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C Poitou and others Treatments in genetic obesity 183:5 R149–R166 Review

MECHANISMS IN ENDOCRINOLOGY Update on treatments for patients with genetic obesity

C Poitou1,2, H Mosbah1 and K Clément1,2

1Assistance Publique-Hôpitaux de Paris, Reference Center for Rare Diseases (PRADORT, Prader-Willi Syndrome and Correspondence Other Rare Forms of Obesity with Eating Behavior Disorders), Nutrition Department, Pitié-Salpêtrière Hospital, Paris, should be addressed France and 2Sorbonne Université, INSERM, Nutrition and Obesity: Systemic Approaches (NutriOmics) Research Unit, to K Clément Paris, France Email [email protected]

Abstract

Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin- melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients’ early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity

European Journal of Endocrinology cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.

European Journal of Endocrinology (2020) 183, R149–R166

Invited Author’s profile Karine Clément (MD, PhD) is a Medical Doctor and Full Professor of Nutrition at Pitié- Salpêtrière hospital and Sorbonne University, Paris. Since 2002, her research unit at INSERM (www.nutriomique.org) works on the pathophysiology of obesity and related disorders. From 2011 to 2016, she created and was the director of the Institute of CardiometAbolism and Nutrition (ICAN). Prof Clément has been primarily involved in genetics of obesity and contributed to the identification of monogenic forms of obesity. Her group is also exploring the link between environmental changes (as changes in lifestyle and nutrition), gut microbiota, immune system and tissue functional modifications (adipose tissue fibrosis and inflammation).

https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-20-0363 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 01:43:16PM via free access

-20-0363 European Journal of Endocrinology https://eje.bioscientifica.com appearing atapproximately 4–8yearsofage),abnormal of life to hyperphagia, with major food impulsivity (from anorexiawithsuckling disordersinthefirstmonths hypotonia, eating disordersevolving in severalphases to 1/20000births,ischaracterized bysevereneonatal related tohypothalamusimpairment. syndromes sharingphysiopathologicalcharacteristics the mainphenotypictraitsformostcommon an identifiedgeneticsubstratum( syndromes havebeen described butnotallofthemhave disorders) and/or malformative syndrome. More than80 delayed walking,learning,autismspectrum neurodevelopmental disorder(intellectualimpairment, to eatingbehaviordisordersandassociatedwith a defined asobesitystartingearlyinchildhoodlinked Syndromic Clinical subtypesofgeneticobesity with geneticobesity. made itpossibletoproposeeffectivesolutionspatients have beendevelopedoverthepastseveralyearsthat present thelatestadvancesconcerningnewtherapiesthat testing. Thus,aftersummarizingtheclinicalpictures,we disorders, should alert clinicians and lead to molecular of thesyndromicform,suchasneurodevelopmental (hypogonadism, growthabnormality),and/orsignsspecific age) associatedwitheatingdisorders,endocrineanomalies should benotedthatearly-onsetobesity(before6yearsof obesity andleadtoitsmoleculardiagnosis( to adulthoodthatmaygiverisethesuspicionofgenetic detail the clinical progression of obesity from childhood As itisdescribedelsewhere( approximately 5–10% of childhood severe obesity ( These geneticformsarenowconsideredtorepresent with apredominantcontributionofgeneticfactors. obesity, whichareoftensevereandshowanearlyonset, phenotypic development,andtherareformsofgenetic in which the environment has a critical impact on the due to polygenic inheritance, the most common form, obesity. There is a proposed continuum between obesity of hundreds of genes involved in the development of studies usingmicroarrays, have ledtothediscovery genome-wide association studies (GWAS), and expression gene approaches,next-generationsequencing(NGS), Technological advancesinrecentyears,suchascandidate Introduction Review PWS , ofwhichthefrequencyisbetween1/15000 obesities (ORPHANETcode240371)are 2 ), wewillnotdescribein C Poitouandothers 3 ). We brieflysummarize 2 ). However, it 1 ). expressed protein-codinggenesincluding q13 regioncontainsaPWSdomainwithfivepaternally segment 15q11–q13 of paternal origin. The15q11.2– with thephysicalorfunctionalabsenceofchromosomal PWS is linked to abnormal parental genomic imprinting uncontrolled eatingandthedevelopmentofobesity( and closelyimplementedcarecanlimittheseverityof and implemented specialized care. In other words, early patient’s environmental care (i.e. provided by caregivers) ismarkedlyinfluencedbythenatureof trajectory behavior. Ofnotethiscriticalperiodinthedevelopmental a switchfromdifficultieseatingtouncontrolled the developmentofsevereobesity, mostlyassociatedwith PWS from childhood to adulthood is often marked by disorders, anddysmorphictraits( impairment, and learning difficulties, as well as behavioral hormone deficiency, hypogonadism),intellectual muscle mass( body composition,withincreasedfatmassandreduced developmental delay, intellectual disability, and early-onset People with16p11.2deletion syndromeusuallyhave 16, detectable by chromosomal microarray analysis. caused byadeletionof small pieceofchromosome have alsobeenproposed( or otherendocrinetissues(pancreas,stomach,intestine) origin involving adipose tissueand adipocyte proliferation and amygdala ( neurons, especially in structures such as the hippocampus BBS proteinsleadstosynapticaberrationsinprincipal associated withhyperphagia.Forexample,theloss of central originofobesityduetohypothalamicdysfunction ( hypotheses havebeenputforward in BBSarestillpoorlyunderstood.However, several precise mechanismsinvolvedinobesitydevelopment contributing, inparticular, toright/leftsymmetry. The Hair cellsarealsoinvolvedinmammaliandevelopment, signaling messagesfromtheoutsidetoinsideofcells. andareusedtotransmit functioning cellularmachinery cilium ( primary are involvedinBBS,alllinkedtofunctioningofthe dysmorphia, andlearningdisabilities.Atleast19genes polydactyly, kidney abnormalities, hypogonadism, early-onset obesity, patientsmayshowretinaldystrophy, autosomal recessive transmission. In addition to severe and frame-small nuclearribonucleoproteinpolypeptideN) NPAP1 (makorin 3), Treatments ingeneticobesity The 16p11.2microdeletion syndromeisadisorder The snoRNAs and BBS (

SNURF-SNRPN 7 MAGEL2 phenotype isalsoheterogeneouswith ). 11 4 8 ), endocrineabnormalities(growth ). Hair cells are critical for properly ). Other hypotheses of a peripheral (MAGE-like 2), Downloaded fromBioscientifica.com at09/30/202101:43:16PM 10 (SNRPNuptreamreading ). 9 5 , 183 ). Theevolutionof 10 :5 ). Oneproposesa NDN (necdin), MRKN3 R150 6 via freeaccess ).

European Journal of Endocrinology subjects. In heterozygous subjects, phenotypic expression that ismuchmoresevere thanthatofheterozygous heterozygous orhomozygous variantshaveaphenotype control of food intake. Reported subjects with compound variants inthesegenesthatplay amajorroleinthecentral monogenic obesitiesaremainlydueautosomalrecessive and kinasesuppressorofras2( plexinA1–4 ( activator-1 ( involved inorregulatingthispathway:steroidcoreceptor early andsevereobesityinvolvinggenesthatareprobably genetic screeninghavefoundvariantsinsubjectswith cyclase 3 ( protein2( receptor accessory and MC4R ( ( leptin ( melanocortin involvedintheregulationofenergybalance: of agenelocatedinthehypothalamicpathwayleptin- code 98267)aremostoftenlinkedtoapathogenicvariant to considerincaseofearly-onsetunexplainedobesity. to MC4Rsignaling( obesity arecomplexandcouldbepartlyduetoresistance of age),withinconstanthyperphagia.Mechanisms ( within orupstreamof and/or epigenetic,sporadicorgenetic-basedalterations, or autosomaldominantlyinheritedgeneticmutations most commonunderlyinggeneticmechanismsare prevalence to be between 0.34 and 1.1 in 100 000. The of parathyroid hormone (PTH). Reports estimatedthe of resistance of target tissues to the biological actions hypocalcemia andhyperphosphatemia)thataretheresult biochemical featuresofhypoparathyroidism(i.e. cyclase. PHP describes disorders that share common Gprotein(Gsa),toactivationofadenylyl stimulatory receptors that are coupled, through the molecular defectsthatimpairhormonalsignalingvia hyperphagia, shortstatureandinsulinresistance( mutations inthisgenepresentaprecociousobesitywith the melanocortinpathway. punctual Patientscarrying gene isinvolvedinregulationofleptinsignalization Among genesencompassedbythisdeletion,the before theonsetofobesityoccurringinadolescence( deletion syndrome,satietywasimpairedinchildren 3 in10000.Inalargecohortofpatientswith16p11.2 obesity. Theprevalenceisestimatedtobeapproximately > PCSK1 POMC Review 90% inchildren),severeandearly-onset(before2years Non-syndromic monogenicobesities(ORPHANET Pseudohypoparathyroidism (PHP)iscausedby ), prohormonesubtilisin/kexin1convertase ), melanocortinreceptortype3and4( LEP ADCY3 ) ( ), leptinreceptor( 2 SRC-1 ), MC4R regulatory protein,melanocortin ), MC4Rregulatory PLXNA ) ( ), semaphorin3A-G( 16 14 ). More recently, several reports on ). Thus, 1–4), neuropilin1–2( GNAS LEPR MRAP2 . Obesity is very frequent . Obesityisvery GNAS C Poitouandothers ), proopiomelanocortin KSR2 analysisisimportant ) ( 15 )

α ( ) andadenylate -subunit of the 17 , SEMA3A-G 18 NRP ). These 13 de novo SH2B1 MC3R ). 1–2), 12 ). ),

hunger aresuggestivesigns.Mutationsinmelanocortin the ageof5years( the apathogenichomozygousvariantof patients carrying absence ofneonatalhypotoniaandsuckingdifficulties. pathway canbeeasilydistinguishedfromPWSbythe BMI exceeds27kg/m the leptin-melanocortinpathwayshouldbesoughtwhen life. The results of a recent report suggest that variants in and severeobesitythatdevelopsfromthefirst3yearsof a normalbirthweightfollowedbyrapid increase immediate attention of clinicians. They most often show are characteristic and should draw the and BMIcurves and satietysignals( early severe obesity accompanied by impaired hunger for the with compoundheterozygousorhomozygousvariants ( consanguinity isfrequentlyobserved higher incertainpopulations,especiallythosewhich this prevalenceisprobablyunderestimatedandmaybe 5% ofthecausesearlyandsevereobesity( of othergenes.Theseformsobesityaccountforatleast may dependinpartontheenvironmentandinfluence those relatedtohomozygous orcompoundheterozygous of ( deficiency (heterozygosity) wasestimatedtobe0.83% subjects withsevereobesity, theprevalenceofpartialPC1 children ( PCSK1 ( gonadotropic, thyrotropic,andcorticotropicinsufficiency early onsetobesity, latepostprandialhypoglycemia, and (homozygosity orcompoundheterozygosity)showsevere of the of obesity ( of the heterozygous variants, as well as methylation anomalies, hair ( somatotropic andgonadotropicinsufficiencyred thyrotropic insufficiency( show corticotropic insufficiency and sometimes moderate deficit (homozygousorcompoundheterozygous)thus LEPR incarriersofthepathogenicvariant also beobserved insufficiency, leadingtogrowthretardation,can thyrotropic insufficiencyofcentralorigin.Somatotropic a hypogonadotropichypogonadismandsometimes Treatments ingeneticobesity 35 25 LEP, LEPR,POMC ). Severeobesityformslinked toheterozygousvariants al.describedheterozygousvariantsof et ). Löffler Subjects with obesity linked to a complete POMC Along withsevereobesityanduncontrolledeating, LEP ( 28 POMC 21 associatedwithobesityandglucoseintolerancein PCSK1 LEP, LEPR, POMC,PCSK1 , or , 34 29 23 32 ). Based on 845 non-consanguineous European ). BeyondcompletePOMCdeficiency, some gene may also be involved in the development ). LEPR genethatleadtocompletePC1deficiency , 33 ). Patients with rare pathogenic variants genespresentpubertaldelayand/or 29 , and 22 2 ). Majorhyperphagiaandinsatiable attheageof2yearsor33kg/m , Downloaded fromBioscientifica.com at09/30/202101:43:16PM 23 PCSK1 , 30 24 , , https://eje.bioscientifica.com aremorefrequentthan 31 , and 25 ). Theyalsodisplay , 183 26 16 MC4R , :5 , 27 20 , , genesshow 21 28 ). Patients ). Weight 19 R151 ), but 2 at via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com In BBS,consideredtobea ciliopathy, thetransportof density ofaxonsaMSHneurons inamousemodel( has beenshowntoberesponsible foradecreaseinthe the genomic region classically deleted in PWS (15q11–13), Moreover, inactivationofthe protein (AgRP)neurons,havebeendescribed( deficiency and activation of the orexigenic Agouti-related suppressing pathways,duetoproconvertase1(PC1) For example,inPWS,abnormalitiesoftheappetite- energy homeostasis,inparticularthehypothalamus. centersof involve centralanomaliesoftheregulatory in their pathophysiology, as most rare forms of obesity psychiatric disorders ( be accompaniedbyneurodevelopmentaland/or clinically certainformsofmonogenicobesitycan syndromic monogenicobesityhasitslimitations,as The distinctionbetweensyndromicobesityandnon- syndromic andnon-syndromicobesity Overlapping pathophysiologybetween ( the modalitiesusedtorecordalteredeatingbehavior studied, thefunctionalimpactof across studies, depending presumably on thepopulation eating behaviorand may decreasewithage.Theassociationbetweenaltered life ( initially reported that they are tallerinthe first 5yearsof fat than non-mutated BMI-matched subjects ( Children withheterozygousvariantshavemorebody populations (Europeans,Americans,Asians)( 166 differentfunctionalvariantsdescribedinvarious severe obesityinchildrenandadults,withmorethan the deficit). Obesitylinkedtoheterozygousvariantsof fertility, normalcorticotropicfunction,nosomatotropic endocrine deficit(reproductivefunctionandnormal LEP severe, closetothatoftheotherformsdescribedfor heterozygous compoundvariantsof personal data). on theenvironment(( attenuated phenotype that could bemoredependent homozygous vsheterozygousvariantsalsoshowingan a frequencyof0.8%vs3.3%,respectively, incarriersof severe and/orearlyonsetobesity( variants. Forexample,inourcohortof6467subjectswith 38 Review , and Obesity linkedtothepresenceofhomozygousor 39 27 MC4R ). ) andmorehyperphagic,butthesecharacteristics LEPR generepresentsapproximately2–3%of ( 27 , 28 MC4R 2 ). However, thereisnoassociated ). In addition, there is anoverlap 21 pathogenicvariantsisvariable ) andCPoitou,unpublished MAGEL2 C Poitouandothers < 6 yearsold),wefound MC4R MC4R gene,locatedin variants,and israrebut 37 ). It was 40 , 36 42 41 ). ). ). their clinical situation. Dietary advice, with the supervision advice, with the supervision their clinical situation. Dietary approachestoimprove specialized, andmultidisciplinary Patients with genetic obesity require comprehensive, Comprehensive andmultidisciplinarycare between syndromicandmonogenicobesity. that certainpharmacologicalapproachescouldbeshared probably promotingweightgain( POMC andBrainDerivedNeurotrophicFactor(BDNF), gene inmurinemodelsleadstoadecrease expression of encompassing the including severeobesity, islinkedtothe17p11.2locus, to MC4Rresistance(viaGsa).SmithMagenissyndrome, example isPHP-linkedobesitythatmaybepartlydue membrane of POMCneurons is affected ( LEPR isalteredandthereforeitslocalizationattheciliary improvement. Fromanutritional point ofview, dietary a specializedandexpertteam isessentialforpatient careby these diseasesarecomplex, multidisciplinary and treating complications related to obesity and, because malformations, among others. It is thus based on detecting orthopedic anomalies,andcardiacurogenital and treatment of sleep disorders, digestive disorders, This includessupplementationofendocrinedeficits comorbidities foundassociatedwitheachsyndrome. of thetypegeneticabnormality( adults. Here,thecausesandageofdeathwereindependent causeswaspredominantinchildren and from respiratory of mortality of 30 years (1 month to 58 years). Mortality PWS between2004and2014alsofoundamedianage study evaluating mortality registers for patientswith and youngadultswithanormalBMI( disease progressionisimportant,includingadolescents causes( 30% duetorespiratory with an average age at death of 29.5 years, with more than United StatesshowsthatmortalityremainsearlyinPWS, severe andlife-threatening.Astudyconductedinthe to aclinicalpicturedominatedbyobesity, whichisoften care ortheabsenceofpreviousininfancyoftenleads improve thepatients’condition( in earlychildhood,asthesemeasureshavebeenshownto therapy, etc.,shouldbeimplementedasearlypossible skills therapy, speechtherapy, hormonereplacement that may include adapted physical activity, psychomotor of eating behavior, add combined with other approaches Treatments ingeneticobesity Thus, overlappingpathophysiologicalaspectssuggest Clinical managementshouldtargetthespecific In adulthood,adisorganizedtransitionafterpediatric RAI1 gene. Haploinsufficiency of this Downloaded fromBioscientifica.com at09/30/202101:43:16PM 46 2 45 ). ). Earlypreventionof ). 183 47 48 ). ArecentFrench :5 43 ). , 44 ). Another R152 via freeaccess European Journal of Endocrinology ( and coordinated care should be taken into consideration the integration of social structures, and comprehensive demandingandanadultlifeproject, aspects areallvery or intellectual impairment are in the foreground. These medical andsocialsupport,especiallyifcognitivedisorders critical moment,oftenassociatedwithbreakdownsinboth and medico-psychologicalcare. cognitive functionandabilitiestoimproveeducational should becarriedoutatdifferentstagesoflifetoassess for mostpatients.Assuchneuro-psychologicalassessment carriers ofthevariant. ending theprogram,whichwasnotcasefornon- returned to their baseline weight within 1 yearafter non-carrier children ( loss inchildrenwith nutritional and physical exercise program led to weight tool inthesesituations. objects, suchasapedometer, canbeausefulmotivational ( satisfactory program was very their levelofphysicalactivity. Acceptabilityofthe byaninstructor,supervised madeitpossibletoincrease activity atafrequencyof1htwiceperweekhome, an accelerometer. A16-weekprogramofadaptedphysical and corpulencebymeasuringphysicalactivitylevelwith comparison toagroupofwomensharingthesameage highlevelofphysicalinactivityin with PWShaveavery performance ( a reductioninweight and an improvement in physical disabilities. In PWS, long-term physical exercise leads to and shouldbeadaptedtothepatients’neurodevelopmental deficit inenergyexpenditure. all theserareformsofobesitycanbecharacterizedbya expenditure, whenpossibleinexpertclinicalcenters,as to eachpatientiscritical,basedonmeasuredenergy programscloselyadapted The establishmentofdietary whether it isfamilyortheir immediate social network. The patient'sentouragerequireseducationandsupport, since uncontrolled eating isadominant phenotype. also beapplicableinthecontextofsyndromicobesity, resulting excessmortality. Thisrecommendationcan prevent obesity, itsassociatedcomplications,andthe food, andtheritualizationoffoodintakearemeansto framework,thelimitationofaccessto of astrictdietary eating disorders. In the context of PWS, the establishment autonomy is generally unfeasible in genetic obesity with 52 Review ). Caregiversmust carefully considerthepediatric-to- The transitionbetweenpediatricandadultcareisa important Neuropsychiatric managementisalsovery In monogenicobesity, theestablishmentofa1-year Advice andguidanceonphysicalactivityisalsocrucial 49 ). We recentlyshowedthatadultwomen MC4R 51 ). However, variantsequivalenttothatof 50 C Poitouandothers ). The use of connected MC4R variantcarriers patient. InBBS,studieshave reportedisolatedcaseswith also reportedobesity-related prematuredeathinone comorbidities werenotimproved ( of follow-up,therewasnoweight lossandtheassociated patients with PWS following bariatric surgery. At 10 years In 2019,aChinesestudyreportedtheoutcomeoffive average weightlossof2.4%5yearsafteragastricbypass. with PWSthanforpatientscommonobesity, withan failure. The results were worse for subjects or respiratory age, 31%werediabeticand15.7%experiencingheart preoperative BMI51.6 PWS whose average age was 19.7 is basedontheanalysisof60Americanpatientswith term patient follow-up are needed. The largest series follow-up times ( with varying ingeneticobesityarebasedononlyafewcases surgery Current dataconcerningtheeffectivenessofbariatric Genetic obesityandbariatricsurgery this criticalperiod. as behavioral problems and obesity frequently worsen in the futureofadolescentssufferingfromgeneticobesity, adult transitionstep,whichrequiresaparticulareffortfor 11 kg/m follow-up. At5years,themeanBMIlossinPWSwas throughout no readmissionsorcomplicationsaftersurgery of co-morbiditieswereincompleteremission.There from the non-PWS group ( group, thedecreaseinBMIwas15kg/m a laparoscopicsleeve-gastrectomy. At1year, inthePWS subjects matchedforage,gender, andBMI.Allunderwent 24 children/adolescentsPWScomparedto72non-PWS in al.publishedresultsofbariatricsurgery et Sheimann kg)) withoutanymajorcomplication( good resultsonweightlossat2years(32.5kg(24.9–38.3 sleeve gastrectomy and onemini-gastric by-pass) with (two bariatricsurgery three patientswithPWSunderwent ( limited relativetothatfoundincommonobesitydata group inthisstudybuttheweightlossappearedtobe results were identical to thoseof the adolescent control and 10.7%( years) resultedinweightlossof14.7%at1year( 24 childrenandadolescentswithPWS(averageage10.7 out inSaudiArabia,asleevegastrectomyperformedon perforation washigher( embolism,wallinfection,andgastric death, pulmonary At thesametime,rateofcomplications,including Treatments ingeneticobesity 54 ). Conversely, in a Chinese study published in 2012, 2 but70%didnothavedataatthatpoint( n

=

7) at5years,withoutcomplications;the ± Downloaded fromBioscientifica.com at09/30/202101:43:16PM 10.1kg/m 53 P = 0.3). Postoperatively, 81.8% ). Inanotherstudycarried 2 https://eje.bioscientifica.com ). More data with long- 2 57 . Despitetheiryoung ± 183 6.4 years and the ). Thislatterstudy :5 2 , notdifferent 55 ). Recently, R153 n

= 56 22) via freeaccess ). European Journal of Endocrinology https://eje.bioscientifica.com variant ofagenetheleptin/melanocortin pathway. The in the cohort, 8.4% (11 subjects) carried a heterozygous ( apathogenicvariant from thatofpatientsnotcarrying follow-up ofvariantcarriers was notsignificantlydifferent genes. Gastric bypass-induced weight loss after 2 years of pathogenic variants,especiallyinthe diagnosed with monogenic obesity due to heterozygous outcomes of 1014 patients, of whom 30 were surgery after 5years( 44% ofweightlossafter9monthsand7% gastroplasty andonegastricbypass)with,respectively, LEPR homozygous from the French Reunion Island, carrying sustained effortstofighthyperphagia( for atleast6years,whileremainingobese,thecostof weight (approximately20kg),whichwasmaintained the case withsevereobesityduetoahomozygousvariantof results anddurationoffollow-up.We reportedapatient outcomeshavebeenreported,againwithvarying surgery the leptin/melanocortinpathway, afewcasesofpost- complaints ( threshold) combinedwithpatientdifficultyinmanifesting complications (absenceoffever, reductioninpain especially forPWS,difficult-to-diagnosepostoperative consider thepsychologicalfragilityofthesepatientsand, thromboembolic risk).Moreover, caregiversneedto linked tothesyndrome (digestive, osteopenia, anemia, with thephysicalvulnerabilityofmulti-organdamage regain and,mostimportantly, therisksassociated results onweightlossoutcomes,withfrequent weight balance islargelyunfavorable,giventhedisappointing expertteam.Indeed,thebenefit-risk multidisciplinary cases, whichmustbeindividuallydiscussedwitha neurodevelopmental disorders, apartfromexceptional contraindicated in syndromic obesity with eating and vulnerability. common insyndromicobesitywithphysicalandmental psychiatric decompensation)thatareparticularly (deficiencies) orpsychologicalcomplications(possible Of note, no study has precisely reported the nutritional no majorcomplicationsforthesereportedcases( 32% totalweightlossat3-yearfollow-up( asleevegastrectomy.who underwent Thisresultedina reported thecaseofaseverelyobesewomanwithBBS in largercohortshavenotbeenpublished. A Belgianteam results,dependingonthetechnique,butstudies varying 63 Review ). InarecentChinesestudy, with131obesesubjects LEPR Concerning monogenicobesitywithalterationsof shouldbegenerally In ouropinion,surgery pathogenic variants underwent bariatric surgery (one bariatric surgery pathogenic variantsunderwent gene.Aftergastroplasty, thepatientinitiallylost 61 21 ). ). ADutchgrouppublishedthebariatric C Poitouandothers POMC 62 58 ). Two patients ). Therewere and 59 PCSK1 , 60 ).

carrying aheterozygous variantof carrying forpatients no argumentsagainstbariatric surgery ( follow-up forthosewhohad asleevegastrectomy( the weightlosswassignificantly lessduringthe2yearsof amutation. On theotherhand, of patientsnotcarrying a gastricbypassshowedweightlossequivalenttothat of the severe early-onsetobesitycarriedheterozygousvariants In aDutchcohort,11patientsfromninefamilieswith shown varying outcomespost-bariatricsurgery.shown varying Aslan et al. unequivocal decision. are currentlyinsufficienttoprovideabasismakean data concerning heterozygous variants ofthesegenes caution before deciding on a surgical procedure. The of newtreatments(seebelow)encouragetheutmost energybalancedisorder,the primary andtheemergence However, thedisappointingresults,probablylinkedto not appeartorepresentanabsolutecontraindication. major eating disorders, or intellectual impairment, do of MC4R), in the absence of psychiatric disorders, variants oftheleptin/melanocortinpathway(i.e.upstream comorbidities. variants ( genes was much lower than that of patients without these variantsforthe carrying weight lossobtainedafter6yearsoffollow-upforpatients more reoperations and postoperative complications ( and risk ofbinge-eatingdisorder(BED)beforesurgery heterozygous variantisassociatedwithanincreased showed thatthepresenceofagainfunction(GOF) have amajorimpact( suggesting thataheterozygousvariantof variant andthoseinacontrolgroupwithoutthevariant, identical weightlossat1yearforpatientswithan interpretation ofthepublisheddata.Valette et al. reported functionality relevantmutations–complicatesthe of theanalyzed the variants.Theyarereviewedin( studies andreports,probablylinkedtothefunctionalityof patients withheterozygousvariantsof patient. wasnotadaptedforthis weight, suggestingthissurgery loss in the first four months, the patient regained thelost gastric bandingandvagotomy( deficiency, leading to insatiable hunger, who underwent reported thecaseofapatientwithcompleteMC4R Treatments ingeneticobesity 63 ). Basedonthepublishedstudies, therearecurrently The effects of bariatric surgery onweightlossof The effectsofbariatricsurgery Concerning MC4Rvariants,severalreportshave Based onthesestudies,thepresenceofhomozygous MC4R 64 ), withalsopoorerimprovementinmetabolic gene.Amongthem,thepatientswhohad MC4R 67 Downloaded fromBioscientifica.com at09/30/202101:43:16PM variants–polymorphismsvs ). However, amorerecentstudy LEP, LEPR, SIM1 65 66 ). Afterinitialweight 183 ). Theheterogeneity MC4R MC4R :5 MC4R , and , apartfrom vary between vary does not R154 PCSK1 MC4R n

39 = via freeaccess 3) ).

European Journal of Endocrinology ( overeating andsocialbehavior intheyoungestchildren to children aged 6–14 years showed a positive effect on administered intranasal oxytocin vs placebo for 8 weeks in PWS.ADutch,randomized, double-blindstudythat studies haveopenedupnewtherapeuticperspectives factors ( the administrationofnasaloxytocinonsocialinteraction PWS initiallyshowedinconstantlyabeneficialeffect of autism spectrum. Studies in adults and adolescents with some PWSpatientsdisplayfeaturesassociatedwiththe autism spectrumdisorders,whichmayberelevant, as Moreover, oxytocin was shown to improve emotions and PWS, especiallyinyoungchildren(reviewed( with oxytocincouldplausiblyhavebeneficialeffects in to alterations in oxytocin regulation. Thus, treatment obesity, andsocialinteractiondisorders,maybelinked A numberofclinicalfeaturesPWS,suchasovereating, whereas elevated levels have been measured in children. oxytocin neuronsandadecreaseincirculating oxytocin, reduction inthenumberofhypothalamic-producing have beendescribed.AdultswithPWSshowasignificant in loss insyndromicandmonogenicobesitiesaredescribed reportedinNCTclinicaltrialsforweight interventions upstream oftheMC4Rreceptor( for patientswithalterationsofthemelanocortinpathway approaches havebeendeveloped,notablyforPWSand the future. of obesitymightalsobenefitfromthesedevelopmentsin wider spectrum of genetic abnormalities. Common forms molecule developedforonedisordermaybeeffectivea common biologicalpathways,itishighlypossiblethata severe conditions.Asthesegeneticdisorderscaninvolve forthese arenecessary alternatives tobariatricsurgery of lifethesepatientsandontheirrelatives.Moreover, obese patients.Thisputsaheavyburdenonthequality because ofthemarkedandearlyobesitygenetically The development of new therapeutic strategies is essential genetic obesity Toward therapeuticinnovationsin development ofnewtreatments. should, however, changeinthecomingyears,dueto obesity. inthosecases Thestrategytousebariatricsurgery the usualwell-knowncontraindicationsforcommon 74 Review Table 1, ). At an earlier age, below 6 months, intranasal In PWS,abnormalitiesoftheoxytocinergicsystem In recentyears,anumberofinnovativetherapeutic 72 with ongoingandcompletedstudies. , 73 ). However, two recentlypublished C Poitouandothers 68 , 69 ). Pharmaceutical 70 , 71 )). The dailyinjectionofadoseAZP-531 for 14daysin47 improve glycemiccontrolandweightlossinhumans. orexigenic effectofacylatedghrelininanimalmodelsand controlled study. AZP-531hasbeenshowntoinhibitthe tested inaEuropean multicentric randomized placebo- (livoletide), anon-acylatedghrelinanalog,wasalso blind study( score in adults with PWSin a randomized double- topiramate hasasignificanteffectonthehyperphagia hyperphagia scoreafter14daysoftreatment( selective compound,showedpromisingresults,reducing stages ofdevelopment.Carbetocin,anoxytocinreceptor- the oxytocinergicsystemmaybemoreplasticatearlier young childrentoimproveeatingdisorders,because should probablybeadministeredearlyininfantsand promising studiessuggestthattreatmentwithoxytocin and social interactions in infants ( administration ofoxytocinimprovedsuckingdisorders but exacerbationofbehavioralproblems( datashowbenefitson weightloss alone; preliminary heart rateandbloodpressureinducedbytesofensine used tocounteracttheadverseeffectsofincreased hyperphagia score,withoutseriousadverseeffects( patients withPWSwasaccompaniedbyareductioninthe with interestingresultsonweight butwasnotapproved aminopeptidase 2inhibitor, hasbeentested inPWS or brain stimulation ( fibers the modulationofgut microbiotabydietary innovative therapiesarecurrently beingtested,suchas with anti-obesityeffects,andmetoprololisa (serotonin, noradrenaline,dopamine)reuptakeinhibitor evaluated in PWS. Tesofensine is a triple monoamine The associationoftesofensineandmetoprolol,isbeing Clinical trialswithGLP-1agonistsareongoing( after 6monthsoftreatmentbutwithouteffectonweight. cases ( tried outinnon-randomizedstudiesorreportedclinical agonists, suchasliraglutideandexenatide,havebeen baseline ( hyperphagia score in patients with the highest scores at choline controlled released), showing a decrease in tested inPWS,suchasK+-ATP channelagonists(diazoxide treatment (NCT03274856).Othertherapiesarebeing effect onhyperphagiaafter4weeksofdouble-blind ghrelin O-acyltransferaseinhibitor, showednosignificant to ensure safety (NCT03790865). Moreover, GLWL-01, a particular on weightandmetabolic improvement, and term effectivenessofthismolecule(over12months),in totestthelonger- A phaseIIbclinicaltrialisunderway Treatments ingeneticobesity Aside fromstudiesonoxytocin,wehaveshownthat 80 , 81 79 , ). Glucagon-likepeptide1(GLP-1)receptor 82 77 ). ForExenatide,appetitescoresdecreased ). Moreover, anewmolecule,AZP-531 Table 1 Downloaded fromBioscientifica.com at09/30/202101:43:16PM ). Beloranib, a methionine https://eje.bioscientifica.com 183 75 :5 ). These recent 76 69 β ). ). Other Table 1 -blocker R155 78 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com

Table 1 Parmacological weight loss interventions in syndromic and monogenic non syndromic obesity. Review

Type of genetic Pharmaceutical Mode of Number of Methodology/trial (number, obesity molecule administration cases phase, status) Results Adverse events References Syndromic Prader–Willi Oxytocin Intranasal 5 ongoing trials (phases II NCT03114371, and III) NCT02804373, NCT04283578, NCT03197662, NCT03649477 n = 24 adults Double-blind RCT, one Significant increase in No SAE Tauber et al. (72) PWS single dose (oxytocin vs trust in others (P = 19–67 placebo) 0.02) and decrease in

years sadness tendencies C Poitouandothers (P = 0.02) with less disruptive behavior (P = 0.03) in the 2 days following administration than patients with placebo n = 30 PWS Double-blind RCT, No effect on hyperphagia No SAE Einfeld et al. (73) aged cross-over. Eight weeks and behavior except an 12–30 of oxytocin or placebo increase in temper years followed by a 2-week outbursts washout period and then another 8 weeks of oxytocin or placebo Treatments ingeneticobesity n = 25 Double-blind RCT, No significant effects of No SAE Kuppens et al. (74) children cross-over. Four weeks oxytocin on social PWS 6–14 of oxytocin or placebo behavior or years directly followed by hyperphagia, but in the another 4 weeks of 17 children younger oxytocin or placebo. No than 11 years, washout significantly less anger (P = 0.001), sadness (P = 0.005), conflicts

Downloaded fromBioscientifica.com at09/30/202101:43:16PM (P = 0.010) and food-related behavior (P = 0.011), and improvement of social behavior (P = 0.018)

during oxytocin 183 treatment vs placebo n = 24 Double-blind RCT, Behavioral, socialization, No SAE Miller et al. (95) :5 children crossover. Five days of anxiety, and appetite PWS 5–11 intranasal oxytocin or 5 endpoints improved years days of intranasal with oxytocin vs

placebo spray, followed placebo but this was R156 by a 4-week washout not statistically via freeaccess period, and then significant (day 6 and patients returned for 5 14) days of treatment with the alternate source European Journal of Endocrinology

Carbetocin Intranasal 1 ongoing (phase III) NCT03649477 Review (oxytocin analog) n = 37 PWS Double-blind RCT, 14 days Statistically significant No SAE Dykens et al. (76) 10–18 carbetocin or placebo reduction in years hyperphagia total score at study end for patients under carbetocin (−15.6) vs patients receiving placebo (−8.9; P = 0.029) DCCR = diazoxide Daily oral 2 ongoing (phase III) NCT03714373, choline controlled NCT03440814 release tablets C Poitouandothers n = 13 PWS 10-week open label Decrease of the peripheral edema, Kimonis et al. (79) 11–21 treatment period, hyperphagia score transient increases years followed by a 4-week (−4.32, n = 11, in glucose double-blind, placebo- P = 0.006), especially in controlled treatment patients with moderate period to severe baseline hyperphagia and in subjects treated with the highest dose RM493/ Daily s.c. 1 completed (phase II) in Clinically meaningful NCT02311673 Setmelanotide PWS adults (16–65 weight loss despite years) only modest

improvement in Treatments ingeneticobesity hyperphagia (with the highest dose, longest period) Bifidobacterium Oral 1 completed (phase III) No posted results NCT03548480 animalis spp. Lactis (probiotic) Fibers (gut Oral 1 ongoing NCT04150991 microbiota) AZP-531/Livoletide Daily s.c. 1 ongoing (phase II) NCT03790865 Downloaded fromBioscientifica.com at09/30/202101:43:16PM n = 47 PWS Double-blind RCT: 14 days Hyperphagia score No SAE Allas et al. (78) 13–46 of double-blind reduced significantly years treatment (AZP-531 or with AZP-531. No

https://eje.bioscientifica.com placebo) change in body weight but reduction in waist

circumference and fat 183 mass. :5 GLWL-01, ghrelin Oral n = 19 PWS Double-blind RCT Hyperphagia score post No SAE NCT03274856 O-acyltransferase mean 22 crossover. Four weeks treatment (0 to 36): (GOAT) inhibitor years of double-blind 15.9 (1.21) in GLWL-01 treatment (GLWL-01 vs subjects vs 14.7 (1.23)

placebo) in placebo subjects R157 via freeaccess (Continued) European Journal of Endocrinology https://eje.bioscientifica.com

Table 1 Continued. Review

Type of genetic Pharmaceutical Mode of Number of Methodology/trial (number, obesity molecule administration cases phase, status) Results Adverse events References Exenatide Daily s.c. n = 10 PWS Open-label, non- Appetite scores No SAE Salehi et al. (80) 13–25 randomized, significantly decreased years longitudinal study (6 from baseline (32.2 ± months) 8.7) after 6 months of treatment (25.4 ± 7.2; p = 0.004). HbA1c significantly decreased but not weight Liraglutide Daily s.c. 1 ongoing (phase III) NCT02527200 n = 1 Case report Decrease in weight at Unknown Senda et al. (81) C Poitouandothers 1 year of treatment (−5.7 kg) n = 1 Case report Decrease in weight at Unknown Cyganek et al. (82) 14 weeks of treatment (−3.2 kg) Tesofensine/ Oral 1 completed (phase II) in Decrease of weight after Exacerbation of NCT03149445 metoprolol PWS adults 18–30 y 8 weeks (4.8 kg, n = 5), behavioral Tan et al. (69) after 13 weeks (7.9 kg, problems and CNS n = 2), vs placebo. disorders. Reduction in the total hyperphagia score

(from 10 to 1 after 8 Treatments ingeneticobesity weeks and 0 after 13 weeks). Octreotide Monthly i.m. n = 9 PWS 56-week prospective, No effect on BMI, on Transient elevation of De Waele et al. (96) 10.8–18.9 randomized, cross-over appetite or compulsive glucose (2), years trial behavior toward food gallstones (3) Topiramate Oral n = 62 PWS RCT study during 8 weeks Significant improvement In the topiramate Consoli et al. (77) 12–45 in the hyperphagia group, 4 cases of years behavior and severity sedative effects or scores with topiramate psychomotor vs placebo. slowdowns, Downloaded fromBioscientifica.com at09/30/202101:43:16PM 4 biological modifications in hepatic function, 4 cases of hyperammonemia,

and 2 infectious 183 episodes :5 R158 via freeaccess European Journal of Endocrinology

Deep brain Implantation of n = 4 PWS Prospective study, Mean 9.6% increase in 2 infections, one Franco et al. (97) Review stimulation electrodes in 18–28 non-randomized: weight, 5.8% increase associated with the lateral years titration (1–2 months), in body mass index skin picking hypothalamic stimulation off (2 area months), low-frequency DBS (40 Hz; 1 month), washout (15 days), high- frequency DBS (130 Hz; 1 month), and long- term follow-up (6 months). Transcranial direct Transcranial n = 32. Double blind, sham- In PWS, significant change No SAE Bravo et al. (98) current 10 adult controlled, multicenter from baseline in TFEQ stimulation PWS, study. PWS and Obese: (Three-Factor Eating 11 adult five consecutive daily Questionnaire) C Poitouandothers obese sessions. Healthy : a disinhibition (P < 0.05, and single session. 30 days) and total 11 adult scores ( P < 0.02, 30 healthy- days), and participant weight ratings of the DHQ control (Dykens Hyperphagia subjects Questionnaire) severity (P < 0.06, 5 days) and total scores (P < 0.05, 15 days). Cannabidiol Oral solution 1 (phase II) Terminated because of NCT02844933

bankruptcy (phase II) Treatments ingeneticobesity Rimonabant Oral 1 (phase II) Drug withdrawn NCT00603109 Beloranib Biweekly s.c. n = 107 PWS RCT study (1:1:1) to Compared with placebo, 4 venous thrombotic Mc Candless (methionine 12–65 biweekly placebo, weight change was events in the et al. (83) aminopeptidase 2 years 1.8 mg beloranib or greater with 1.8 mg beloranib group inhibitor) 2.4 mg beloranib (mean difference (2 fatal events of injection for 26 weeks. −8.2%, 95% CI −10.8 to pulmonary −5.6; P < 0.0001) and embolism). 1 2.4 mg beloranib mental status (−9.5%, 95% CI −12.1 change, 1

Downloaded fromBioscientifica.com at09/30/202101:43:16PM to −6.8; P < 0.0001) aggression in the beloranib group. Precocious halting of the study. https://eje.bioscientifica.com Bardet-Biedl RM493/ Daily s.c. 2 ongoing (phases II NCT03746522, setmelanotide and III) NCT03013543 Alström RM493/ Daily s.c. 2 ongoing (phases II NCT03746522, 183

setmelanotide and III) NCT03013543 :5 Smith Magenis RM493/ Daily s.c. 1 ongoing (phases II NCT03013543 setmelanotide and III) 16p11.2 deletion RM493/ Daily s.c. 1 ongoing (phases II NCT03013543 (including SH2B1 setmelanotide and III) R159 gene) (SH2B1 deficiency

via freeaccess obesity)

(Continued) European Journal of Endocrinology https://eje.bioscientifica.com

Table 1 Continued. Review

Type of genetic Pharmaceutical Mode of Number of Methodology/trial (number, obesity molecule administration cases phase, status) Results Adverse events References Pseudohypo Rimonabant Oral n = 1 Case report BMI 40.5 to 33.5 (−16 kg No SAE Al Salameh parathyroidism in 6 months). et al. (84) Treatment withdrawn in October 2008. Theophylline Oral 1 not yet recruiting NCT04240821 (phase II) Monogenic Leptin Recombinant Daily s.c. n = 1 child Open-label study, Loss between 2 and 19 kg Antibodies anti-leptin Farooqi et al. human leptin (1999) non-randomized. of fat mass during 6–48 (99, 100)

and n = 3 months of treatment, C Poitouandothers children with reduction in (2002) energy intake (45–84%) at 2 months. Leptin receptor RM493/ Daily s.c. 3 ongoing, including long NCT03287960, setmelanotide term treatment NCT03651765, (phases II and III) NCT03013543 n = 3, 14–23 Open-label study, Loss between 10–25 kg in Darkening of skin Clément et al. (93) years non-randomized. 13-61 weeks of and a change in Setmelanotide treatment with a hair color treatment in 3 patients decrease in hunger carrying homozygous score pathogenic variant in Treatments ingeneticobesity leptin receptor Propiomelanocortin RM493/ Daily s.c. 3 ongoing, including long NCT03651765, setmelanotide term treatment NCT03013543, (phases II and III) NCT02896192 n = 2 adults Open-label study, Patient 1 : loss of 51 kg at Darkening of skin Kuhnen et al. (92) 21–26 non-randomized. 42 weeks, Patient 2 : and a change in years Setmelanotide loss of 20.5 kg at hair color treatment in 2 patients 12 weeks carrying homozygous/ compound Downloaded fromBioscientifica.com at09/30/202101:43:16PM heterozygous pathogenic variant in POMC Thyroid hormone ACTH: n = 2 Open-label study, No weight loss with Not reported Krude et al. (24) and ACTH4–10 intranasal. children non-randomized. ACTH4–10 after 3

Thyroid ACTH/thyroid hormone months treatment and 183 hormone: treatment of 2 patients with levothyroxin after oral carrying homozygous/ 1-year treatment :5 compound heterozygous pathogenic variants in

POMC. R160 PCSK1 RM493/ Daily s.c. 2 ongoing (phases II NCT03651765, via freeaccess setmelanotide and III) NCT02896192 European Journal of Endocrinology

MC4R RM493/ Continuous s.c. n = 8 adults, Double blind RCT (phase Significant weight loss in Darkening of skin Collet et al. (94) Review setmelanotide infusion 22–57 1b). Patients carrying MC4R variant carriers years heterozygous variants at Day 29 (−3.48 kg in MC4R and healthy (−4.99, −1.96)), but no obese individuals significant difference from placebo. Sibutramine Oral n = 1 boy, 14 Case report. Patient Sibutramine treatment No SAE Hainerová years carrying a MC4R resulted in et al. (85) homozygous maintenance of weight pathogenic variant and decrease in the (complete LOF). hunger score, after 1 year treatment Liraglutide Subcutaneous n = 42 adults Prospective case–control Liraglutide induced an Gastrointestinal side Iepsen et al. (86) study not randomized. equal, clinically effects, no serious 14 obese adults with significant weight loss adverse event C Poitouandothers pathogenic MC4R of 6% in both groups variants and 28 (at 16 weeks) matched control without MC4R variant

This table summarizes ongoing and completed (with or without published results) pharmaceutical interventions in syndromic and monogenic non syndromic obesity, targeting weight loss or food behavior. Search was performed using Pubmed research (keywords: syndrome name AND therapy OR treatment OR clinical trial OR therapeutics) and using ClinicalTrials.gov website. BMI, body mass index; LOF, loss of function; MC4R, melanocortin 4 receptor; PCSK1, proprotein convertase subtilisin/kexin type 1; POMC, propiomelanocortin; PWS, Prader–Willi syndrome; RCT, randomized controlled trial; SAE, serious adverse event; CNS, central nervous system; LOF, loss of function. homozygous pathogenicvariantof of psychiatricside-effects. on weightbutthisdrugwaswithdrawnin2008because pseudohypoparathyroidism ( been triedinPWS(NCT00603109)andapatientwith Rimonabant, aCB1cannabinoidantagonistreceptor, has the caseofhomozygousvariants of of theendogenousMC4Rligand (aMSH),inparticular now makesitpossibletoreplace thelackorinefficiency of MC4R( genetic alterations in the melanocortin pathway upstream launching clinicaltrialswiththismoleculeinpatients effects, andstimulatesfatoxidation( energy expenditureatrest,withoutcardiovascularside ( sensitivity, withnoeffectonbloodpressure orheartrate total energyexpenditure,weightloss,andimprovedinsulin human primatesledtodecreasedfoodintake,increased the MC4R(RM-493orsetmelanotide)for8weeksinnon- However, the useofanotherhighlyselectiveagonist of majoradverseeffectsonheartrateandbloodpressure. MC4R agonist(LY2112688) ledtodisenchantmentbecause with MC4Rstimulation( the increasedriskofelevatedbloodpressureandheartrate MC4R invitro( to restorenormalactivityofsomemutatedformsthe Of note,newMC4Rpharmacologicalagonistswereshown of new pharmacologicalagoniststhatactontheMC4R. recently, thepicturehaschanged,withdevelopment leptin/melanocortin pathway alterations in monogenic leptin/melanocortin pathwayalterationsinmonogenic linked obesity( that themoleculecanalsobepro-satietogenicin non-carriers (approximately6%weightloss),suggesting mg liraglutide/day for 16 weeks was equivalent to that of MC4R including liraglutide,havebeentestedinpatientswith effect onweightloss( pathogenic variants of two patients carrying combining thyroidhormoneswithintra-nasalACTHin convincing resultsonweightloss( given seriousadverse effects (thrombotic events) ( and rapideffectonthereductioninfoodintake( mainly linkedtoareductioninfatmass,withsignificant injectable s.c. leptin treatment, resulting in weight loss, with congenitalleptindeficiencywereeligiblefordaily clinical conditions. Until now, only the rare patients pathway should be valuable in treating these severe and syndromicobesity, specificallytargetingthis Treatments ingeneticobesity 90 ). Similarly, treatmentofhumanswithRM-493increases Sibutramine was tested in a patient carrying a a Sibutramine wastestedinapatientcarrying These promising results have paved the way to These promisingresultshavepavedthewayto variants.Weight lossof Table 1 88 86 ). The use of this MC4R agonist indeed ). TheuseofthisMC4Ragonist indeed ). However, therewereconcernsabout ). However, giventheimportanceof 24 Downloaded fromBioscientifica.com at09/30/202101:43:16PM ). Morerecently, GLP-1analogs, 89 ). The first development of an ). Thefirstdevelopmentofan 84 MC4R https://eje.bioscientifica.com ) withinterestingresults POMC 91 variant carriers on 3 variantcarrierson3 183 ). 85 :5 MC4R

). A treatment ). Atreatment ( 31 POMC ) or , without , without 87 LEPR had no had no ). More ). More R161 MC4R 83 . In . In via freeaccess ). - European Journal of Endocrinology https://eje.bioscientifica.com of raregeneticobesityshould leadtoabetterprognosis management The earlydiagnosisandmultidisciplinary Conclusion patients withraregeneticformsofobesityinthefuture. potential innovativetreatmentsthatcouldbenefit of theirfunctionality, inparticularMC4R, areother melanocortin pathway activating receptors or restoration these patients. on theskin,resultingingeneralizedhyperpigmentation of as setmelanotidealsoactivatestheMC1Rreceptorlocated given tothechronicstimulationofmelanocytes,insofar will bemonitored.Particularattentionshouldprobably ( syndromes andtheimpairedfunctionofPOMCneurons and 16p11.2deletion,becauseofthelinksbetweenthese such as BBS, Alström syndrome, Smith-Magenis syndrome, molecule isalsobeingtestedforothersyndromicobesities, in patientswithcertainheterozygous variants for the homozygous, heterozygous,orcompoundheterozygous inpatientswith trials withsetmelanotideareunderway the type of response,dependingon and inhumans,withavarying setmelanotide caninduceweightlossinmousemodels variants. Moreover, itappearedthattreatmentwith restoring signalinginasubgroupofpatientswiththese was moreefficientthantheendogenousligand,aMSH, in heterozygous pathogenicvariantsof from thistreatment.Incellmodelsexpressingvarious those withheterozygousvariantsin of setmelanotide and whether other patients, such as Questions remainconcerningthelong-termefficiency and irritationatthesiteofsetmelanotideinjection. Side effectsconsistmostlyofincreasedpigmentation serious adverseeventshavebeennotedinthesepatients. Importantly, noelevationinbloodpressureorother overeating overfollow-upperiodsof45–61weeks( variant of effectiveness inpatientswithahomozygouspathogenic hyperphagia scores( two patients)andarapidsustainedimprovementin after 42and12weeksoftreatment,respectively, forthe was associatedwithweightloss( ahomozygousvariantof carrying Germany), weshowedthatthetreatmentoftwopatients 2016, togetherwithP. Kuhnen(CharityBerlinHospital, Table 1 Review New developmentstargetingantibody-type ). Potential medium- and long-term side effects ). Potentialmedium-andlong-termsideeffects LEPR MC4R in terms of weight loss and reduction of intermsofweightlossandreduction POMC, LEPR variant involved ( 92 ). Setmelanotide has also shown its ). Setmelanotidehasalsoshownits , and POMC C Poitouandothers PCSK1 94 − MC4R MC4R, 51.0 and MC4R ). Currently, clinical with setmelanotide withsetmelanotide genes, as well as genes, as well as , setmelanotide , setmelanotide variants. This variants.This could benefit could benefit − 20.5 kg 20.5 kg 93 ). ).

Karine Clément is consultant for Danone Research, LNC-therapeutics and LNC-therapeutics Research, Danone for consultant is Clément Karine Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest of patientswithgeneticobesity. pathway, andcouldchangetheclinicalcareprognosis for PWSandabnormalitiesoftheleptin/melanocortin worsen. Newtreatmentsnowshowpromise,particularly this criticalperiod,whenbehavioralproblemsandobesity adolescents sufferingfromgeneticobesitymustfocuson and coordinatedcare).Anessentialeffortforthefutureof integration intomedico-socialstructures,comprehensive both themedicalandsocialaspectsoftheircare(lifeplan, critical moment, often associated with disruptions of between pediatriccareandadultmedicineremainsa for thesepatientsinadulthood.However, thetransition References thanks toPHRC(ProgrammeHospitalierdeRechercheClinique). for supports Previous genetic research was sponsored by Assistance-Publique Hôpitaux de Paris protocols. these in involvement family their and patients thank authors The Pharma. Alize by and sponsored pharmaceuticals arecurrently Rhythm protocols investigation Clinical field. this in work support to obtained funding as well as manuscript, the of reading The authors thank William Hempel of Alex Edelman & Associates for critical Acknowledgements these for received activities thatwouldalterthecontentofthispresentreview. been has funding personal No Confo-Therapeutics. Treatments ingeneticobesity 6 5 4 3 2 1 Goldstone AP, Holland AJ,Hauffa BP, Hokken-Koelega AC,Tauber M Tauber M, Thuilleaux D&Bieth É.LesyndromedePrader-Willi en Lloret-Linares C, Faucher P, Coupaye M,Alili R,Green A, Kaur Y, deSouza RJ, Gibson WT&Meyre D.Asystematicreviewof Huvenne H, Dubern B,Clément K&Poitou C.Raregeneticformsof Kleinendorst L, Massink MPG,Cooiman MI,Savas M,vander & speakerscontributorsattheSecond ExpertMeetingofthe medsci/20153110011) 2015. (https://doi.org/10.1038/ijo.2012.228) obesity.primary with PraderWilli syndromeorlesionalhypothalamicdisease,with composition, basalmetabolicrateandoutcomesofadults Basdevant A, Clement K&Poitou C.Comparisonofbody (https://doi.org/10.1111/obr.12531) genetic syndromeswithobesity. Facts obesity: clinicalapproachandcurrenttreatmentsin2016. jmedgenet-2018-105315) of generation sequencingresultsof1230patientswithobesity. Knoers NVAM, PloosvanAmstel HK Baan-Slootweg OH, Roelants RJ,Janssen ICM,Meijers-Heijboer HJ, Med 2016 Medecine Sciences ical Genet 9 158–173. ics Int 2018 ernational (https://doi.org/10.1159/000445061) 2015 55 Downloaded fromBioscientifica.com at09/30/202101:43:16PM 578–586. 31 J ournal 853–860. Obes

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