CASE�REPORT

ABSTRACTRettsyndromeisarareinheritedneurodegenerativediseasewhichmostlyaffectsfemalesbuthasalethalimpactonmales.RettsyndromeismostlycausedbymutationsofMethylCpGbindingprotein-2(MECP2)genelocatedonchromosomeXq28.A7-yeargirlfromaconsanguineousPakistanifamilypresentedwithhistoryofabnormalsocialbehavior,toniccolonicseizures,limb'sataxia,intellectualdisability,growthretardationandspeechabnormalities.Physicalandneurological examinations established likely clinical features of Rett syndrome with abnormalelectroencephalogram (EEG). Genetic testing of MECP2 gene did not identify any functional nucleotidevariationindicatingtheinvolvementofanothergenemutationinthispatient.AconsanguineouscaseofRettsyndromedidnotcarrythemutationofMECP2 gene.Duetoheterogeneityofthephenotype,itisproposedthattheremightbeinvolvementofanotherlocusforthisdisease.Infuture,targeted next generation sequence can be helpful to identify the causative mutation in this patient.

KeyWords:MECP2, Pakistan, Rett Syndrome, Seizures.

How to cite this: Dad R, Sawal HA, Ahmad A, Ullah MI. Rett Syndrome without MECP2 Mutation in a Pakistani Girl. Life and Science. 2020; 1(2): 83-85. doi: http://doi.org/10.37185/LnS.1.1.77

GRIN1 andKIF1A andcyclin-dependentkinase-like5(CDKL5)havebeendemonstratedincongenitalRTT

4,5andaspathogenicgenesofearlyseizures.ThemostcommoncausativegeneforRettsyndromeis MECP2 (NM_001110792) which is located atcandidate region on chromosome Xq28; however,recentlysomeothergeneshavebeenidentifiedfor

4thisphenotype. AnumberofmutationsinMECP2havebeenreported indifferentethnicgroupsand

6,7populations. According to various reports, 70%-80% cases of Rett syndrome show mutations inMECP2genewhileothercasesareassociatedwith

8other genes. Depending on the cell type anddevelopment phases in the brain,MECP2 impartsvariableeffectsintheseprocesses.RTTisreflectedtothefailureoffunctionsatdifferentlevels,likegeneregulation and expression, synaptic function andneuronal circuitry, and during developmental

9stages.In the present study, we ascertained aconsanguineous familywith one affected girlwhoshowed classical features of Rett syndrome andmutation screeningofMECP2 genedid not revealanynucleotidevariation.Thusestablishingthebasisofheterogeneityofthisdisorder.

CasePresentationA7-yearoldgirlvisitedthehospital,withahistoryofhyperactive behavior, delayed milestones,

IntroductionRett syndrome (RTT; OMIM 312750) is a rareneurodevelopmentaldisorderwithprevalenceof1

1in15,000infemales. Clinicalfeaturesincludeataxia,lossof speechabilities, seizuresonset, intellectualdisability, severe developmental delay, cognitiveimpairments,breathingandswallowingdifficulties,chewing and teeth grinding issues and sleep

2disorders. Methyl-CpG-binding protein 2 (MECP2)gene isresponsiblefortypicalRTT in95%patients

3andwith different RTT feature in 73.2% patients. OthergeneslikeforkheadboxproteinG1(FOXG1),

RettSyndromewithoutMECP2MutationinaPakistaniGirl1 2 3 4 5RubinaDad ,HumairaAzizSawal ,ArsalanAhmad ,MuhammadIkramUllah ,MuhammadJawadHassan

Correspondence:Dr. Muhammad Jawad HassanAssociate Professor, Biological SciencesNational University of Medical Sciences, RawalpindiE-mail: jawad.hassan@numspak.edu.pk

1Department of Applied BiosciencesAtta-ur-Rahman School of Applied Biosciences (ASAB)National University of Sciences & Technology (NUST), Islamabad2Armed Forces Institute of PathologyCombined Military Hospital, Rawalpindi3Division of NeurologyShifa International HospitalShifa Tameer e Millat University (STMU), Islamabad4Department of Clinical Laboratory SciencesJouf University, Kingdom of Saudi Arabia5NUMS Department of Biological SciencesNational University of Medical Sciences (NUMS), Rawalpindi

Life&Science2020Vol.1,No.2 RettSyndromeinPakistaniGirl

Funding Source: NIL; Conflict of Interest: NILReceived: Oct 14, 2019; Revised: Feb 19, 2020Accepted: Mar 02, 2020

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generalizedtonicclonicseizures,(onsetat6-monthage).Her familyhistory showedaconsanguineousrelationship betweenher parents (Fig 1). Shewastreated previously with medication and remainedasymptomatic,followedbya period of relapse. She had remained stable for 2-3 years. Sincepastthreetofouryears,shehadbecomeaggressive.

On recent clinical examination, she was mentallyslowwithpartiallossoffluencyofthelanguageandspeech. She also developed stereotypic handmovements bilaterally. She had disturbance inbreathingwhenawakeandshowedimpairedsleeppattern.Shehadgrowthretardationandwithsmallhands and feet. She was having inappropriatescreamingspells,withintenseeyecommunication.Neurological examination revealed normal cranialnerve functions.Manualmuscular testing showedweakness of limband abnormalmuscle tone.Herdeep tendon ref lexes were normal andsymmetricallypreserved.Herplanterresponsewasequivocal on right side and flexor on left side.Electroencephalogram (EEG) showed frequentgeneralized spikes and wave discharges withmildbackgroundsloppingandCTscanofheadwithchestshowedbi-frontalatrophy (Fig2a,b, c).Urine formucopolysaccharidosiswasnegativeandBenedict'stestforurineglucosewasnegative.Thesetestswereperformed to rule out mucopolysaccharidosis, asthere is symptoms overlap. She was givencarbamazepine 100mg twice a day with calciumsupplements.GenetictestingofMECP2genedidnotidentify any functional nucleotide variationassociatedwiththisphenotype.Fig1:Pedigreerepresentationoffamily.Filledcircle

showsaffectedfemaleandclearsquaresandcirclesrepresentnormalindividuals.Horizontallinebetweentwoindividualsdemonstratestherelationwhileverticallinesdescribethegenerations

Fig2:ElectroencephalogramandCTscanofaffectedgirla:EEGshowsgeneralizedspikebandc:CTscanofbrainshowedbilateralatrophicchanges

DiscussionRettsyndromeisarareneurodevelopmentaldiseaseof childhood. It presents with diverse clinicalfeatureslikeabnormalsocialinteractions,seizures,ataxia, microcephaly, speech and swallowingabnormalities,intellectualdisability,delayingrowth

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and loss of motor movements at later stage of10disease. Mutationsmay be present inMECP2 or

otherrelatedgenesincludingCDKL5, FOXG1,GRIN1andKIF1A.5,11

In the present case,we report a girlwho showedhyperactivesocialbehavior,fitsandseizure,lossofspeech abilities, limb weakness, intellectualdisabilityandgrowthretardation.HerEEGshowedabnormal wave discharge confirming epileptic fitsandCT-scan showedatrophic changes. Supportivediagnosis of Rett syndrome included breathingdifficulties, abnormal EEG and seizures, spasticityandataxia,microcephaly,intellectualdisabilityand

12delayingrowth.Genetic testing in the present case did not findmutation inMECP2 gene althoughmost common

3mutations reported worldwide are in MECP2. Mutations in genes other than MECP2, including CDKL5,FOXG1, arealsoreportedinGRIN1andKIF1A,families with Rett like features due to genetic

5,11heterogeneityofthisdisease.In Pakistan, very few reports with Rett syndromeepilepsy have been described. Although, diversefeatures make differential diagnosis verycomplicated, molecular studies established

13-15mutations inMECP2 and FOXG1 inourcountry. Nextgenerationsequencingisaremarkabletoolforidentificationof causativegenes inheterogeneousdisorderslikeRettsyndrome.

ConclusionThis is the fourth case of Rett syndrome reportedfromPakistanandthiscaseiswithoutMECP2genemutations. In future, other known genes will besequenced to identify the pathogenic variantthroughnextgenerationsequencinginthisgirl.

AcknowledgmentsWearethankfultothefamilyforparticipatinginthisresearch.

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