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, France!olivier.bonnot@chu-nantes.fr 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.

olivier.bonnot@chu-nantes.frwww.u2peanantes.org