Braz. j. . vol.82 número5

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www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

The

impact

of

laronidase

treatment

in

otolaryngological

manifestations

of

patients

with

mucopolysaccharidosis

夽

Ana

Paula

Fiuza

Funicello

Dualibi

a,∗

_,

_Ana

_Maria

_Martins

b

_,

Gustavo

Antônio

Moreira

b

_,

_Marisa

_Frasson

_de

_Azevedo

a

_,

Reginaldo

Raimundo

Fujita

a

_,

_Shirley

_Shizue

_Nagata

_Pignatari

a

a_Universidade_Federal_de_São_Paulo_{(EPM---UNIFESP),}_Escola_Paulista_de_Medicina,_Departamento_de_{Otorrinolaringologia}_e

CirurgiadeCabec¸aePescoc¸o,SãoPaulo,SP,Brazil

b_Universidade_Federal_de_São_Paulo_{(EPM---UNIFESP),}_Escola_Paulista_de_Medicina,_Departamento_de_Pediatria,_São_Paulo,_SP,_Brazil

Received24July2015;accepted3September2015 Availableonline17December2015

KEYWORDS

MucopolysaccharidosisI; Laronidase;

Enzymatic

replacementtherapy; URTinfections; Sleepapnea; Hearingloss

Abstract

Introduction:Mucopolysaccharidosis(MPS)isalysosomalstoragediseasecausedbydeficiency

of␣-_l-iduronidase.Theotolaryngologicalfindingsincludehearingloss,otorrhea,recurrent

oti-tis,hypertrophyoftonsilsandadenoid,recurrentrhinosinusitis,speechdisorders,snoring,oral

breathingandnasalobstruction.

Objective:To evaluate the impact of enzymatic replacement therapy with laronidase

(Aldurazyme®₎_in_patients _with _{mucopolysaccharidosis} _(MPS_I), _regarding _sleep_and _hearing

disorders,andclinicalmanifestationsintheupperrespiratorytract(URT).

Methods:NinepatientswithMPSI(8Hurler-Scheie,and1Scheiephenotypes)ofbothsexes,

agesranging between3and20 years,wereincludedinthisstudy.Patientswere evaluated

betweensevenand11monthsbeforethetreatmentandbetween16and22monthsafterthe

onsetoftheenzymaticreplacement.Theywereallsubmittedtoaclinicalandotolaryngological

evaluation,includingnasofibroscopical,polysomnographicandaudiologicexams.

Results:Theresults’datashoweddecreasingofthefrequencyofear,noseandthroat

infec-tions, with improvementof the rhinorrheaand respiratory quality. No remarkable changes

wereobserved regardingmacroglossiaandtonsilandadenoidhypertrophy. Audiometricand

polysomnographicevaluationsdidnotshowstatisticalsignificance.

夽 _Please_cite_this_article_as:_Dualibi_AP,_Martins_AM,_Moreira_GA,_de_Azevedo_MF,_Fujita_RR,_Pignatari_SS._The_impact_of_laronidase_treatment inotolaryngologicalmanifestationsofpatientswithmucopolysaccharidosis.BrazJOtorhinolaryngol.2016;82:522---8.

∗_{Corresponding}_author.

E-mail:jpedualibi@uol.com.br(A.P.Dualibi).

http://dx.doi.org/10.1016/j.bjorl.2015.09.006

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Conclusion: EnzymaticreplacementtherapyinpatientswithmucopolysaccharidosisIprovides

controlofrecurrentURTinfections,rhinorrheaandrespiratoryquality,howeveritisdoesnot

seemtoimproveaudiologicandpolisomnographicparameters,withnoeffectonadenoidand

tonsilshypertrophyandmacroglossia.

by Elsevier Editora Ltda. This is an open access article under the CC BY license (http://

creativecommons.org/licenses/by/4.0/).

PALAVRAS-CHAVE

MucopolissacaridoseI; Laronidase;

Terapiadereposic¸ão enzimática;

Infecc¸õesdoTRS; Apneiadosono; Perdaauditiva

Impactodotratamentocomlaronidasenasmanifestac¸õesotorrinolaringológicas depacientescommucopolissacaridose

Resumo

Introduc¸ão: Mucopolissacaridose(MPS) éuma doenc¸a de depósitolisossômico causada pela

deficiênciade␣-_l-iduronidase.Osachadosotorrinolaringológicosincluemperdaauditiva,

otor-reia,otitesderepetic¸ão,hipertrofiaadenotonsilar,rinossinusiterecorrente,distúrbiosdafala,

roncos,respirac¸ãobucaleobstruc¸ãonasal.

Objetivo: Avaliaroimpactodaterapiadereposic¸ãoenzimáticacomlaronidase(Aldurazyme®₎

em pacientescommucopolissacaridose I(MPSI) em relac¸ãoao sono, distúrbios auditivose

manifestac¸õesclínicasdotratorespiratóriosuperior(TRS).

Método: NovepacientescomMPSI(oitocomfenótipoHurler-ScheieeumcomfenótipoScheie),

deambosossexos,comidadesvariandoentre3e20anos,foramincluídosnesteestudo.Os

pacientes foramavaliadosentre7 e11 mesesantes dotratamentoe entre16 e 22 meses

após o início da reposic¸ão enzimática. Todos foram submetidos a uma avaliac¸ão clínica e

otorrinolaringológica,incluindonasofibroscopia,polissonografiaeexamesradiológicos.

Resultados: Os dados dos resultados mostraram diminuic¸ão da frequência de infecc¸ões de

orelha, nariz e garganta, commelhora da rinorreia e da qualidade respiratória. Mudanc¸as

significativasnão foramobservadasemrelac¸ãoàmacroglossiaeàhipertrofiaadenotonsilar.

Avaliac¸õesaudiométricasepolissonográficasnãoapresentaramsignificânciaestatística.

Conclusão:Aterapiadereposic¸ãoenzimáticaempacientescommucopolissacaridoseIfornece

controledeinfecc¸õesrecorrentesdoTRS,rinorreiaequalidaderespiratória,porém,nãoparece

melhorarosparâmetrosaudiológicosepolissonográficos,ouexercerefeitosobreahipertrofia

adenotonsilaremacroglossia.

por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http://

creativecommons.org/licenses/by/4.0/).

Introduction

Mucopolysaccharidosis(MPS)isalysosomalstoragedisease

caused bydeficiency ofan enzyme involved inthe

degra-dation of glycosaminoglycans (GAGs). They are classified

accordingtotheinvolvedenzymeandGAGinseventypes:

I (Hurler, Hurler Scheie and Scheie), II (Hunter), III

(San-fillipo), IV (Morquio), VI (Maroteaux Lamy), VII (Sly) e IX

(Natowicz).1---3

MPSIis causedby deficiencyof ␣-_l-iduronidase,which

leads tointralysosomal depositsofdermatan andheparan

sulfate. Itis an autosomicrecessive geneticdisease,with

estimatedincidencevaryingfrom1:100,000forseverecases

to1:800,000forcaseswithmildmanifestations.4

Clinical manifestations of MPS I are extremely

het-erogeneous, with symptoms that evolve in many ways,

fromverymild manifestationsof latedevelopment,

with-out cognitive disorders, and high life time expectation

(Scheie),toverysevere casesof early onset,rapidly

pro-gressive,withneuraldegenerationandlimitedcapabilities

in life, usually manifested by the first decade (Hurler),

and passing through an intermediary level of severity

(Hurler---Scheie).1,2,5

The disease may involve nervous, skeleton, digestive,

cardiac,superiorandinferiorrespiratorysystemspresenting

different levels of severity in an independent manner.

Regardingtheotolaryngologicalfindings,themostfrequent

symptomsincludehearing loss,otorrhea, recurrentotitis,

hypertrophyof tonsilsand adenoid,recurrent

rhinosinusi-tis, speech disorders, snoring, oral breathing and nasal

obstruction.1,2,6

Obstructivesleepapneaandhypopneasyndrome(OSAHS)

isfrequentlydiagnosed inMPSIpatients.Obstructiveand

restrictivefactorssuchasreductionofthethoracicvolume

(musculoskeletal alterations), restriction of the

diaphrag-maticmovement due tohepatosplenomegaly,presence of

atelectasis secondary to the reduction of the lung

vol-ume,depositofGAGsintothepulmonaryinterstitialtissue,

trachealstenosis,vocal cordthickening,adenoidand

(3)

positioned epiglottis, presence of abundant thick nasal

mucous,andlimitedmouthopeningaremainlyresponsible

for therespiratory disorders.6---11 _Hearing _loss_is _also

com-moninpatientswithMPSI.Althoughthenatureofhearing

lossmaybeconductive,sensorineuralormixed,conductive

hearinglossismorefrequentandcanbeexplainedby

sev-eralfactors,suchasthethickeningofthemiddleearmucus

andeardrumproducedbydepositsofGAGs,Eustachiantube

obstruction, ossicular chain malformation,

hypopneumati-zationofthetemporalboneandpresenceofthickcopious

mucus.Mechanismstoexplainthesensorineuralhearingloss

areunclear.Itisbelievedthataprogressivehyperplasiaof

thearachnoidmembranecancompressthecochlearnerve,

and that the storage of GAGs inside neurovascular

struc-turesof theinner ear,along withalterations of thehairy

cellsconsequenttometabolicdisordersusuallypresent in

patientswithMPS,maybecontributoryfactors.2,9,12---17

Duetothemultisystem involvement,treatment is

usu-allymultidisciplinary.Untilthe1970s,treatmentconsisted

in palliative methods toimprove the qualityof life.

Cur-rently, the two principal therapeutic tools of MPS I are

basedonenzymaticreplacement(ERT)andtransplantation

of hematopoietic cells (HCT). The enzymes produced by

stemcells frombone marrowor umbilicalcordrestore to

thepatienttheabilityofdegradation.Since1981,morethan

200childrenhavebeensubmittedtothistypeoftreatment.

TheHCTproducesresolutionorimprovementofOSAHSand

conductivehearingloss.Themajorproblemrelatedtothis

treatmentisthehighrateofmorbidityandmortality(40%),

andthedifficultytofindcompatiblebonemarrow.Because

ofthe high risk relatedtothis therapy,it is restricted to

children with severe disease, preferable before the 18th

month of life, when the CNS alterations usually begin to

occur.18---21

Laronidase(Aldurazyme®₎_is_the_enzyme _used_in_MPS_I,

and it is produced by recombinant DNA technique.

Clini-caltrialswithERThaveshownimprovingoftherespiratory

status. It was approved by commercial use in 2003, and

sincethenmorethan330patients havebeentreated.22---26

Althoughimprovementoftherespiratoryconditionsis

fre-quently mentioned in the majority of the reports, few

studieshaveaddressedthehearingproblemsandother

oto-laryngologicalfindingsthatremainunclear.27,28

Theindividualsincludedinthisstudyarepartofthefirst

clinicaltrialoftreatmentofMPSIwithlaronidaseinBrazil.

The objective wastoevaluate the impactof ERT with

laronidaseinrespiratoryandaudiologicalmanifestationsof

patientswithMPSIandclinicalmanifestationsintheupper

respiratorytract(URT).

Method

NinepatientswithMPSI(no-Hurlerphenotype)were

evalu-atedafterapprovaloftheCommitteeofEthicsinResearch

(protocol0337/05).

Each patient received 52 infusions of laronidase,

0.54mg/kg/dose.

Theywereallsubmittedtoatleasttwootolaryngological

evaluations, including nasofibroscopic, polysomnographic

andaudiologicalexamination,betweensevenand11months

beforeandbetween16and22monthsafterthebeginning

ofthetreatment.

Tonsils3 and4 accordingtoBrodsky classification,and

adenoids occupying more than 70% of the choanae were

consideredhypertrophic.29

Thedata obtainedfrompolysomnographic examination

(PSG) wereanalyzed accordingtothe parametersdefined

bytheAmericanThoracicSociety(indexofapneahipopnea

>1event/hinchildrenunder14yearsofageand>5events/h

inolderchildren).30,31

Audiological evaluation was accomplished by

conven-tionalaudiometricexamaloneorwithvisualreinforcement.

AnalysisofthedatawasbasedonSRT(‘‘speechreception

threshold’’). It was considered normal when the SRTwas

< or equal 20(dB).Imitanciometric curvewas interpreted

accordingtoJergerclassification(1970).32,33

StatisticalevaluationwasanalyzedbytheFriedmantest

(non-parametric).The valueofrejection forhypothesis of

nullitywasfixedforvalues<orequal0.05.Significancewas

markedas(*).Non-significant(NS).

Results

Fromtheninepatientsinitiallyevaluated,twodidnotreturn

for the second visit afterthe beginning of treatment and

werenotincludedinthestatisticalanalysis.Fourpatients

werefemaleandfivemale,andagesrangedbetween3and

20years(medianof8years).

One patientdid not have a pre-treatment

polysomno-graphicexamandwasnotincludedinthefinal

polysomno-graphicevaluation.

Three patients had undergone ENT surgery before the

startofthisstudy:inadditiontomyringotomywith

ventilat-ingtubeplacement,onepatientunderwentadenoidectomy

at the ageof 7, onepatientwasreferred to

adenotonsil-lectomy attheageof4 andanotherpatientheldelective

tracheotomyandadenoidectomyat4yearsofage.

Fig. 1 shows that nasal obstruction, snoring, oral

breathing,apnea,rhinorrhea,andrecurrentURTinfections

improvedwithERTinpracticallyallpatients.

Otolaryngologicalexaminationshowedthatmacroglossia

andappearanceofthetympanicmembrane(retraction)did

notchangeafterERT.Inthethreepatientswithouttympanic

membraneretraction, twohadpatentventilatingtubesin

place. All patients experienced reduction of nasal mucus

afterERT(Fig.2).

Naso-fiberscopic examination alsoshowed reduction of

the nasalsecretion,however, reductionof tonsil sizewas

notobserved(Fig.3).

The results obtained by audiometric evaluation are

shown in Table1. Statistical analysisdidnot demonstrate

significanceofthedifferencesbetweenpre-andpost-ERT.

Tympanometrywasperformedinonlyfivepatients,since

twohad bilateralpatent ventilatingtubesin placeat the

moment of the evaluation. In the first evaluation four of

thempresentedB-typecurveandonepatientpresented

A-typecurve,remainingunchangedafterERT.

Resultsobtainedwithpolysomnographicexamsareshown

in Table 2. Statistical analysis did not show significance

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0 1 2 3 4 5 6 7

Number of patients

URT symptoms

First evaluation pre treatment

Second evaluation pre treatment

Post treatment evaluation

Nasal obstr uction

Snor ing

Oral breathing apnea

Rhinorrea

Recurrent UR T inf

ections

Hear ing loss

Figure1 Otolaryngologicalsymptomsobtainedfromdirectedanamnesis.

0 1 2 3 4 5 6 7 8

Macroglossia Nasal secretion Tympanic membrane retraction

Number of patients

Otolaryngological findings

Figure2 Otolaryngologicalfindings.

Discussion

Sincethefirstdescription ofMPS, at thebeginningof the

20thcentury,theknowledgeofthisprogressivediseaseof

largephenotypicdiversity,aswellassignificant limitation

ofqualityandexpectancyoflifehaveexpanded

consider-ably.However,despitetheremarkableimprovementofthe

understanding of its natural history and treatment, many

questionsremainunsolved.There is alack of information

regarding the evolution of non-treated patients, and the

0 1 2 3 4 5 6

Nasal secretion Hypertrophic tonsils

Number of patients

Nasofiberscopic findings

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Table1 ResultsofSTR(dB).

Patients 1stevaluation

pretreatment

2ndevaluation

pretreatment

3rdevaluation

posttreatment

RE LE RE LE RE LE

1 30 35 15 20 20 15

2 20 20 25 25 20 30

3 50 60 50 60 65 55

4 55 50 60 35 55 35

5 80 60 90 95 75 80

6 45 50 75 70 80 70

7 75 75 60 60 55 70

Friedman’stest:2calc=0.240;N.S.,p=0.887.

rarity and large phenotypicheterogenicity of MPSI make thedevelopmentofastudy ofclinical relevancedifficult, particularlydue tothe diversity of clinical presentations. The absenceof specific scores and biomarkers represents anadditionalproblemtomonitortheefficacyofanykindof therapeuticprotocol.4

MostofthestudiesenrollingpatientswithMPSIandERT

haveaddressed moreadvancedstagesof thedisease.The

presentstudyisprospective,observationallongitudinal,and

the patients were already presenting established lesions.

Thismayhavecontributedtothelowexpressiveresults.

Otolaryngological complaints (oral breathing, snoring,

hearingloss, nasalobstruction, rhinorrhea, recurrentURT

infections)andclinicalfindings(macroglossia,hypertrophy

oftonsilsandadenoid,nasalsecretionandretractionof

tym-panic membrane) are frequently reported in the medical

literature.8---12

Inourstudy,weobservedadecreaseinfrequencyof

prac-ticallyallotolaryngologiccomplainsafterERT,withmarked

reductionin rhinorrhea and URT recurrent infections. We

believethatthereductionoftheGAGdepositsinthemiddle

earandURT,andconsequentimprovementofthenasalflow

andEustachiantube could have been thereasonfor such

improvement.Interestingly,hypoacusiafrequencyincreased

afterERT.

Most of our results are similar to those reported in

the literature. In phase I/II clinical trials, authors have

reported90%ofthepatientspresentingwithrecurrentURT

infections, and improvement after ERT.23 _Sardón _et _al.

describedtwopatientsunderERT,withsignificantreduction

ofthetracheotomysecretionsinoneofthepatientsafter

40 weeks of laronidase, although no improvement of the

hypoacusia could be observed.28 _Tokic _et _al., _in _2007,

reported two cases of MPS I submitted to ERT, with

remarkable improvement of the URT recurrent infections

inbothpatients,andalsoimprovementoftheaudiological

parameters.29

Alongthetime,naso-fiberopticexaminationshowed

con-tinuousincreaseofhypertrophyoftonsilsandadenoids,as

muchasnasalsecretions,inevaluationsbeforeERT.After

the beginning of ERT, nasal secretion showed important

reduction, but no changes regarding tonsils’ hypertrophy

were observed. There areno references in the literature

regarding the volume of the tonsils and adenoids in MPS

I patients submitted to ERT. However, some authors

per-formed tonsillectomy and adenoidectomy in at least five

patients undergoing ERT, and this fact may reflect the

absenceofimprovementofthisclinicalparameter.27

Regardingthehearingloss,thereisa consensusamong

thereportsthatMPSIpatientspresentwithhypoacusia,and

althoughsomeauthorsreportimprovementafterHCT,few

haveevaluatedtheevolutionofdysacusiaafterERT.Sardón

et al., in 2005, evaluated two patients performing brain

evokedresponseaudiometry(BERA),detecting conductive

hearing lossin one.The patientdid notpresent

improve-mentafterERT.23 _Tokic_et_al.,_in_2007,_also_evaluated_two

Table2 Apnea---hypopneaindexes(IAH)andtimeofsleepwithoxygensaturationinferiorto90%.

Patients IAH Tsat<90%

1st 2nd 3rd 1st 2nd 3rd

1 10.9 12.3 12.3 2.7 12.5 12.5

2 11.2 1.3 39.3 2 0 7

3 0.3 0 0.4 10 20 32

4 48.1 54.5 60.6 100 91 94

5 9.3 14 10.6 3.4 7 2

6 17.6 15.4 14.1 2.3 0.2 0

Friedman’stest.

IAH,2calc=1.826;N.S.,p=0.401.

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patients hearingby using traditionalaudiometry.A mixed conductive-sensorineuralhearinglosswasobservedin one patient,withnochangesafterERT,andconductivehearing loss wasobservedin theother, which presented improve-mentofthethresholdsfrom30dBto10dBinoneearand 90dBto60dBintheotherearafterERT.29

Onehundredpercentofourpatientspresentedhearing

loss of varying levels. Two patients had ventilation tubes

inplaceandwerenotsubmittedtotympanometry.Type-B

curvewasobserved in80% oftheremaining fivepatients.

Therewasnostatisticalsignificanceofthevaluesbetween

justbeforeandafterERT,however,accordingtothe

medi-ans,itwaspossibletoverifythatthehearinglosswasgetting

worsebeforeERT,andhadaslightincreaseaftertreatment.

AlongwiththeimprovementoftheURTinfectionsand

rhin-orrhea,abetterresultregardingthehearingthresholdswas

alsoexpected,but possiblyother factorssuchasossicular

chainmalformation,thickeningofthemiddleearmucosa,

andEustachian tube dysfunctionwere responsible for the

maintenanceoftheaudiologicalstatus.Ontheotherhand,

sensorineuralhearinglossesareusuallyprogressiveandtend

toworsentheaudiologicthresholdofMPSIpatients,even

duringERT,sincetheenzymedoesnotcrossthe

hematoen-cephalicbarrier.17

Whenfirstsubmittedtopolysomnographicexamination,

allpatientspresented OSAHS,exceptonepatientwhohad

hadtracheostomybeforethebeginningofthestudy,andno

OSAHSwasregisteredinanyoccasion. Overall,theresults

did not show statistical differencebetween the pre- and

post-ERTmeasurements,however,basedonthemedians,we

observedthatthepolysomnographicparameterswere

dete-riorating beforetherapy and presented stabilization after

theERT.Thisphenomenonwasalsoobservedforthemedians

ofthetimeofoxyhemoglobinunder90%.

Accordingtotheliteraturemostofthepatientsimproved

their respiratory status after ERT. Phases I/II clinical

tri-als have shown that all patients with OSAHS presented

reduction of the IAH after 52 weeks of ERT (mean of

2.1---1event/h); two patients had reductionof sleeptime

withoxygensaturationunder90%;onepatienthad

improve-mentinsleeptime.Aftersixyearsoffollow-up,fiveoutof

sixpatientswerere-evaluated,fourpresentedimprovement

or stabilization of therespiratory status, andone patient

wasworse.26

Phase III study also showed reduction of the IAH in

patientstreatedwithenzymewhencomparedtoaplacebo

group(reductionof6events/hinthetreatedgroup,increase

of0.3event/hintheplacebogroup).Inastudyaddressing

childrenundertheageof5years,reductionof8.5%ofthe

IAH was observed. However,amongsix patients who

pre-sentednormalIAHbeforetreatment,fourremainednormal

andtwogotworseaftertherapy.25_Tokic_et_al._also_reported

normalization to the IAH in two patients after 12 weeks

of treatment, along with improvement of the respiratory

pattern.29

Few isolatedreports,however,present contraryresults

regardingtherespiratoryquality.Sardónetal.hadapatient

with tracheotomy whodid not show improvement of the

respiratory quality after ERT.23 _Thomas _et _al. _described

a severely diseased patient treated with ERT for three

yearswithnochangesontheprogressionoftheobstructive

picture.34

DuetotheprogressivepatternofMPSI,stabilizationor

reductionoflesionsandspeedofthediseaseprogressionare

consideredasbenefitsfromthetherapy.2,26

Whenaquestionnaireiscompletedbythepatients,

stud-ieshaveshownimprovementindailyactivitiesperformance.

Ourpatients have alsodescribed ageneral improvement,

evenregardingthehypoacusia,sleepandrespiratory

qual-ity, which we could not demonstrate through the results

oftheobjectiveexams(audiometricandpolysomnographic

evaluations).

CurrentchallengesforERT,besidesthedevelopmentof

anearlydiagnosticprotocol(neonatalscreeningtest),

con-sistofpredictionoftheseverityofthedisease,inorderto

makeanadequatechoiceoftreatment,todevelopan

ade-quatetreatmentfortheneuropathies,andtofindwaysfor

aneffectivemonitoring,withspecificinstrumentsto

quan-tifytheimprovementoflifequalityaswellasefficacyand

effectivenessof the employed therapy.Longer follow-ups

canalsocontributetotheknowledgeofthesideeffectsof

theERTasmuchastheevaluationoftheevolutionofeach

systeminordertoplanassociatedtreatmentprograms.2,35,36

Although thiswasa study project ofa smallsampling,

overalltherewasaremarkableimprovementofthequality

of life of patients and a high level of satisfactionby the

relativesandhealthcareprofessionalsproducedbytheERT.

Conclusion

According to the results obtained from this study, we

observed that MPS I patients submitted to ERT with

laronidase(Aldurazyme®₎_present_improvement_of_the_URT

recurrent infections, rhinorrhea, and general respiratory

status,without howeverpresenting expressiveand

signifi-cantimprovementofthehearingloss,tympanometriccurve

pattern,sleepdisorders,macroglossiaandtonsilsand

ade-noidhypertrophy.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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