents (f ¼ 1/128) also from the Bas-Saint-Laurent region of Quebec. Family history was other-wise unremarkable. She was born after an uneventfulpregnancy at 40 weeks with Apgars of 6 and 8. She man-ifested meconium aspiration syndrome. She also hadpertussis at 1 year of age. Her initial psychomotor devel-opment was normal. Her past medical history wasnoncontributory.

TABLE.The Demographic Characteristics, Clinical Evolution, Investigations, and Genetic Mutations of the Five Patients

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Sex M F F M F

Origin (mother:father) Bas-Saint-Laurent,QC:Bas-Saint-Laurent,QC (N-C)

Bas-Saint-Laurent,QC:Bas-Saint-Laurent,QC (C)

Abitibi, QC:Abitibi,QC (N-C)

Gaspésie, QC:Gaspésie,QC (N-C)

Mauricie, QC:Mauricie,QC (N-C)

Initial psychomotordevelopment

N N N N N

Possible triggeringfactors

Sustained fever andtonsillitis a few daysbefore presentation

Pharyngitis few weeksbefore presentation

Pregnancy None None

CSD at presentation*/age at presentation

0/31 mo 3/25 mo 0/20 yr 0/3 yr 6mo 0/17 yr

Clinical presentation Mild left hand tremorand ataxia

Vomiting, refusal towalk, ataxia, aphasia,and headachesunspecified

Migraines withhemiparesthesiaand encephalopathy

Difficulty climbingstairs and intermittentmild tremor

Headaches withhemibody paresisand paresthesia

Course of neurologicaldeterioration

EC and CP EC and CP EC and CP SP EC and SP

CSD at last visit/age atlast visit

3/5.5 yr 3/15 yr 2/29 yr 3/35 yr 1/19 yr

Neurologicalabnormalities atlast visit

Spasticity, ataxia,and tremor

Ataxia and spasticity Mild ataxia, dysmetria,dysarthria, anddysdiadochokinesis

Spasticity and ataxia Mild dysarthria, mildspasticity, and possiblecognitive signs

Investigations Head CT: diffuseleukoencephalopathy;EMG: N; EEG: N;ophthalmology E: N;audiology E: discreteimpairment in the lowfrequency range with noneurogenic impairment;chromatography of AA:nonspecific changes,lactate, ammonia, andTSH; B12: N

Head CT: diffuseleukoencephalopathy;EMG: N, EEG: N;ophthalmology E: N;chromatography ofurinary AA: N; plasmaAA: N; urine organicacids: N; lumbarpuncture: N; auditoryEP: possible rightcochlear damage; suralnerve biopsy: N; skinbiopsy: N, ESR,arylsulfatase, totalhexosaminidase,galactosidase, pyruvate,and lactate;hemogram: N

Single-photon emissionCT: nonspecificabnormalities; EMG:N; EEG: slowbackground withoutepileptic abnormality;ophthalmology E: N;lumbar puncture: N;arylsulfatase: N;hemogram: elevatedwhite blood cells at17 � 109

Head CT: diffuseleukoencephalopathy;EMG: N; EEG: N; lumbarpuncture: elevated CSFproteins (58 mg/dL);somatosensory EP:prolonged interval inN13 and N19 withpreservation of sensoryconduction in lowerlimbs; nerve conductionstudies: N, proteolipidprotein, hexosaminidase,b-D-galactosidase, b-galactocerebrosidase,and VLCFA; arylsulfataseA: N

Head CT: diffusesupratentorialleukoencephalopathy;EMG: N; lumbarpuncture: N; sensoryEP: N; visual EP:increased interocularP100 latency bilaterally,VLCFA, hemogram, ESR,TSH, calcium, ACTHstimulation test, vitaminB12; anti-DNAantibodies: N

Mutated gene EIF2B3 EIF2B3 EIF2B3 EIF2B2 EIF2B5Exon 3/3 3/3 3/3 5/5 3/3Mutation(s) 260C>T/260C>T 260C>T/260C>T 260C>T/c.272G>A 638A>G/638A>G 338G>A/338G>AAmino acid

substitutionA87V/A87V A87V/A87V A87V/R91H E213G/E213G R113H/R113H

Abbreviations:AA ¼ Amino acidsACTH ¼ Adrenocorticotropic hormoneC ¼ ConsanguineousCP ¼ Chronic progressiveCSD ¼ Clinical score of disabilityCT ¼ Computed tomographyCSF ¼ Cerebrospinal fluidE ¼ ExaminationEC ¼ Episodic courseEEG ¼ ElectroencephalographyEMG ¼ ElectromyographyEP ¼ Evoked potentialsESR ¼ Erythrocyte sedimentation rateF ¼ FemaleM ¼ MaleN ¼ Normal or negativeN-C ¼ NonconsanguineousQC ¼ QuebecSP ¼ Slowly progressiveTSH ¼ Thyroid stimulation hormoneVLCFA ¼ Very long chain fatty acids

* Clinical score of disability, elaborated by Ohlenbusch et al.6: “0, no functional handicap and no neurological abnormalities; 1, mild coordination or gait difficulties notrequiring assistance; 2, moderate learning or neurological abnormalities requiring support or intervention in a few areas, able to walk with assistance; 3, severe learning orneurological abnormalities, requiring support in many areas; 4, requiring constant supervision, confined to bed, and loss of cognitive abilities; 5, dead.6”

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FIGURE 1.AmapofQuebec, Canada. The geographic origins of the patients’ families are in italic and in red font. (Color versionof thisfigure is available in the online edition.).

M.-È. Robinson et al. / Pediatric Neurology 51 (2014) 225e232228

Initial baseline laboratory investigations and EEG resultwere normal. Head CT characterized a diffuse leukoence-phalopathy (not available for review). The remaining in-vestigationswere noncontributory and are present in Table 1.

Her impairments completely resolved after 17 days. At3 years and 3 months of age, she began to experienceintermittent tremor in both hands. Around the same time,she fell from a swing and developed axial hypotonia, spasticparaparesis, ataxia, and refused to walk for 5 months.Subsequently, she began to improve; the tremor stopped,and she regained the ability to walk. At that time, her MRIcharacterized diffuse and confluent T2 hyperintensity of thewhite matter (not available for review). Over the followingyears, the patient experienced multiple episodes of similardeteriorations at 4, 5, 8, 12 and 16 years of age, each timeleading to an incomplete recovery. In addition, she slowlyprogressed with increasing lower limb spasticity leading topermanent wheelchair use by the age of 12 years. At thesame age, she began to deteriorate cognitively, particularlyher memory and concentration.

At the age of 16 years, she fell during a transfer. In thefollowing weeks, she experienced six episodes of transienthemiparesthesia, possible hemiparesis, and headache. Herheadaches would typically be unilateral, pulsatile, andassociated with nausea, vomiting, and blurry vision. Theywould be accompanied by a tingling sensation around themouth with numbness of and difficulty moving the tongue,followed by numbness and tingling sensation of the right

hand or arm. On one occasion, the patient described that shehad difficulty moving her arm. Her mouth was slightlydeviated on one other occasion. All impairments usuallyresolved after 30 minutes. Those episodes share multiplefeatures of sporadic hemiplegic migraines, a subtype of mi-graineswith aura, but do not qualify as such in accordance tothe 2nd Edition of the International Headache Classificationof the International Headaches Society (IHS ICHDII) criteriasince they lasted only 30 minutes in duration.

An EEG (performed because of headaches) documentedmild-to-moderate diffuse disturbances of cerebral activitywithout epileptiform abnormality. Her examination revealedscoliosis and equinovalgus deformity. Her neurologicalexamination was significant for dysarthria, saccadic ocularpursuits, and spastic quadraparesis with preferential in-volvement of the lower extremities. Diffuse hyper-reflexiawith sustained bilateral ankle clonus was evident. Cere-bellar examination revealed disdiadochokinesia bilaterally,moderate dysmetria, and severe ataxia. Genetic testing (Pre-ventionGenetics Laboratory) revealed that the patient washomozygous for the260C>T (A87V)mutation in exon3of theEIF2B3 gene.

Patient 3

The history of this female patient was previously pub-lished in Archives of Neurology by La Piana et al.26 The pa-tient was first observed at the age of 20 years for hemiplegic

FIGURE 2.Magnetic resonance imaging of the brain of Patient 1 demonstrating typical features of vanishing white matter disease. (A and D) Sagittal T2-weightedimage at the level of the midline and axial T2-weighted image of the brain at the level of the basal ganglia demonstrating hyperintense signal of the whitematter with preservation of the outer rim of the corpus callosum. (B) Axial T1-weighted image of the brain at the level of the basal ganglia demonstratinghypointensity of the white matter. (C) Axial T2-weighted image of the brain at the level of the pons demonstrating the typical involvement of the centraltegmental tracts. (E) Axial Fluid attenuation inversion recovery (FLAIR) of the brain at the level of the basal ganglia demonstrating diffuse hyperintensity ofthe white matter with rarefaction of the white matter, i.e., linear hypointensities within the hyperintense white matter.

M.-È. Robinson et al. / Pediatric Neurology 51 (2014) 225e232 229

migraines. Family history was unremarkable, and her par-ents were nonconsanguineous French-Canadians from theAbitibi region of Quebec. She was born after an uneventfulpregnancy, and her psychomotor development was normalthroughout her childhood and teenage years. Her pastmedical history was positive for secondary amenorrhea andpremature ovarian failure at 21 years of age.

At21yearsof age, anMRIof thehead characterizeddiffuseleukoencephalopathy, and the magnetic resonance spec-troscopy (MRS) indicated a reduction in all metabolites.26 At29 years of age, in spite of the diagnosis of primary ovarianfailure, the patient became pregnant. She began experi-encing constant headaches with intermittent left hemibodyparesthesias, aphasia, nausea, and vomiting. These head-aches were thought to be hemiplegic migraines, but it is notclear whether the patient experienced motor signs. Whenshewas 10weeks pregnant, she presented at the emergencydepartment with an acute episode of fever, migraine, andencephalopathy. Her physical examination on arrival wasvery limited because of lack of cooperation. It demonstratedthat shewas confused and disoriented; she had a fluctuatinglevel of consciousness and personality changes. When the

encephalopathy subsided, the physical examinationrevealed cerebellar signs but was otherwise unremarkable.

Laboratory investigations were normal, apart from mildleukocytosis at 17 � 109/L (normal between 4 � 109/L and10 � 109/L). The EEG revealed a slow background withoutepileptic abnormality. Her cranial MRI revealed a diffuseleukoencephalopathy with T2 hyperintensity and T1 hypo-intensity of the white matter compared with grey matterstructures, as well as small cystic areas at the frontal horns(white matter rarefaction). The remaining investigationswere noncontributory and are present in Table 1.

Her signs gradually improved in the following month, butshecontinued to showbehavioralperturbationsand impairedcognitive status. Genetic testing (PreventionGenetics Labo-ratory) revealed that the patient was heterozygous for thefollowingtwomutations inexon3of theEIF2B3gene:260C>T(A87V) and 272G>A (R91H).

Patient 4

This boy was first encountered by pediatric neurology atage 5 years because of insidious onset of motor regression.

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Family history revealed that the parents were non-consanguineous French-Canadians from Paspébiac, in theGaspésie region of Québec. The patient had one healthysister, a family history of sensorineural hearing loss on thepaternal side, a distant maternal cousin with neuropathy,another with cerebral palsy, and finally a distant maternalcousin with leukodystrophy. The patient was born after anuneventful pregnancy, and his psychomotor developmentwas normal until the age of 3.5 years. His past medicalhistory was significant for recurrent bronchitis and mildasthma.

The parents reported that since the age of 3.5 years, hehad progressive difficulty climbing stairs and intermittenttremor, especially of the legs. The patient did not have anyinfections or head trauma preceding his neurological ab-normalities. His physical examination at the age of 5 yearsrevealed verbal dyspraxia, dysdiadochokinesia, inability todo tandem gait, and difficulty hopping on one foot. The restof his neurological examinationwas normal. After the age of5 years, he developed dysarthria, which gradually worsenedover the years. At the age of 6 years, he was hospitalized forataxia. His examination at the time revealed mild left facialweakness, verbal dyspraxia, normal tone, marked intentiontremor, brisk deep tendon reflexes, abnormal propriocep-tion, dysdiadochokinesia, and ataxia. At the age of 7 years,his tremor became so debilitating that he could no longerwrite nor draw.

Basic laboratory investigations and EEG result werenormal. A lumbar puncture revealed elevated protein at58 mg/dL (normal range between 9 and 33 mg/dL). Head CTperformed at age 10 years revealed diffuse leukoencephal-opathy. The remaining investigations were noncontributoryand are present in Table 1.

The patient’s gait difficulties worsened over time, and,at age 18 years, he was only able to walk with assistanceand became wheelchair bound at the age of 22 years. Atthe age of 30 years, he began needing help for his transfers.Over time, he developed dysphagia. His tremor remainedsevere and incapacitating with suboptimal response topropranolol but, interestingly, seemed to improve withalcohol. At the age of 35 years, he had a major depressiveepisode. The examination at his last visit at age 35 yearsrevealed severe dysarthria and abnormal extraocularmovements with vertical nystagmus on upward gaze.Motor examination revealed quadraparesis. He had a se-vere postural and kinetic tremor of both upper extremities.Reflexes were all brisk at 3, and plantar responses wereextensor bilaterally. Sensory examination revealedimportant diminution of vibration sense in the lower limbswith complete absence of vibration sense and diminutionof proprioception in the toes. Cerebellar examinationrevealed dysdiadochokinesia of the upper limbs, dysme-tria at the finger-to-nose examination, and truncal ataxia.Genetic testing revealed that the patient was homozygousfor the 638A>G (E213G) mutation in exon 5 of the EIF2B2gene.

Patient 5

This girl first presented at age 17 years with three epi-sodes of transient hemiparesthesia, hemiparesis, andheadache in the course of 4 months. She was born of

nonconsanguineous French-Canadian parents from Maur-icie, Quebec. Her family history was notable for a brotherwho manifested attention deficit and a mother who man-ifested migraines. She was born prematurely at 7 months ofgestation after a pregnancy complicated by untreatedhyperemesis gravidarum. The patient walked at 18 months.Her psychomotor development was otherwise normal. Shedeveloped progressive school difficulties starting in highschool. In her last two years of high school, she failednumerous classes. Her past medical history wasnoncontributory.

Her signs at presentation consisted of hemibody pares-thesia with dysarthria developing over 3-4 minutes,accompanied by a “heavy feeling in the arms.” These signsresolved completely after 20 minutes, immediately fol-lowed by a 24-hour right-sided severe headache. The pa-tient did not experience any nausea, vomiting, photophobiaor sonophobia, or visual signs. The first two episodesaffected the left hemibody, whereas the third one affectedthe right hemibody. Furthermore, she experienced recur-rence of the sensory motor signs about 1 hour after the firstepisode. The second and third episodes were accompaniedby dizziness and incoherent dysphasia. We can concludethat these episodes share multiple features of sporadichemiplegic migraines but do not meet the InternationalHeadache Society criteria given the absence of photophobia,phonophobia, nausea, or vomiting.

A head CT characterized diffuse bilateral supratentorialleukoencephalopathy. The patient’s MRI was typical forVWMD with diffuse T2 hyperintensity and T1 hypointensityof the white matter, faint involvement of the centraltegmental tracts at the level of the brain stem, the pyra-midal tracts at the level of the pons, and preservation ofthe outer rim of the corpus callosum, as well as whitematter rarefaction, best observed on FLAIR sequence. Basiclaboratory investigations were within normal limits. Theremaining investigations were noncontributory and aresummarized in Table 1. Her neurological examination atlast visit was performed at the age of 19 years and revealedmild dysarthria, mild spasticity in all limbs, brisk deeptendon reflexes, nonsustained bilateral ankle clonus, andextensor plantar responses bilaterally. Hoffman signs werepositive bilaterally, more pronounced on the right side.Rapid alternating movements of the right hand wereslower. Genetic testing revealed that the patient was ho-mozygous for a 338G>A (R113H) mutation in exon 3 of theEIF2B5 gene.

Discussion

We report three French-Canadian patients from Quebecwith the rare A87V mutation in the EIF2B3 gene.11 Two ofthe five patients from Quebec were homozygous with A87Vsubstitutions in the EIF2B3 gene, and one was compoundheterozygous with the A87V amino acid substitution as oneof his two mutations in the EIF2B3 gene. Mutations inEIF2B3 represent 4-9% of all patients with VWMD.13,18,19 TheA87V mutation in the EIF2B3 gene was only reported in oneother patient.11,27 The carrier frequency of the mutation isunknown in the 1000 Genomes database and was neverreported in European Sequence Variant Database. The factthat three of five Quebec patients carry this rare mutation

M.-È. Robinson et al. / Pediatric Neurology 51 (2014) 225e232 231

suggests a founder effect in Quebec. Along with the rarenature of the mutation, the higher rates of homozygosityamong the Quebec patients further support the possibilityof a founder effect. In fact, most reported patients withVWMD carry compound heterozygous mutations.18 Only28% of patients with eIF2B-related disorders presented withhomozygous mutations in EIF2B genes.13 It is interesting tonote that four of five patients from Quebec (80%) carry ahomozygous mutation, whereas only one family wasconsanguineous. Distant consanguinity is suspected inthree of the other families because they are from the sameadministrative regions of Quebec.

As reported, the inversely proportional correlation be-tween age of onset and disease severity7,28 was observed inthe majority, but not all, of the patients (three of five pa-tients). The patients with the younger age of onset(31 months) had a more severe phenotype compared withpatients with a older age of disease onset (aged 17 and20 years). On the other hand, two of the patients had anearly age of onset (25months and 3 years 6months) but hada relatively slow deterioration.

In addition, the observations support the hypothesis thatsome mutations are associated with a milder diseasephenotype. We report a patient, Patient 4, with a homozy-gous E213G mutation in the EIF2B2 gene. Mutations inEIF2B2 represent 13% of all patients with VWMD.13,18,19 Thismutation has been identified in a homozygous state indifferent patients from a wide geographic distributionsuggesting that the genomic sequence encoding thisparticular residue is a mutation hot spot.16 As reportedpreviously by Fogli et al.,18 and as we observed in this study,the E213G amino acid change is associated with a milderdisease phenotype.

Finally, the results suggest that transient episodes ofhemiparesis, hemiparesthesia or both, accompanied byheadaches can occur in a significant proportion of patientswith VWMD, as observed in three of five French-Canadianpatients from Quebec. An extremely small number of pa-tients26,29,30 have been reported to have transient hemi-body paresthesia in the course of VWMD. Three of thepatients (Patients 2, 3, and 5) had hemibody paresthesiaepisodes accompanied by headaches in the course of theirdiseases, whereas two of them also had associated hemi-paresis. Those events share characteristics of sporadichemiplegic migraines, a subtype of migraines with aura.Ramaswamy et al.29 reported a patient who was homozy-gous for the R113H mutation in the eIF2B epsilon subunitwith episodes or right-sided hemiparesis with contralateralheadache.26,30 Similarly, Patient 5 presentedwith hemibodyparesthesia, paresis, and headaches and was also homozy-gous for the same mutation, which raises the possibilitythat this specific mutation might correlate with a morespecific phenotype of hemiplegic episodes but is most likelysimply because of the fact that the R113H mutation is themost frequent mutation associated with VWMD.17 Ram-aswamy et al.29 reported that both hemiplegic migrainesand VWMD can be triggered by periods of stress. Similarly,these transient neurological abnormalities accompanied orfollowed by severe headaches can possibly be secondary tometabolic stress. As previously reported by La Piana et al.,26

exacerbations of Patient 30s headaches and paresthesiawere preceded by stressful events, fever and pregnancy.

Similarly, Patient 20s hemiparesis episodes and headacheswere preceded by a fall.

Conclusion

The A87V mutation on exon 3 of the gene EIF2B3 is likelya founder mutation for VWMD in Quebec. The inverselyproportional correlation between age of onset and diseaseseverity was observed in the majority of French-CanadianQuebec patients, but not all. Transient hemiparesthesiaand hemiparesis accompanied by headaches as presentingabnormalities of VWMD are rare but seemed to be morefrequent among French-Canadian Quebec patients than therest of the patients presented in the literature. The episodesseemed to be preceded by periods of stress.

The authors wish to thank the patients and their families. Dr. Bernard has received aResearch Scholar Junior 1 of the Fonds de Recherche du Québec en Santé (FRQS). Shewishes to thank the Fondation du Grand Défi Pierre Lavoie, the Fondation sur lesLeucodystrophies, the Montreal Children’s Hospital Foundation, the MSSA (MedicalStaff Service Association), and the Montreal Children’s Hospital Associates inNeurology. We would also like to thank for their services the Genome QuebecInnovation Centre and McGill University.

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Rare things in medicine are not

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rare, only observers are rare.

H. R. Clouston