The complexrelationship betweenorganicityand psychiatry · PDF fileThe complexrelationship...

The complex relationship between organicity and psychiatryHighlight on neurometabolic disorders

Olivier Bonnot, MD, PhDDepartment of Child and Adolescent Psychiatry

University of Nantes, [email protected] website: www.u2peanantes.org

Beirut,May 2017

Reportofpotentialconflictofinterest

• Actelion (AdBoard andHonoraria)• 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

History

• AntoineLaurentBAYLEin1822: generalparalysis asmodelforpsychiatric disease

• Hideyo NOGUCHI in1913treponem paleidentification

ORGANIC PSYCHIATRY

History

History• Psychoanalysis said there isnocause

• Newfindings suggest acomplex relationshipbetween organicity andpsychiatry

History

OldO/Pornature/nurture dichotomy isnotrelevantanymore

Nutritional deficiencyPellagra

(Vitamin B3 deficiency)Biermer

(Vitamin B12 deficiency) Bushman 1999Other vitamin deficiency?

Endocrine diseasesAddison’s Disease Cushing's Disease Hirsh 2000

Dysregulation of thyroid and hyper-parathyroid

Inborn errors of metabolismHomocysteine metabolism disorders (MTHFR and CBs)

Reif 2005Wilson’s Disease Wichovicz 2006

Urea cycle disordersPorphyria Ellencweig 2006

Niemann-Pick disease Type CXanthomatosis

Infectious diseasesCerebral abscess Encephalitis (HSV ++) Neuro-syphilis

Auto-immune diseasesChorea / Multiple Sclerosis Lupus / Sarcoidosis NMDA

Chromosomal abnormalitiesMac 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 MedicationEpilepsy

Main Organic Disorders in Schizophrenia

FromBonnotO.2015FrontinNeurosciences

Pathology % in ASD % with ASD GenesFragile X 2–5% 20–40% FMR1Tuberous Sclerosis 3–4% 43–86% TSC1-TSC2Duplication 15qAngelman / Prader Willi 1–2% sup 40% UBE3A

GABAr22q11 deletion16p11 deletion 1 % High but

unknownSHANK3PCKB1

2q37 deletion ? 50 K1F1A, GBX2Joubert Syndrome ? 40% AH1Timothy Syndrome ? 60–70% CACNA1C

Focal Cortical Epilepsy with dysplasia ? 70% CNTNAP2

Main Genetic Disorders in ASD

ASD, autistic spectrum disorder

Firstexemple:22q11microdel• C =hypoCa2+• A =Abnomal face,• T =Thymic hypoplasia,• C =Cleft palate• H =Heart defect

CATCH22

22q11:Association1. Schizophrenia 20-35%+=25%

• 22q11inpatientswith SCZ 0.3- 2%• 22q11inpatientswith EOS 5.3%Sporn 2004

2. ADHD35-46%Arnold2001,Feinstein 20023. Mood Disorders 12-20%Anxiety 17-29%4. Autism 14- 45%Antshed 2006,Vorstman 2007

30à56%ofpsychiatric disorders

22q11:Cognition

1. Intellectual Defficiency (30-40%)QIP>QIV2. Attention/Visuo –Spatial3. Dyscalculia (Majerus 2007,Simon2005)

4. SpeechDisorders5. Psychomotor disturbances(VanAken 2007)

Heavyconsequences:70to90%with learning disorders(Hay2007)

LinkstoSCZ:Why

LinkstoSCZ:Why ?• Neurovisual skills impairments,

Parieto frontalunder 4,parieto occipitalbelow

LinkstoSCZ:Why ?• Neurovisual skills impairments,

Dysparaxia andmotor coordinationimpairement areassociated with NSI

What’s thepoint?

NVI

MotorControl

EmpathyVisuo-spatialdyspraxia

What’s thepoint?

NVI

MotorControl

Empathy

Cassidy etal.Molecular Autism(2016)7:48

What’s thepoint?

NVI

MotorControl

Empathy

Thakkar KN, Brugger P, Park S (2009) Exploring Empathic Space: Correlates of Perspective Transformation Ability and Biases in Spatial Attention. PLoS ONE

What’s thepoint?

NVI

MotorControl

Empathy

Nottheonly genetic diseases• FraX• Williams• Turner

• …

Neuroscience.2009November24;164(1):257

Neuroscience.2009November24;164(1):257–271.

ANOTHER FIELD OFORGANIC DISEASEMIGHT BE INTERESTING….

TreatableEthiopathogenicUnderestimated…..

Nutritional deficiencyPellagra

(Vitamin B3 deficiency)Biermer

(Vitamin B12 deficiency) Bushman 1999Other vitamin deficiency?

Endocrine diseasesAddison’s Disease Cushing's Disease Hirsh 2000

Dysregulation of thyroid and hyper-parathyroid

Inborn errors of metabolismHomocysteine metabolism disorders (MTHFR and CBs)

Reif 2005Wilson’s Disease Wichovicz 2006

Urea cycle disordersPorphyria Ellencweig 2006

Niemann-Pick disease Type CXanthomatosis

Infectious diseasesCerebral abscess Encephalitis (HSV ++) Neuro-syphilis

Auto-immune diseasesChorea / Multiple Sclerosis Lupus / Sarcoidosis NMDA

Chromosomal abnormalitiesMac 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 MedicationEpilepsy

Main Organic Disorders in Schizophrenia

FromBonnotO.2015FrontinNeurosciences

Diseases ASD + associated signs Diagnosis Treatment

Phenylketonuria Neonatal onset, seizure, microcephaly,musty and mousy odour

Phenylpyruvic acid in urinePlasma amino acids analysis

Restricted dietAmino acids

Adenylosuccinase deficiency Profound retardationfirst yearepilepsy, 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 creatineArginine restrictionOrnithine 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 movementControversial

CNS folate Folic acid

Xantomatosis Cerebo-TendinousWith 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 monogéniquesX Fragile

PhénylcétonurieSclérose tubéreuse

Lié à l’X ; répétition CGG > 230Autosomique récessif ; déficit enzymatique

Autosomique dominant

Multifactoriel Retard mental « familial » Mixte: génétique, environnementale…

Microdélétion

Syndrome Vélo-Cardio-FacialSyndrome de Prader-WilliSyndrome d’Angelman

Syndrome de Williams-Beuren

Délétion sur le chromosome 22 (q11)Délétion sur le chromosome 15 (q11-q13) d’origine paternelleDélétion 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• Lysosomal disorders,• Metachromaticleucodystrophy,• Fabry,• Gaucher,• Tay-Sachs,• NeuronalCeroid Lipofuscinosis,• α-Mannosidosis TypeII,• Peroxisomal Disorders,X-linked

Adrenoleukodystrophy,• MapleSyrupUrineDisease,

• Pelizaeus-MerzbacherDisease,• MyoclonicEpilepsywithRaggedRed• Fibers(MERRF) ,• WolframDisease(DIDMOAD)• andstillother

FindthecompletelistinWalterfang,Bonnotetal.2016fromKaplan&Sadock’sComprehensiveTextBookofPsychiatry

Cas cliniqueUnhistoireclassique• TDAHà 6ans• DI+TOP+TDAH+Tb

Dynamique fam =ESenInternat

• 18ans =Sansprojet

Despointsd’alerte (Faible)• Opéré d’unpiedcave(pes

cavus)• Diarrhée chronique

• Polyneuropathie distale al’EEG à 18ans

Xanthomatose CerebroTendineuse

• Cholesteanol sanguin• Confirmationmoléculaire

• Acide Chenodesoxycholique=250mgX3

• Pasd’autre traitement

Bonnotetal,CNSSpectrum2010

Bonnotetal,CNSSpectrum2010

+speedinwriting

What areInbornErrorsofMetabolism?

Substrate Product

SupplementationDietChelator

Enzyme

ENZYME

• Allinherited• Underestimatedprevalenceingeneralpopulation(4/10000?, Tooleetal.,2000)• Psychiatricsignscommonlyassociated.

PossibleimportantunderestimationInpsychiatricpopulation

AreIEMfrequentinpsychiatricpopulation?

Lysosomal storagediseaseAcomplexmetabolicpathway Epidemiologicalstudyintargeted

population(Devdisorders)

• 300patients,age15-35• Largegroupoffacilitiesfor

disabilities(ADAPEI)• Largeinclusioncriteria• Exclusion;knownorganic

disease


population(Devdisorders)

• 300patients,age15-35• Largegroupoffacilitiesfor

disabilities(ADAPEI)• Largeinclusioncriteria• Exclusion;knownorganic

disease

PsychosisCogDis

Psychosis

PsychosisCogDis

MoodDis


population(Dev disorders)StartedSept2016

• 350patients,aged15-35• Medico-socialassociations

(ADAPEI)• IntheNantesarea.• Wideinclusioncriteria• Exclusion:previouslyknown

organicdisease

nature: lysosphingolipids =sphingolipid degradationproducts

lysoSM509("lysoSM (SPC)+CO2"),otherlysosphingolipids,lysosphingolipid-panels

scientificevidence: Welford et al. 2014 (PLoS One), Giese et al. 2015 (OJRD)

availability: currentlyonecommerciallabonly,otherlabscatchup,overallcapacitieshigh

efficiency: sensitive (>99%) and specific (96.5%)[LysoSM509]

advantages: drybloodspot,smallbloodsampleonly,easytouse&ship,verystable,noauto-oxidationorotherfalsifyingprocesses,worksatallages,cheap,quicktestresults,alsoprovidesresultforNPA/B(SMPD1)

limitations: newtothescientificcommunity,unknownmolecule

LysoSM509BiomarkerAtaGlance

Whyshouldthisbeinterestingforpsychiatrists?

HOMOCYSTEINEPATHWAY

• Methylation• RNAprocess&Protein• Epigeneticrole

• Linkedtovariousneurodevelopmentaldisordersinpsychiatry

Disorder Clinical signs Context Eye exam

(CbS)

ThromboembolismScoliosis

Marfan-like Cerebellar signs

Protein dietPost-surgery

Severe myopia Ectopic lens

(MTHFR)Early-onset severe disease usually

associated with microcephaly/ apnea / convulsion

REMETHYLATION

Simpletotreat

Schizophrenia&MoodDisorders

Niemann Pick type C• AR complex disorder of

lipid storage.

• Heterogeneous

clinical presentation

We did a systematic review

58casesofPSYCHIATRIC&NEUROLOGICALNPCfrom

litterature

Bonnot et al., J Clin Psy submitted

1- Psychiatricsignsarefirsttoappear2- AgeofdiagnosedNPCis28.5(5yearsafterneurologicalsigns)

Limits&Context:• Reports• Psychiatricdescriptions• NPC+SCHIZ=45-52%• NPC+CogDecline=64%

0

10

20

30

40Nu

mber

of ca

ses

Psychiatric symptoms

BehaviourMemory lossSchiz-likeCognitive decline

Bonnot et al., J Clin Psy submitted

Most frequent symptom: cognitive decline

Cysthionine beta Synthetase(22q22.3)

• Episodicdepression(10%),chronicdisordersofbehavior(17%),obsessive-compulsivedisorder(5%),andpersonalitydisorder(19%)(n=63)

• Aggressivebehavior• A31yearoldwomanpresentedwithathreeweekhistoryofdeliriumand

inappropriateandlabileaffect

Abbottetal.AmJMedGenet1987Apr;26(4):959-969.LiSC&StewartPM.Pathology1999Aug;31(3):221-224.

Dg:Homocysteinemiatt:VitB6

• MarphanLike• Myopia• Thromobosis• Scoliosis• Severe

MethylTetraHydroFolateReductasedeficiency1p36.3(usuallysevereneonatapneamicrocephalia)

• Insidious• Acute (aftersurgery)withvisualand/orauditoryhallucinations,thoughtdisorder

anddelusions.• Unipolardepression,schizophreniaandbipolardisorders(MTHFRC677Tgene

variant)• Notuncommun

Mattsonetal.TrendsNeurosci2003Mar;26(3):137-146.RozeEetal.ArchNeurol2003Oct;60(10):1457-1462.GilbodySetal,Americanjournalofepidemiology2007Jan1;165(1):1-13.

Dg:Homocysteinemiatt:VitB12- Folate

UreaCircleDisorders• Pathwaystoeliminatenitrogen(variousenzymedefectlevels)• Psychosisaspresentationispossible• AtypicalDepressions• LateonsetUCDmaybepresentingwitha

psychiatric(essentiallybehavioralandwithhallucination)andorganicsigns,especiallyvomiting

• Anorexia– likedisorderswithproteinrefusalAggravation:Protein//Youth//Valproate//Corticoïdes

Arnetal.NEnglJMed1990Jun7;322(23):1652-1655.Ennsetal.Obstetricsandgynecology2005May;105(5Pt2):1244-1246.Bachmannetal.Europeanjournalofpediatrics2003Jun;162(6):410-416.Krivitzkyetal.Pediatricresearch2009Jul;66(1):96-

Dg:Amoniemiatt:ProteinerestrictedDiet

Wilson Disease

•copper accumulation in the liver, brain, kidney and skeletal system, caused by reduced excretion in the bile

•Between6yet20y++++•PsychiatricSigns50%--- Preseting20%++++•Schizophrénielikein10%- WorstedwithAP++++(evenifchelator)•ButalsoMDD/BPD/changeinPersonnalityandbehavoiur

•Visuo-SaptialImpairementandMemoryLoss.ExecutivefunctionRathbun,1986;Medalia,1989

– Portalaetal.,2002;Deningetal.,1989&Akiletal.,1995

Dg:Coppertt:Chelation

Porphyria(acuteform)

•accumulation of porphyrins and/or their precursors – delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) – in the liver or bone marrow

•PsychiatricSigns24-70%--- Preseting40%++++•Hallucinations+++++andDeliriumACUTE•13- year-oldboywithsixepisodesofpsychosiswithvariouspresentations,includingdelusions,hallucinations,hypomaniaandcatatonia,butwithnoobviousorganicsigns

Dg:delta-aminolevulinicacid(ALA)andporphobilinogen(PBG)inurinett:injectionofhumanheminand/orperfusionofcarbohydrates

Disorder Clinical signs Context Eye exam Biological markers

WilsonTremor

DystoniaDysarthria

Kayser-Fleischer ring Coeruloplasmin

Urea cycle Confusion

Abdominal painNausea vomiting


Drugs (valproate / corticoids)

Ammoniaemia

Homocysteinemia (CbS)

ThromboembolismScoliosis

Marfan-like Cerebellar signs


Severe myopia Ectopic lens

HomocysteiniemiaMethioninemia

Homocysteinemia (MTHFR)Early-onset severe disease usually

with microcephaly/ apnea / convulsion

HomocysteiniemiaMethioninemia

Niemann-Pick disease Type C

Dystonia + ataxia DysarthriaSplenomegaly

Neonatal icterusSlow progression

Supranuclear vertical Gaze palsy

Skin-biopsyFilipin test

NPC1 and NPC2 gene testCerebrotendinous

xanthomatosisChronic diarrhoeaSpastic paralysis

Juvenile cataract Cholesteanoemia

Porphyria

Urine black or redConstipationConfusion

Abdominal painNausea / vomiting

Periodic Porphobilinogens (URINE)

Summary of IEM in schizophrenia

FromBonnotO.2014OrphanetJRareDiseases&2015FrontinNeurosciences

Howtoidentifyorganicdisordersamongpsychiatricpopulation?

Atypical Psychiatric Features

Bonnotetal.,2014OrphanetJrareDisBonnotetal.,2015FrontinNeurosciences

Atypical Psychiatric Signs of Schizophrenia

No0

Slightly1

Evident2

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)

Statisticalweighofeachatypicalpsychiatricfeatureregardingprobabilityoforganicity

• Usedincancerology…• Basedonexpertsopinion

tobuildconsensus• Fromastatisticalspecific

methodCategorical variables will be summarized with counts and percentages tabulated by round. In order tofacilitate visual comparison of the various questions in each round, these variables will be also treated ascontinuous scores and analysed and represented by calculating the mean values with 95% confidenceintervals (95 % CIs) for each severity category from each item and round. Median and percentiles 25 and75 will also be calculated.Paired tests will be used to assess changes in responses between the two rounds and for each severitycategory from each item.Continuous variables will be analysed by means of the paired Student’s T test, and categorical variablesusing the McNemar or Bowker paired tests.Comparison between clinical specialties will be performed using the nonparametric statistical Kruskal–Wallis test for continuous variables, and contingency tables using Chi-square or Fisher test (whenappropriate) for categorical variables.A two sided 0.05 level of significance will be used in all analyses.

HsuC-C,SandfordBA.TheDelphitechnique:makingsenseofconsensus.PractAssessResEval.2007;12(10):1–8.

Scoring

THEFINALOBJECTIVEISAVALIDATEDALGORITHM

Conclusion

• Itisnecessarytoidentifyorganicdisordersandinbornerrorsofmetabolisminpsychiatricpatients.

• Atypicalfeaturesofpsychosisareaclearindicationtoperformanextensivesearchoforganiccauses

• Evenifbiological, psychiatryisfirstlyclinical.

• Interestingintermofetiopathogeny anddevlopemental processes.

[email protected]

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