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Connaître et comprendre les associations entre anomalies du neuro-métabolisme et pathologies psychiatriques
Vers un algorithme efficace ?
Olivier Bonnot, MD, PhD!Department of Child and Adolescent Psychiatry!
University of Nantes, [email protected] website: www.u2peanantes.org!
!Tours,November29th
Reportofpoten5alconflictofinterest
• Actelion(AdBoardandHonoraria)• Orphan-Europe(Honoraria)• Lundbeck(Honoraria) • Sunovion(Honoraria)• Shire(Honoraria)
Objectives!
• What are we talking about ?!
• Why is that important for psychiatrists ?!
• How could we improve diagnosis in Psychiatric population ?!
!
General Considerations!
• Organic disorders are poorly recognized in psychiatric patients!
• Prevalence is unknown except in few sub-samples!
• Cross-discipline diseases are obviously more difficult to diagnose!
Nutritional deficiency !Pellagra!
(Vitamin B3 deficiency)!Biermer!
(Vitamin B12 deficiency) Bushman 1999! Other vitamin deficiency?!
Endocrine diseases!Addison’s Disease! Cushing's Disease Hirsh 2000!
Dysregulation of thyroid and !hyper-parathyroid!
Inborn errors of metabolism!Homocysteine metabolism disorders (MTHFR and CBs)
Reif 2005!
Wilson’s Disease Wichovicz 2006!
Urea cycle disorders!Porphyria Ellencweig 2006 !
Niemann-Pick disease Type C!Xanthomatosis!
Infectious diseases!Cerebral abscess! Encephalitis (HSV ++)! Neuro-syphilis!
Auto-immune diseases!Chorea / Multiple Sclerosis! Lupus / Sarcoidosis! NMDA !
Chromosomal abnormalities! Mac Carthy, Nat Genet 2009; Ingason, Mol Psy, 2011; Abdolmaleky, Am J Med Genet 2005, Stefansson, Nature 2009; Levinson, Am J Psy 2011!
!
1q21, 2p53, 2q29, 15q11.2, 15q11.3, 17q12, 22q11.2! NRXN1 (Neurexin 1)! 7q36.3, 25q11-13, 16p11.2, 16p13.1!
Other CNS diseases! Toxic ! Medication !Epilepsy ! ! !
Main Organic Disorders in Schizophrenia!
FromBonnotO.2015FrontinNeurosciences
Pathology! % in ASD! % with ASD! Genes!Fragile X! 2–5%! 20–40%! FMR1!Tuberous Sclerosis! 3–4%! 43–86%! TSC1-TSC2!Duplication 15q!Angelman / Prader Willi! 1–2%! sup 40%! UBE3A!
GABAr!22q11 deletion!16p11 deletion! 1 %! High but
unknown!SHANK3!PCKB1!
2q37 deletion! ?! 50! K1F1A, GBX2!Joubert Syndrome! ?! 40%! AH1!Timothy Syndrome! ?! 60–70%! CACNA1C!
Focal Cortical Epilepsy with dysplasia! ?! 70%! CNTNAP2!
Main Genetic Disorders in ASD
ASD, autistic spectrum disorder!
Diseases! ASD + associated signs! Diagnosis! Treatment!
Phenylketonuria! Neonatal onset, seizure, microcephaly, musty and mousy odour!
Phenylpyruvic acid in urine!Plasma amino acids analysis!
Restricted diet!Amino acids!
Adenylosuccinase deficiency! Profound retardation!first year!epilepsy, hypotonia!
Succinyl aminoimidazole, carboxamine riboside and succinyl adenosine in urine and CNS!
D-Ribose!
Creatine deficiency! Mental retardation, hypotonia, epilepsy, dyskinetic movements, regression +++!
Blood and urinary creatinine, MRI, Spectroscopy! Oral creatine!Arginine restriction!Ornithine substitution!
Smith-Lemli-Opitz! Onset in infancy, mental retardation, sensory hyperactivity, sleep disturbance, hypotonia, …!
Abnormal sterol pattern (low plasma and tissue cholesterol and increased plasma and tissue !7-dehydrocholesterol reductase)!
Cholesterol replacement therapy!
Serotonin deficiency ! Various! CNS serotonin level! Serotonin + L-Dopa?!
Cerebal folate deficiency! Ataxia, abnormal movement!Controversial!
CNS folate! Folic acid!
Xantomatosis Cerebo-Tendinous!With Aad Verrig Niemegen 12 cases !
Xantome! Cholesteanol in blood sample! Chenodesoxycholic acid!
Main IEM in ASD
ASD, autistic spectrum disorder; CNS, central nervous system; IEM, inborn error in metabolism; MRI, magnetic resonance imaging
Tableau I – Principales causes de retard mental : classification, étiopathogénie, et fréquence estimée (d’après Szymanski et Bryan, 1999)!
Classification! Exemples! Etiopathogénie!
Causes prénatales d’origine génétiquea – 32 %!
Aberrations chromosomiques ! Syndrome de Down ou Mongolisme! 95 % : trisomie 21 (non transmise) ; 5 % : translocation (peut être transmise) !
Mutations monogéniques!X Fragile!
Phénylcétonurie!Sclérose tubéreuse!
Lié à l’X ; répétition CGG > 230!Autosomique récessif ; déficit enzymatique!
Autosomique dominant!
Multifactoriel! Retard mental « familial »! Mixte: génétique, environnementale…!
Microdélétion!
Syndrome Vélo-Cardio-Facial!Syndrome de Prader-Willi!Syndrome d’Angelman!
Syndrome de Williams-Beuren!
Délétion sur le chromosome 22 (q11)!Délétion sur le chromosome 15 (q11-q13) d’origine paternelle!Délétion sur le chromosome 15 (q11-q13) d’origine maternelle!
Microdelétion du chromosome 7 (q11.23)!
Metaboliques! 82 causes de pathologies neurométaboliques! enzymatiques!
Causes prénatales d’origine externe – 12 %!
Infections maternelles! Infection VIH! Encéphalopathie virale!
Causes toxiques! Syndrome d’alcoolisme fœtal! Exposition in utero à l’alcool!
Causes obstétricales! Prématurité! Variable, multifactorielle!
Malformations d’origine inconnue – 8 %!
Malformations du SNC! Non fermeture du tube neural! Parfois associé à une hydrocéphalie!
Syndrome poly-malformatifs! Syndrome de Cornelia de Lange! Inconnue!
Causes périnatales – 11 %!
Infections! Encéphalite! Infection au virus Herpes Simplex 2!
Problèmes pendant la délivrance! Anoxie néonatale! Variable, infarctus cérébral!
Autres! Hyperbilirubinémie! Incompatibilité rhésus mère enfant!
Causes post natales – 8 %!
Infections! Encéphalite! Infection virale ou bactérienne!
Causes toxiques! Saturnisme! Intoxication au plomb!
Psychosocial! Pathologie de déprivation! Malnutrition, abus, négligence, dépression anaclitique!
Autres! Traumatismes ou tumeurs cérébrales! Variable, atteinte du SNC!
Causes inconnues – 25 %!
a Le changement dans le matériel génétique n’est pas toujours hérité des parents!
VanKarnebeeketal.,201482treatablecausesofIEMinIntellectualDeficiency
IEMinPsychiatry• Lysosomaldisorders,• Metachroma5cleucodystrophy,• Fabry,• Gaucher,• Tay-Sachs,• NeuronalCeroidLipofuscinosis,• α-MannosidosisTypeII,• PeroxisomalDisorders,X-linked
Adrenoleukodystrophy,• MapleSyrupUrineDisease,
• Pelizaeus-MerzbacherDisease,• MyoclonicEpilepsywithRaggedRed• Fibers(MERRF),• WolframDisease(DIDMOAD)• ands5llother
FindthecompletelistinWalterfang,Bonnotetal.2016fromKaplan&Sadock’sComprehensiveTextBookofPsychiatry
CascliniqueUnhistoireclassique• TDAHà6ans• DI+TOP+TDAH+Tb
Dynamiquefam=ESenInternat
• 18ans=Sansprojet
Despointsd’alerte(Faible)• Opéréd’unpiedcave(pes
cavus)• Diarrhéechronique
• Polyneuropathiedistaleal’EEGà18ans
XanthomatoseCerebroTendineuse
• Cholesteanolsanguin• Confirma5onmoléculaire
• AcideChenodesoxycholique=250mgX3
• Pasd’autretraitement
Bonnotetal,CNSSpectrum2010
Bonnotetal,CNSSpectrum2010
+speedinwri5ng
WhatareInbornErrorsofMetabolism?
Substrate Product
Supplementa5onDietChelator
Enzyme
ENZYME
• Allinherited• Underes5matedprevalenceingeneralpopula5on(4/10000?,Tooleetal.,2000)• Psychiatricsignscommonlyassociated.
PossibleimportantunderesJmaJonInpsychiatricpopulaJon
AreIEMfrequentinpsychiatricpopula5on?
LysosomalstoragediseaseAcomplexmetabolicpathway Epidemiologicalstudyintargeted
populaJon(Devdisorders)
• 300pa5ents,age15-35• Largegroupoffacili5esfor
disabili5es(ADAPEI)• Largeinclusioncriteria• Exclusion;knownorganic
disease
LysosomalstoragediseaseAcomplexmetabolicpathway Epidemiologicalstudyintargeted
populaJon(Devdisorders)
• 300pa5ents,age15-35• Largegroupoffacili5esfor
disabili5es(ADAPEI)• Largeinclusioncriteria• Exclusion;knownorganic
disease
LysosomalstoragediseaseAcomplexmetabolicpathway Epidemiologicalstudyintargeted
populaJon(Devdisorders)
• 300pa5ents,age15-35• Largegroupoffacili5esfor
disabili5es(ADAPEI)• Largeinclusioncriteria• Exclusion;knownorganic
disease
PsychosisCogDis
Psychosis
PsychosisCogDis
MoodDis
LysosomalstoragediseaseAcomplexmetabolicpathway Epidemiologicalstudyintargeted
populaJon(Devdisorders)StartedSept2016
• 350pa5ents,aged15-35• Medico-socialassocia5ons
(ADAPEI)• IntheNantesarea.• Wideinclusioncriteria• Exclusion:previouslyknown
organicdisease
nature: lysosphingolipids=sphingolipiddegrada5onproductslysoSM509("lysoSM(SPC)+CO2"),otherlysosphingolipids,lysosphingolipid-panels
scienJficevidence: Welford et al. 2014 (PLoS One), Giese et al. 2015 (OJRD)
availability: currentlyonecommerciallabonly,otherlabscatchup,overallcapaci5eshigh
efficiency: sensitive (>99%) and specific(96.5%)[LysoSM509]
advantages: drybloodspot,smallbloodsampleonly,easytouse&ship,verystable,noauto-oxida5onorotherfalsifyingprocesses,worksatallages,cheap,quicktestresults,alsoprovidesresultforNPA/B(SMPD1)
limitaJons: newtothescien5ficcommunity,unknownmolecule
LysoSM509BiomarkerAtaGlance
Whyshouldthisbeinteres5ngforpsychiatrists?
HOMOCYSTEINEPATHWAY
• Methyla5on• RNAprocess&Protein• EpigeneJcrole
• Linkedtovariousneurodevelopmentaldisordersinpsychiatry
Disorder! Clinical signs! Context! Eye exam!
(CbS)!
Thromboembolism!Scoliosis!
Marfan-like !Cerebellar signs!
Protein diet!Post-surgery!
Severe myopia !Ectopic lens!
(MTHFR)!Early-onset severe disease usually
associated with microcephaly/ apnea / convulsion!
REMETHYLATION
SimpletotreatSchizophrenia&MoodDisorders
Niemann Pick type C!• AR complex disorder of
lipid storage.!
• Heterogeneous !
clinical presentation!
We did a systematic review
58casesofPSYCHIATRIC&NEUROLOGICALNPCfrom
liqerature
Bonnot et al., J Clin Psy submitted
1-Psychiatricsignsarefirsttoappear2-AgeofdiagnosedNPCis28.5(5yearsa]erneurologicalsigns)
Limits&Context:• Reports• Psychiatricdescrip5ons• NPC+SCHIZ=45-52%• NPC+CogDecline=64%
0
10
20
30
40 Nu
mber
of ca
ses
Psychiatric symptoms
Behaviour Memory loss Schiz-like Cognitive decline
Bonnot et al., J Clin Psy submitted
Most frequent symptom: cognitive decline
CysthioninebetaSynthetase(22q22.3)
• Episodicdepression(10%),chronicdisordersofbehavior(17%),obsessive-compulsivedisorder(5%),andpersonalitydisorder(19%)(n=63)
• Aggressivebehavior• A31yearoldwomanpresentedwithathreeweekhistoryofdeliriumand
inappropriateandlabileaffect
Abboqetal.AmJMedGenet1987Apr;26(4):959-969.LiSC&StewartPM.Pathology1999Aug;31(3):221-224.
Dg:Homocysteinemia^:VitB6
• MarphanLike• Myopia• Thromobosis• Scoliosis• Severe
MethylTetraHydroFolateReductasedeficiency1p36.3(usuallysevereneonatapneamicrocephalia)
• Insidious• Acute(aversurgery)withvisualand/orauditoryhallucina5ons,thoughtdisorder
anddelusions.• Unipolardepression,schizophreniaandbipolardisorders(MTHFRC677Tgene
variant)
• Notuncommun
Maqsonetal.TrendsNeurosci2003Mar;26(3):137-146.RozeEetal.ArchNeurol2003Oct;60(10):1457-1462.GilbodySetal,Americanjournalofepidemiology2007Jan1;165(1):1-13.
Dg:Homocysteinemia^:VitB12-Folate
UreaCircleDisorders• Pathwaystoeliminatenitrogen(variousenzymedefectlevels)• Psychosisaspresenta5onispossible• AtypicalDepressions• LateonsetUCDmaybepresen5ngwitha
psychiatric(essen5allybehavioralandwithhallucina5on)andorganicsigns,especiallyvomi5ng
• Anorexia–likedisorderswithproteinrefusalAggrava5on:Protein//Youth//Valproate//Cor5coïdes
Arnetal.NEnglJMed1990Jun7;322(23):1652-1655.Ennsetal.Obstetricsandgynecology2005May;105(5Pt2):1244-1246.Bachmannetal.Europeanjournalofpediatrics2003Jun;162(6):410-416.Krivitzkyetal.Pediatricresearch2009Jul;66(1):96-101.Legrasetal.Cri5calcaremedicine2002Jan;30(1):241-244.Myersetal.TheAmericanjournalofemergencymedicine1996Oct;14(6):553-557Panlaquietal.Intensivecaremedicine2008Oct;34(10):1922-1924.ThurlowetalAnnalsofclinicalbiochemistry2010May;47(Pt3):279-281.
Dg:Amoniemia^:ProteinerestrictedDiet
WilsonDisease
• copper accumulation in the liver, brain, kidney and skeletal system, caused by reduced excretion in the bile
• Between6yet20y++++• PsychiatricSigns50%---Prese5ng20%++++• Schizophrénielikein10%-WorstedwithAP++++(evenifchelator)• ButalsoMDD/BPD/changeinPersonnalityandbehavoiur
• Visuo-Sap5alImpairementandMemoryLoss.Execu5vefunc5onRathbun,1986;Medalia,1989– Portalaetal.,2002;Deningetal.,1989&Akiletal.,1995
Dg:Copper^:ChelaJon
Porphyria(acuteform)
• accumulation of porphyrins and/or their precursors – delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) – in the liver or bone marrow
• PsychiatricSigns24-70%---Prese5ng40%++++• Hallucina5ons+++++andDeliriumACUTE• 13-year-oldboywithsixepisodesofpsychosiswithvariouspresenta5ons,includingdelusions,hallucina5ons,hypomaniaandcatatonia,butwithnoobviousorganicsigns
Dg:delta-aminolevulinicacid(ALA)andporphobilinogen(PBG)inurine^:injecJonofhumanheminand/orperfusionofcarbohydrates
Disorder! Clinical signs! Context! Eye exam! Biological markers!
Wilson!Tremor!
Dystonia!Dysarthria!
Kayser-Fleischer ring! Coeruloplasmin!
Urea cycle !Confusion!
Abdominal pain!Nausea vomiting!
Protein diet!Post-surgery!
Drugs !(valproate / corticoids)!
Ammoniaemia!
Homocysteinemia (CbS)!
Thromboembolism!Scoliosis!
Marfan-like !Cerebellar signs!
Protein diet!Post-surgery!
Severe myopia !Ectopic lens!
Homocysteiniemia!Methioninemia!
Homocysteinemia (MTHFR)! Early-onset severe disease usually with microcephaly/ apnea / convulsion!
Homocysteiniemia!Methioninemia!
Niemann-Pick !disease Type C!
Dystonia + ataxia Dysarthria!Splenomegaly!
Neonatal icterus!Slow progression!
Supranuclear vertical !Gaze palsy!
Skin-biopsy!Filipin test!
NPC1 and NPC2 gene test!
Cerebrotendinous xanthomatosis! Chronic diarrhoea!Spastic paralysis! Juvenile cataract! Cholesteanoemia!
Porphyria!
Urine black or red!Constipation!Confusion!
Abdominal pain!Nausea / vomiting!
Periodic! Porphobilinogens (URINE)!
Summary of IEM in schizophrenia!
FromBonnotO.2014OrphanetJRareDiseases&2015FrontinNeurosciences
Howtoiden5fyorganicdisordersamongpsychiatricpopula5on?
Atypical Psychiatric Features!
Bonnotetal.,2014OrphanetJrareDisBonnotetal.,2015FrontinNeurosciences
Atypical Psychiatric Signs of Schizophrenia!
No!0!
Slightly!1!
Evident!2!
Main clinical feature!3!
Visual hallucinations more important than auditory!
Confusion!
Catatonia!
Progressive cognitive decline!
Treatment resistance!
Fluctuating schizophrenia core symptoms!
Acute onset!
Early onset!
Intellectual disabilities!
Unusual side effects !(level and type)!
0
1
00
0
3
1
2
1
0
Atypical Psychiatric Features!• Suggest the need for a more extensive
search!
• Are too empirical!
! TheDELPHI–NPCProject
TeamLeaders:Bonnot(Fr),HKluneman,PBauer(De),MWalterfrang(Australia,CGama(Brasil)
Sta5s5calweighofeachatypicalpsychiatricfeatureregardingprobabilityoforganicity
• Usedincancerology…• Basedonexpertsopinion
tobuildconsensus• Fromasta5s5calspecific
method
Categorical variableswill be summarizedwith counts and percentages tabulated by round. In order tofacilitatevisualcomparisonofthevariousques5onsineachround,thesevariableswillbealsotreatedascon5nuous scores and analysed and represented by calcula5ng themean values with 95% confidenceintervals(95%CIs)foreachseveritycategoryfromeachitemandround.Medianandpercen5les25and75willalsobecalculated.Paired testswillbeused toassess changes in responsesbetween the two roundsand foreach severitycategoryfromeachitem.Con5nuousvariableswillbeanalysedbymeansof thepairedStudent’sT test,andcategoricalvariablesusingtheMcNemarorBowkerpairedtests.Comparison between clinical special5es will be performed using the nonparametric sta5s5cal Kruskal–Wallis test for con5nuous variables, and con5ngency tables using Chi-square or Fisher test (whenappropriate)forcategoricalvariables.Atwosided0.05levelofsignificancewillbeusedinallanalyses.
HsuC-C,SandfordBA.TheDelphitechnique:makingsenseofconsensus.PractAssessResEval.2007;12(10):1–8.
Scoring
THEFINALOBJECTIVEISAVALIDATEDALGORITHM
Conclusion!
• Itisnecessarytoiden5fyorganicdisordersandinbornerrorsofmetabolisminpsychiatricpa5ents.
• Atypicalfeaturesofpsychosisareaclearindica5ontoperformanextensivesearchoforganiccauses
• Evenifbiological,psychiatryisfirstlyclinical.
Jevousremerciepourvotreaqen5on.