1

Dott. Francesco Borghini psichiatra, docente di psicobiofisica medica (PBFM)

nel Corso di Specializzazione in psicoterapia, "Scuola di Formazione Psicosomatica",

Ospedale "CRISTO RE" Roma. frabor@tiscali.it

1 LEZIONE di PBFM 3° anno

A.A. 2011-2012

2

PBF nelle psicosi

Disturbi Pervasivi dello Sviluppo (DPS)

3

Disturbi Pervasivi dello Sviluppo (DPS) Quadro clinico caratterizzato da:

precoce e generalizzata alterazione in diverse aree dello sviluppo. Essi comprendono:

il Disturbo Autistico, la Sindrome di Asperger, la Sindrome di Rett, il Disturbo Disintegrativo dell’Infanzia, i DPS non altrimenti specificati (NOS).

4

5

Il Disturbo Autistico Pervasive Developmental Disorder (PDD-DPS)

del DSM-IV e del ICD10 Grave compromissione della TRIADE:

interazione sociale, linguaggio comunicativo e gioco simbolico, iniziata prima dei 3 anni.

Frequenza 10-20/10.000; M>F 4:1 75% con ritardo mentale. Associate atipie comportamentali:

iperattività, auto-etero aggressività, ed alterata regolazione affettiva con intense crisi di angoscia.

6

•  An Update on Autism -- Perspectives and Treatment Andrew N. Wilner, MD Posted: 08/19/2010

•  Autism is a common disorder of children that presents with a spectrum of neurobehavioral and cognitive disorders, particularly problems with socialization, communication, and repetitive behaviors. There are no biologic markers for autism. The diagnosis is clinical, based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). Lack of timely development of language, or regression in communication skills, are indications for an evaluation for autism (Tab.1). Multiple diagnostic tools are available to assist clinicians in the assessment of a child with suspected autism (Tab.2).

7

•  Tab. 1. Absolute Indications for Autism Evaluation

•  No babbling *(baby babbling-vv.youtube), pointing, or other gesture by 12 months

•  No single words by 16 months •  No 2-word spontaneous (not echolalic)

phrases by 24 months •  Any loss of any language or social skills at

any age •  Data from the American Psychiatric Association.[1]

8

•  Tab. 2. Diagnostic Tools •  Diagnostic Parental Interviews •  The Gilliam Autism Rating Scale •  The Parent Interview for Autism •  The Pervasive Developmental Disorders

Screening Test-Stage 3 •  The Autism Diagnostic Interview-Revised •  Diagnostic Observation Instruments •  The Childhood Autism Rating Scale •  The Screening Tool for Autism in 2-Year-Olds •  The Autism Diagnostic Observation Schedule-

Generic

9

•  Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences.

10

Except for Rett syndrome, attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene, the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or non-genetic cause (polimorfismo 5HTT?).

Convincing evidence for multiple interacting genetic factors as the main causative determinants of autism

11

La sindrome di Rett Solo nelle femmine. Tra il 5° e il 48° mese rallentamento della

crescita della circonferenza cranica, perdita delle capacità manuali acquisite, comparsa di stereotipie manuali (tipo lavarsi le mani), rapida regressione cognitiva, disinteresse per l’ambiente sociale, deterioramento motorio, compromissione linguistica, epilessia spesso grave, fino ad un grave definitivo ritardo mentale.

12 mutations of the methyl-CpG-binding protein 2 (MeCP2) gene

La sindrome di Rett

13

.

Epidemiologic studies: environmental factors (toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus) account for few cases.

The "idiopathic" autism is heritable. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent.

14

This suggests that interactions between

multiple genes (epistasi) cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits.

15

•  Neuron. 2010 Oct 21;68(2):187-91.

•  Changing the landscape of autism research: the autism genetic resource exchange.

•  Lajonchere CM; AGRE Consortium. •  Collaborators (18) Brown WT, Bucan M, Cantor R, Constantino J,

Geschwind D, Gilliam TC, Herbert M, Ledbetter DH, Miller J, Nelson SF, Samango-Sprouse C, Schellenberg GD, Shestack J, Spence S, State M, Tanzi RE, Deutsch C, Hallmeyer J.Autism Speaks, Los Angeles, CA 90036, USA. clajonchere@autismspeaks.org

•  Abstract •  Autism Speaks' Autism Genetic Resource Exchange (AGRE)

represents the largest private collection of genetic and phenotype data for families with ASD that is made available to qualified researchers worldwide. The availability of large and comprehensive registries that include detailed phenotype and genetic information for individuals affected with an ASD and family members is crucial for the discovery of autism susceptibility genes and the development and application of biologically based approaches to diagnosis and treatment. The model that AGRE has developed can be applied broadly to other disorders with complex etiologies.

16

Cos’è la Genetica

17 fantasma di determinismo irreversibile !

25 giugno 2000 decodificata

la prima

sequenza del

genoma umano

18

STRUTTURA DEL DNA

     

• L’ADENINA  SI  APPAIA  CON      LA  TIMINA    A  -­‐  T    • LA  GUANINA  SI  APPAIA  CON  LA  CITOSINA    G  -­‐  C    • ELICA  DESTROGIRA  

     

                     

19

20

CARIOTIPO

CARIOTIPO DEI CROMOSOMI UMANI 22 PAIA DI CROMOSOMI AUTOSOMICI ED 1 PAIO DI CROMOSOMI SESSUALI

21

I Geni

•  dirigono lo sviluppo fisico e comportamentale di un essere vivente

•  I tuoi geni regolano il metabolismo degli alimenti, l’uso dei nutrienti e l’eliminazione delle tossine.

•  Il fenotipo può essere considerato come il

prodotto di alcuni geni e dell'interazione di tale prodotto con l'ambiente

•  i tuoi geni sono i tuoi geni per la vita – essi non

cambiano

22

Espressione genica

Cibi, farmaci, attività fisica, tutto può influenzare l’espressione dei geni

23

STRUTTURA DEI GENI EUCARIOTICI

DOGMA CENTRALE

23

24

IL CODICE GENETICO SI LEGGE A TRIPLETTE

24

25

IL CODICE GENETICO E’ UNIVERSALE

•  Phe TTC,TTT •  Leu CTA,CTC,CTG,CTT,TTA,TTG •  Ile ATA,ATC,ATT •  Met ATG •  Val GTA,GTC,GTG,GTT •  Ser AGC,AGT,TCA,TCC,TCG,TCT •  Pro CCA,CCC,CCG,CCT •  Thr ACA,ACC,ACG,ACT •  Ala GCA,GCC,GCG,GCT •  Tyr TAC,TAT

•  His CAC,CAT •  Gln CAA,CAG •  Asn AAC,AAT •  Lys AAA,AAG •  Asp GAC,GAT •  Glu GAA,GAG •  Cys TGC, TGT •  Trp TGG •  Arg AGA,AGG,CGA,CGC,CGG,CGT •  Gly GGA,GGC,GGG,GGT •  Stop TAA,TAG,TGA

26

ll progetto genoma umano ha consegnato alla comunità scientifica internazionale una sequenza genetica di tre miliardi di paia di basi condivisa al 99,9% da tutti gli individui.

A-T C-G

27 27

La variabilità genetica ci rende tutti diversi

… sia all'interno che all'esterno

28

La variazione genetica è antica Più del 90% dei polimorfismi a singolo nucleotide (SNPs), sono polimorfici in tutte le popolazioni…ma la loro frequenza può variare

29

VARIABILITA’ GENETICA:

• Polimorfismi a singolo nucleotide (SNP)

•  Inserzioni

• Delezioni

30 30

Le differenze fra individui sono costituite per la maggior parte da polimorfismi nucleotidici ovvero cambiamenti nelle basi del DNA.

31 31

questi cambiamenti definiti SNP (Single Nucleotide Polymorphism) sono presenti in numero di circa 10 milioni, uno SNP ogni 30 basi circa.

.

32

fra questi, circa 500.000

sono capaci di influenzare il fenotipo individuale

33

Delezione/Inserzione Delezione Inserzione

34

•  Le caratteristiche biofisiche del DNA, sfruttate per l’analisi della sua struttura, delle sue interazioni e in terapia (rTMS), ne confermano l’intrinseca natura elettromagnetica:

35

D N A

E N T A N G L E D

36

La rilevanza di un continuo e variabile entanglement nel DNA

Elisabeth Rieper1, Janet Anders 2† and Vlatko Vedral1,3,4 1Center for Quantum Technologies, National Univ. of Singapore, Republic of Singapore; 2Dep.ment of Physics and Astronomy, Univ.ty College London, London WC1E 6BT, U K

3Atomic and Laser Physics, Clarendon Laboratory, University of Oxford, Parks Road, Oxford OX13PU, United Kingdom

4Dep.ment of Physics, National University of Singapore, Republic of Singapore. SUMMARY

We consider a chain of harmonic oscillators with dipole-dipole interaction between nearest neighbours resulting in a van der Waals type bonding. The binding energies

between entangled and classically correlated states are compared. We apply our model to DNA. By comparing our model with numerical simulations [1]

..abbiamo concluso che l’ entanglement potrebbe svolgere un ruolo cruciale nel regolare la stabilità della doppia elica

del DNA.

[quant-ph] 21 Jun 2010

37

In un modello teorico semplificato di DNA ogni nucleotide è costituito da una nube di elettroni attorno ad un nucleo centrale positivo. Questa nube negativa può muoversi rispetto al nucleo, creando un dipolo. Il movimento della nube avanti e indietro è un oscillatore armonico.

38

This graphic shows a sketch of a DNA strand. The chain is along z direction. Each bar in the double helix represents one DNA base pair, either adenine-thymine (AT) or guanine-cytosine (GC). The inset shows two simplified GC pairs. Around the core of atoms is the blue outer electron cloud. The oscillation of these electron clouds is modelled here as non-permanent harmonic dipoles, depicted by the black arrows.

The relevance of continuous variable entanglement in DNA Elisabeth Rieper1, Janet Anders 2† and Vlatko Vedral1,3,4 1Center for Quantum Technologies, National University of Singapore, Republic of Singapore; 2Department of Physics and Astronomy, University College London, London WC1E 6BT, United Kingdom; 3Atomic and Laser Physics, Clarendon Laboratory, University of Oxford, Parks Road, Oxford OX13PU, United Kingdom 4Department of Physics, National University of Singapore, Republic of Singapore.

arXiv:1006.4053v1 [quant-ph] sub. Jun 2010

39

COME SI ESEGUE UN TEST GENETICO?

40

Il DNA totale può essere estratto da un tampone buccale.

PCR REAL TIME

Provette per AMPLIFICAZIONE con PCR

SELEZIONE DEI FILAMENTI

PURIFICAZIONE DEL DNA ESTRAZIONE DEL DNA

41

Mappatura del DNA

42

La Genetica deterministica

43

LA NUOVA GENETICA FUNZIONALE

44

EPIGENETICA

Epi-Genetica – “sopra” l’informazione genetica codificata dal Dna.

45

EPIGENETICA •  L’epigenetica induce un

cambiamento ereditario nell’espressione genica senza alterare la struttura della sequenza del Dna

•  L’informazione che regola l’attività genica, non espressa nella sequenza del Dna, viene trasmessa da una generazione all’altra.

46

47

L’INFLUENZA EPIGENETICA

• Sviluppo di organismi

•  Interazione gene-ambiente

• Sviluppo di malattie

48

"...We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine (C-Me) DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype."

Fraga et al.,. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9.

EPIGENETICA: DIVERSI ASPETTI DELLA VITA

49

MECCANISMO MOLECOLARE ALLA BASE DELL’EPIGENETICA

50

Si parla del G-Me come il quinto nucleotide importante nel controllo dell'espressione

genica, i nuovi sistemi high throughput presto ci diranno quanto questo fenomeno sia

dinamico o statico; se la metilazione cambia solo durante situazioni estreme, oppure se è

una funzione ordinariamente adibita alla

o m e o s t a s i g e n e t i c a

della materia vivente

51

52

53

54 GENI-TORI = LATORI di GENI

MAMMA

55

Alimentazione come Stress Biotico Cibi e regimi nutrizionali come Fattori Scatenanti Stress Nutrizionale

56

Una dieta ricca di ac. folico o di vit. B12 influenza nei topi il colore del pelo, legato

al grado di metilazione del gene agouti durante lo sviluppo embrionale.

L’ambiente elettromagnetico può svolgere un’azione epigenetica con

effetti visibili sulle generazioni future.

57

Schizophrenia Bulletin Prenatal Nutritional Deficiency and Risk of Adult Schizophrenia Alan S. Brown; Ezra S. Susser Abs: Converging evidence suggests that a neurodevelopmental disruption plays a role in the vulnerability to schizophrenia. … in utero exposure to nutritional deficiency as a determinant of schizophrenia. Es. the early gestational exposure to the Dutch Hunger Winter of 1944-1945 and to a severe famine in China. …micronutrients as potential risk factors for schizophrenia. They include folate, essential fatty acids, retinoids, vitamin D, and iron. Epidemiologic study based on the association between prenatal homocysteine, an indicator of serum folate, and schizophrenia risk. … prenatal nutritional biomarkers in relation to schizophrenia in large birth cohorts, studies of epigenetic effects of prenatal starvation, association studies of genes relevant to folate and other micronutrient deficiencies

58

Definizione di salute mentale dell'OMS:

"uno stato di benessere in cui l'individuo ha coscienza delle proprie capacità,

riesce ad affrontare il normale stress della vita quotidiana,

è in grado di lavorare in maniera produttiva e proficua e di dare un

contributo alla propria comunità"

59

Prima della nascita l’esone 1(7) del promotore dei GCR non è metilato

Al momento della nascita l’esone è ipermetilato e

accoppiato con istoni che bloccano la trascrizione

Trends neurosci 2005 sept 28(9)456-63 Neurosci biobehave rev 2005 29(4-5) 843-65 Ann NY Acad Sci 2004 dec 1036; 167-180

(cromatina attiva)

(cromatina inattiva)

60

In particolare nello stress da parto, secondo l'ipotesi igienica, i livelli di metilazione globale del DNA sarebbero maggiori nei nati con taglio cesareo (↓bifidobatteri ↑Clostridium Difficilis) rispetto a quelli partoriti vaginalmente … la colonizzazione post cesareo potrebbe essere il fattore epigenetico scatenante di questa metilazione e forse, in caso di persistenza oltre i primi 3-5 giorni, tale effetto potrebbe rimanere in memoria anche per tutta la vita.

(Acta Paediatr. 2009; 98: 1082-4 e 1096-9)

61

62

63

In animali trascurati alla nascita da madri Low LG (Licking-Grooming: leccare-accudire) e low-ABN (Arched-Back: copertura), il livello di ipermetilazione-repressione si mantiene costante e quindi la cromatina

continua a rimanere

inattiva.

64

In animali accuditi da madri premurose (High LG-ABN), viene prodotto NGF, che legandosi stabilmente agli istoni ne determina il distacco dal promotore dei GC-R; questo processo permette la demetilazione del DNA che, attivando la cromatina, ripristina

un segnale provvisorio

65

riprova dell’effetto epigenetico delle cure materne sulla reattività agli stress nell’arco della vita…

J Consult Clin Psychol. 2009 Feb;77(1):1-11.

Parenting moderates a genetic vulnerability factor in longitudinal increases in

youths' substance use. Brody GH, Beach SR, Philibert RA, Chen YF,

Lei MK, Murry VM, Brown AC.University of

Georgia, Center for Family Research, 1095 College

Station Road, Athens, GA 30602-4527, USA

66

J Child Psychol Psychiatry. 2009 Jul 22. The role played by the interaction between genetic factors and attachment in the stress response in infancy. Frigerio A, Ceppi E, Rusconi M, Giorda R, Raggi ME, Fearon P.Eugenio Medea' Scientific Institute, Italy.

•  Background: The importance of understanding which environmental and biological factors are involved in determining individual differences in physiological response to stress is widely recognized, given the impact that stress has on physical and mental health. Methods: The child-mother attachment relationship and some genetic polymorphisms (5-HTTLPR, COMT and GABRA6) were tested as predictors of salivary cortisol and alpha amylase concentrations, two biomarkers of hypothalamic-pituitary-adrenocortical (HPA) axis and sympathetic adrenomedullary (SAM) system activity, during the Strange Situation (SS) procedure in a sample of more than 100 healthy infants, aged 12 to 18 months. Results: Individual differences in alpha amylase response to separation were predicted by security of attachment in interaction with 5-HTTLPR and GABRA6 genetic polymorphisms, whereas alpha amylase basal levels were predicted by COMT x attachment interaction. No significant effect of attachment, genetics and their interaction on cortisol activity emerged. Conclusions: These results help to disentangle the role played by both genetic and environmental factors in determining individual differences in stress response in infancy. The results also shed light on the suggestion that HPA and SAM systems are likely to have different characteristic responses to stress.

67

•  Secondo Mary Ainsworth, allieva di Bowlby, i bambini con attaccamento “sicuro” protestano per la separazione, ma si rasserenano facilmente, e al ritorno della madre le corrono incontro, riprendendo il contatto fisico ed emotivo; i bambini con attaccamento “insicuro” sembrano non accorgersi che la madre si è allontanata e al suo rientro tendono ad evitare il contatto. (Strange-

Situation)

68

STRANGE SITUATION (1969) •  Mary Ainsworth elaborò

una situazione sperimentale per determinare il tipo di attaccamento tra madre e figlio. La situazione, denominata "Strange Situation”, era suddivisa in otto episodi, ciascuno della durata di tre minuti, dove il bambino veniva sottoposto a situazioni potenzialmente generatrici di "stress relazionale".

69

a) Le cure materne aumentano il turnover di 5HT nell’Ippocampo con il relativo incremento di recettori 5HT7, di cAMP, PKA e CBP (creb binding protein);

b) ne consegue un aumento della produzione di fattori come il NGFI-A e la AP2, con maggior espressione dei GC-R

Neurosci biobehave rev 2005 29(4-5) 843-65 Ann NY Acad Sci 2004 dec 1036; 167-180

70

RADIAZIONI IONIZZANTI

RADIAZIONI NON IONIZZANTI (NIR)

RAGGI

γ

RAGGI X

REGIONE OTTICA ZONA DI TRANSIZIONE

ONDE HERZIANE

UVVISIBILE

MICROONDE (MO)

ONDE ULTRACORTE

CORTISSIME

ONDE

CORTE

MF1

MF2

MF3

LF1 ONDE LUNGHISSIME

LONTANO

VICINO

VICINO

LONTANO

EHF

SHF

UHF

VHF

HF MF LF

VLF

ELFULF

Hz33K30K300K3M300M30G300G3x1010G

RADIAZIONI IONIZZANTI

RADIAZIONI NON IONIZZANTI (NIR)

RAGGI

γ

RAGGI X

REGIONE OTTICA ZONA DI TRANSIZIONE

ONDE HERZIANE

UVVISIBILE

MICROONDE (MO)

ONDE ULTRACORTE

CORTISSIME

ONDE

CORTE

MF1

MF2

MF3

LF1 ONDE LUNGHISSIME

LONTANO

VICINO

VICINO

LONTANO

EHF

SHF

UHF

VHF

HF MF LF

VLF

ELFULF

RADIAZIONI IONIZZANTIRADIAZIONI IONIZZANTI

RADIAZIONI NON IONIZZANTI (NIR)RADIAZIONI NON IONIZZANTI (NIR)

RAGGI

γ

RAGGI

γ

RAGGI XRAGGI X

REGIONE OTTICAREGIONE OTTICA ZONA DI TRANSIZIONE

ZONA DI TRANSIZIONE

ONDE HERZIANEONDE HERZIANE

UVUVVISIBILE

VISIBILE

MICROONDE (MO)

MICROONDE (MO)

ONDE ULTRACORTE

ONDE ULTRACORTE

CORTISSIME

CORTISSIME

ONDE

CORTE

ONDE

CORTE

MF1

MF1

MF2

MF2

MF3

MF3

LF1LF1 ONDE LUNGHISSIME

ONDE LUNGHISSIME

LONTANO

LONTANO

VICINO

VICINO

VICINO

VICINO

LONTANO

LONTANO

EHF

EHF

SHF

SHF

UHF

UHF

VHF

VHF

HFHF MFMF LFLF

VLF

VLF

ELFELFULF

ULF

Hz33K30K300K3M300M30G300G3x1010G Hz33K30K300K3M300M30G300G3x1010G

le INTERAZIONI BIO- ELETTROMAGNETICHE

IR

71

FSN Stress ossidativo

72

Psychiatry Clin Neurosci. 2008 Aug;62(4):435-41. Semba J, Wakuta M.

Chronic effect of nicotine on serotonin transporter mRNA in the raphe nucleus of rats: reversal by co-administration of bupropion.

CONCLUSIONS: Chronic nicotine infusion reduces the synthesis of 5HTT

protein, which may consequently precipitate depression during

nicotine withdrawal .

73

Am J Med Genet B Neuropsychiatr Genet. 2008 Jul 5;147B(5):543-9. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. We conclude that both genetic variation and epigenetic modifications contribute to the regulation of SLC6A4 function and that more in-depth studies of the molecular mechanisms controlling gene activity and the relationship of these mechanisms to behavioral illness .

74

•  J Toxicol Environ Health A. 2008;71(11-12):786-94. Sequence variations in subjects with self-reported Multiple Chemical Sensitivity (sMCS): a case-control study.

•  Wiesmüller GA, Niggemann H, Weissbach W, Riley F, Maarouf Z, Dott W, Kunert HJ, Zerres K, Eggermann T, Blömeke B. No significant differences of the allelic distribution of genetic polymorphisms in the genes for 5HTT, NAT1, NAT2, PON1, PON2, and SOD2 were found between cases and controls. The results are in contrast to the study of McKeown-Eyssen and coworkers (2004) but in accordance with the German MCS multicenter study.

75

There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes:

1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member; interactions of at least 10 genes.

2) cytogenetic studies on relevant inherited or de novo chromosomal abnormalities in affected individuals and their families (at the 15q11-q13 locus)

76

3) evaluation of candidate genes known to affect brain development in these significantly linked regions (speech and language region at 7q31-q33) or, selected a priori because of their presumptive contribution to the pathogenesis of autism.

Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit (5q34) and UBE3A on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in non-autistic populations.

77

Genetica e attaccamento Una ricerca dell’IRCCS “Eugenio Medea - La

Nostra Famiglia” di Bosizio Parini (Lecco) ha dimostrato che su oltre 100 bambini, tra 12 e 18 mesi, quelli con attaccamento insicuro portatori di una o due coppie dell’allele corto S del gene 5-HTT e omozigoti per l’allele C del gene GABRA6 (T1521C-) mostravano un aumento di α-amilasi (SAM) per stress da separazione rispetto ai bambini con lo stesso genotipo ma con un attaccamento di tipo sicuro. Dunque i bimbi più predisposti geneticamente allo stress, ma con relazione di attaccamento “sicuro”, regolano meglio la loro risposta emotiva e non mostrano iper-reattività psicofisiologica. J Child Psychol Psychiatry. 2009 Jul 22.The role played by the interaction between genetic factors and attachment in the stress response in infancy Frigerio A et al.

78

Official Symbol: GABRA6 Name: gamma-aminobutyric acid (GABA) A receptor, subunit alpha 6 [Homo sapiens] Chromosome: 5; Location: 5q34 Addict Biol. 2009 Jan; 14(1): 43–64. Stress, alcohol and drug

interaction: an update of human research Magdalena Uhart1 and Gary S. Wand1,2 Given that the GABA system is a plausible candidate for modulating the stress response, Uhart et al. (2004) examined the association of the 1521T>C single nucleotide polymorphism (SNP) [rs 3219151] located in the 3′ untranslated region of the GABAAα6 receptor subunit gene (GABRA6) with the hormonal and autonomic responses to psychosocial stress.

Il GABA, il principale neurotrasmettitore inibitorio del cervello, è un aminoacido non essenziale, prodotto da un altro aminoacido (glutammina). Glutamic acid decarboxylase (GAD) converts the excitatory neurotransmitter glutamate into the inhibitory GABA in a single step

79 Plasma cortisol response to the Trier Social Stress Test (TSST) as a function of T1521C γ-aminobutyric acid alpha-6 receptor gene genotype. Healthy subjects homozygous for the C allele of this polymorphism show a blunted cortisol response to the TSST when compared with subjects expressing the T allele (P = 0.010). Data are presented as means (SE) change from baseline. Reprinted by permission from Macmillan Publishers Ltd: Molecular Psychiatry 9(11), copyright (2004)

Addict Biol. 2009 January; 14(1): 43–64. Stress, alcohol and drug interaction: an update of human research

Magdalena Uhart1 and Gary S. Wand1,2 1 Department of Medicine, The Johns Hopkins University School of Medicine, USA 2 Department of Psychiatry, The Johns Hopkins University School of Medicine, USA

Correspondence to: Gary S. Wand, The Johns Hopkins University School of Medicine, Ross Research Building, Room 863, 720 Rutland Avenue, Baltimore, MD 21205, USA. E-mail: gwand@jhmi.edu

ADULTI (> BAMBINI)

iperespressi

Trier Social Stress Test (TSST)

80

•  L'acido glutammico è un amminoacido polare, la sua molecola è chirale. •  L'enantiomero L è uno dei 20 amminoacidi ordinari, il suo gruppo laterale reca un

carbossile, che gli conferisce il comportamento acido da cui prende il nome. •  Negli esseri umani non è un amminoacido essenziale, ovvero l'organismo umano è

in grado di sintetizzarlo, ma è considerato condizionatamente essenziale in quanto il suo fabbisogno aumenta in caso di stress psicofisico e malattie, che il corpo non riesce a coprire.

•  Costituente delle proteine, nel SNC è anche un neurotrasmettitore eccitatorio ed un precursore dell'acido gamma-amminobutirrico (GABA).

•  L'acido glutammico non attraversa la barriera ematoencefalica; per giungere al cervello, dove viene usato per la sintesi proteica, deve essere convertito in glutammina.

•  Coinvolto in funzioni cognitive (apprendimento e memoria),in quantità eccessive può causare danni neuronali tipici di sclerosi progressive (come la SLA) e del morbo di Alzheimer.

•  Il suo sale sodico o glutammato di sodio (MSG–Mono sodium glutamate), è ampiamente usato nell'industria alimentare come esaltatore di sapidità. Nell'Unione Europea, il glutammato monosodico viene classificato come additivo alimentare (e identificato con il codice E621) .

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Neurosci Bull. 2008 Jun;24(3):195-200. •  The role and the mechanism of gamma-aminobutyric acid

during central nervous system development. Li K, Xu E. •  Source Institute of Neurosciences, the Second Affiliated Hospital of

Guangzhou Medical College, Guangzhou, China. •  gamma -aminobutyric acid (GABA) is an inhibitory

neurotransmitter in adult mammalian central nervous system (CNS). During CNS development, the role of GABA is switched from an excitatory transmitter to an inhibitory transmitter, which is caused by an inhibition of calcium influx into postsynaptic neuron derived from release of GABA. The switch is influenced by the neuronal chloride concentration. When the neuronal chloride concentration is at a high level, GABA acts as an excitatory neurotransmitter. When neuronal chloride concentration decreases to some degree, GABA acts as an inhibitory neurotransmitter. The neuronal chloride concentration is increased by Na+-K+-Cl(-)-Cl(-) cotransporters 1 (NKCC1), and decreased by K+-Cl(-) cotransporter 2 (KCC2).

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•  Nei NEONATI CC il GABA è eccitatorio perché la stimolazione dei recettori GABRA attiva il flusso degli ioni Cl- verso l’interno (IN) del neurone provocandone l’iperpolarizzazione (con mancata inibizione del flusso postsinaptico di Ca++ e conseguente maggiore eccitabilità neuronale);

•  con la crescita (dal 3° anno?) e in età adulta il flusso ionico del Cl- nei recettori GABRA si inverte verso l’esterno della cellula (OUT), e la loro stimolazione da parte del GABA, comporta: a) la depolarizzazione e l’attivazione del neurone

b) la depressione dell’eccitabilità neuronale post sinaptica per inibizione della trasmissione di Ca++

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•  Una ricerca appena pubblicata su The Journal of Lipid Research e firmata da un gruppo internazionale italo-francese, coordinato da due medici dell’Azienda Ospedaliera Universitaria Senese, il neonatologo Claudio De Felice e il neuropsichiatria Joussef Hayek ha infatti identificato un marker predittivo della sindrome di Rett. Si tratta di una scoperta potenzialmente in grado di cambiare la storia naturale di questa grave malattia genetica che colpisce la bambine, finora diagnosticata solo intorno all’anno di vita, quando la sintomatologia è conclamata ed è presente un danno cerebrale irreversibile. “Si tratta di un marker biochimico, chiamato ‘F2-dihomo-isoprostani’ – spiegano De Felice e Hayek – derivante dell’ossidazione di un acido grasso polinsaturo presente nella sostanza bianca cerebrale. Tale composto è risultato essere in concentrazioni da 100 a 300 volte più elevate nel plasma delle pazienti in stadio 1 della malattia”. Inoltre, analizzando la numerosa casistica della Neuropsichiatria Infantile dell’ospedale senese, che da oltre 20 anni è centro di riferimento nazionale per la sindrome di Rett, si è evidenziato che proprio questa molecola è il più precoce indicatore nelle piccole pazienti della prima fase della malattia, tra i 6 e i 12 mesi di vita. “La scoperta – proseguono De Felice e Hayek – apre la strada a una diagnosi e una terapia precoce con sostanze di origine naturale, come gli acidi grassi polinsaturi omega-3. La filosofia alla base della nostra ricerca è stata quella di spingere l’acceleratore verso una diagnosi quanto più precoce possibile perché nonostante i numerosi traguardi raggiunti dalla genetica molecolare sulle mutazioni genetiche, sino a ora non ci sono state particolari innovazioni per diagnosi precoce, terapia genetica e analisi dei meccanismi che portano dalla mutazione alle varie manifestazioni cliniche della malattia”. Lo studio è stato effettuato in collaborazione con il professor Thierry Durand del CNR di Montpellier, uno dei massimi esperti di chimica degli isoprostani, e l’Università di Siena, con la ricercatrice Cinzia Signorini e la professoressa Lucia Ciccoli, entrambe esperte di stress ossidativi.

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Elevated serotonin levels have been consistently found in 30%-50% of autistic patients and may represent a marker for familial autism. Hyperserotonemia in autism appears to be due to enhanced 5-HT uptake, as free 5-HT levels are normal and the current report of an excess of the long/long 5-HTTLPR genotype in autism could provide a partial molecular explanation for high platelet serotonin content in autism.

Am J Med Genet. 2001 May 8;105(4):381-6

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…Increased platelet serotonin level (PSL) has been consistently found in a portion of autistic patients. Suggested mechanisms for hyperserotonemia:

1) increased synthesis of serotonin (5HT) by tryptophan hydroxylase (TPH),

2) increased uptake into platelets through 5HT transporter (5HTT),

3) diminished release from platelets through 5HT2A receptor (5HT2Ar)

4) decreased metabolism by monoamine oxydase (MAOA).

Coll Antropol. 2008 Jan;32 Suppl 1:75-80.

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•  Autism is a pervasive developmental disorder diagnosed in early childhood with abnormalities of serotoninergic neurotransmission. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1019-27.

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…A 1.5-fold increased rate (V(max)) of platelet 5-HT uptake was observed in LL genotype individuals compared to those with LS and SS genotypes (Mol Psychiatry. 2002;7(8):831-6).

… These first findings may be relevant to previous reports that have shown an association between the 5-HTTLPR long form and obsessive-compulsive disorder and autism. (Am J Psychiatry. 2003 Apr;160(4):671-6). …mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. (Am J Hum Genet. 2005 Aug;77(2):265-79).

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•  Tra i vari polimorfismi funzionali che differenziano il nostro patrimonio genetico, focalizziamo quello di inserzione/delezione di un segmento di 44 coppie di basi (bp) del gene 5HTTLPR (5 HidrossiTriptamina Transporter Linked Promoter Region) (SERT) SLC6A4 (Solute Carrier family 6 member 4), nelle sue varianti alleliche S (short), SL, L(G) low expression, L(long), L(A) high expression, localizzato nel cromosoma 17q11.1 -17q12.

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The human SERT gene is located at the SLC6A4 locus on chromosome 17 (17q11.1-17q12), red marking , spans 31kbp and contains 14 exons (blue). A variable number of tandem repeat (VNTR) element 17bp 9-12 rep., was found in the second intron (white) and a 44bp insertion/deletion polymorphism has been identified in the transcriptional control region (yellow) upstream of the serotonin transporter gene (Ohara et al. 1998).

also a SNPs in the promoter region

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La frequenza della mutazione (D=S) riportata in letteratura é del 39% con una eterozigosi (I/D=LS) del 52%.(Armin Heils et al. J. Neurochemistry vol 66 no 6, 1996):

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Varianti della regione regolatrice e dell’espressione strutturale del gene codificante per il 5-HTT. L'attività trascrizionale del promotore è regolata dalla regione polimorfica 5-HTTLPR collocata ca.1 kb a monte del sito d'inizio della trascrizione

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•  The function of serotonin is exerted upon its interaction with specific receptors. Several serotonin receptors have been cloned and are identified as 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7. Within the 5HT1 group there are subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E, and 5HT1F. There are three 5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C as well as two 5HT5 subtypes, 5HT5a and 5HT5B. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cν (PLCγ). The 5HT3 class of receptors are ion channels.

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•  Some serotonin receptors are presynaptic and others postsynaptic. The 5HT2A receptors mediate platelet aggregation and smooth muscle contraction. The 5HT2C receptors are suspected in control of food intake as mice lacking this gene become obese from increased food intake and are also subject to fatal seizures. The 5HT3 receptors are present in the gastrointestinal tract and are related to vomiting. Also present in the gastrointestinal tract are 5HT4 receptors where they function in secretion and peristalsis. The 5HT6 and 5HT7 receptors are distributed throughout the limbic system of the brain and the 5HT6 receptors have high affinity for antidepressant drugs.

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Ruolo dei recettori 5HT1A nella trasmissione serotoninergica

Risposte cellulari

5HT-

2 5H

T4

Nuclei del raphe

Aree di proiezione

5HT 5HT

5HT1B/D

5HT1

A

5HT1A

5HT

MAO

CaMKII

Ca2+

*

PKC

PKA cAMP

1P3 + DAG Ca2+

PLC

AC

AC

G

G

G

–

+

5HT

Fosfoproteine

SSRI -

Funzioni cellulari

5HT

Gli SSRI potenziano la neurotrasmissione serotoninergica non solo bloccando la ricaptazione della serotonina, ma anche attraverso una progressiva desensibilizzazione (down-regulation) dei recettori 5HT-1A presinaptici. Tali recettori, localizzati sul soma e sui dendriti dei neuroni serotoninergici, svolgono un ruolo inibitorio sul “firing” degli stessi neuroni. (N.Brunello)

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Gli SSRI determinano un aumento della concentrazione di 5HT a livello delle terminazioni e dei corpi cellulari localizzati nei nuclei del rafe. Ad una iniziale attivazione dei recettori 5HT-1A, che riduce l’attività dei neuroni serotoninergici, segue una loro progressiva down-regulation (riduzione di sensibilità e numero) e la conseguente disinibizione della trasmissione serotoninergica. Questo fenomeno spiegherebbe la ritardata comparsa dell'effetto terapeutico degli SSRI.

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Altri effetti della somministrazione

prolungata degli SSRI sono: a) la down-regulation di autorecettori

presenti sui terminal i di neuroni serotoninergici (5HT-1B nel ratto; 5HT-1D e 5-HT2A/2C nell'uomo) che normalmente inibiscono il rilascio di serotonina e dei recettori β e α1 nella sinapsi noradrenergica .

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Recettore

Protein chinasi

nucleo

effettore

Regolazione espressione dei recettori

Controllo dell’espressione genica

Regolazione dei meccanismi di trasduzione a livello citoplasmatico

b) un aumento di quantità del secondo messaggero cAMP, e la conseguente attivazione di sistemi enzimatici che possono regolare la funzione cellulare attraverso la fosforilazione di specifiche proteine mediata dalla protein- kinasi cAMP dipendente di tipo II (PKA).

BDNF Trk-B (N.Brunello)

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“Nature Medicine” Pub. online: 17 October 2010 A negative regulator of MAP kinase

causes depressive behavior Vanja Duric1, Mounira Banasr1, Pawel Licznerski1, Heath D Schmidt1, Craig A

Stockmeier2,3, Arthur A Simen1, Samuel S Newton1 & Ronald S Duman1 1)Department of Psychiatry, Yale University, New Haven, Connecticut, USA. 2)Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson,

Mississippi, USA. 3) Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA. Abst… we use whole-genome expression profiling of postmortem tissue and show

significantly increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), .. in the hippocampal subfields of subjects with MDD compared to matched controls. MKP-1, … is a member of a family of proteins that dephosphorylate both threonine and tyrosine residues and thereby serves as a key negative regulator of the MAPK cascade, a major signaling pathway involved in neuronal plasticity, function and survival…

in rat and mouse models of depression increased hippocampal

MKP-1 expression, as a result of stress or viral-

mediated gene transfer.. chronic antidepressant

treatment normalizes stress-induced MKP-1 expression and behavior, and mice lacking MKP-1 are resilient to stress.

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Una delle proteine fosforilate dalla PK cAMP-dipendente è il fattore di trascrizione CREB (cAMP response element-binding protein) che media molte azioni intracellulari del cAMP a livello dell’espressione genica. Il CREB è stato proposto come target post-recettoriale candidato a mediare le risposte adattative successive a trattamento prolungato con diverse classi di farmaci antidepressivi.

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•  Tra i geni coinvolti nella risposta clinica agli antidepressivi sembrano giocare un ruolo importante quelli che codificano per il fattore trofico BDNF (Brain Derived Neurotrophic Factor) e per il suo recettore tirosino-chinasico trkB. La somministrazione cronica di antidepressivi aumenta l'espressione di BDNF e TrkB a livello dell’ippocampo. L’aumentata espressione del BDNF e TrkB sarebbe la conseguenza della up-regulation della via del cAMP e del fattore CREB.

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Good Morning America in April 2002 Dr. Redford Williams of Duke University: anger might be a hereditary trait. In a sample composed of predominantly white males, those with one or two copies of the long 5HTTLPR allele had CSF levels of 5HIAA that were 50% higher than persons with the short/short genotype. The basal activity of the long allele promoter region was more than twice that of the short allele promoter region based upon a luciferase assay.

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Il ripetersi di più stress della vita è stato correlato ad un

lineare progressivo aumento degli episodi depressivi nei

soggetti SS-SL, e ad una sostanziale stabilità

dell’umore nei soggetti LL.

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Some carry genes that magnify parenting's influence

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•  Science 18 July 2003: Vol. 301. no. 5631, pp. 386 - 389 Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene

•  Avshalom Caspi,1,2 Karen Sugden,1 Terrie E. Moffitt,1,2* Alan Taylor,1 Ian W. Craig,1 HonaLee Harrington,2 Joseph McClay,1 Jonathan Mill,1 Judy Martin,3 Antony Braithwaite,4 Richie Poulton3

•  1 Medical Research Council Social, Genetic, and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College London, PO80 De Crespigny Park, London, SE5 8AF, UK. 2 Department of Psychology, University of Wisconsin, Madison, WI 53706, USA. 3 Dunedin School of Medicine, 4 Department of Pathology, University of Otago, Dunedin, New Zealand.

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Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003 Jul 18;301(5631):386-9.

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Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003 Jul 18;301(5631):386-9.

110 Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R.

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Serotonin transporter and Sleep Sleep quality is worse in s-allele carriers but ONLY when stressed

Brummett et al, 2007, Psychosomatic Medicine, Volume 69(7), September 2007, pp 621-624

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•  Psychiatr Q. 2011 May 6. [Epub ahead of print] •  Gene-Environment Interaction and the Intergenerational Transmission

of Parenting: Testing the Differential-Susceptibility Hypothesis. •  Beaver KM, Belsky J. College of Criminology and Criminal Justice, Florida State

University, 634 West Call Street, Tallahassee, FL, 32306-1127, USA, kbeaver@fsu.edu. •  Abstract: The current study evaluated the differential-susceptibility

hypothesis in explaining the intergenerational transmission of parenting, using data from the National Longitudinal Study of Adolescent Health (Add Health). Exposure to maternal parenting was measured prospectively when respondents were adolescents and parental stress was measured when they were parents themselves, some 14 years later, on average. Cumulative-genetic plasticity was measured by dominantly coding the presence of putative plasticity alleles from four genes: the 10R allele of DAT1, the A1 allele of DRD2, the 7R allele of DRD4, and the short allele of 5HTTLPR. Results showed that the more plasticity alleles individuals carried (range 0-4), the more that parenting experienced in adolescence predicted future parenting experience. Those respondents with the most plasticity alleles not only experienced the highest levels of parental stress when exposed to negative maternal parenting in adolescence but the lowest levels when exposed to positive maternal parenting in adolescence. These results indicate that differential susceptibility is operative in the case of the intergenerational transmission of parenting, which could explain why estimates of such transmission have proven so modest in studies which fail to consider GXE interactions.

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SERT e STRESS Rassegna bibliografica

data based Pubmed key:

5HTT, SLCLPR6A4, SERT and stress

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Sert e stress (1-30) •  1) Science. 2003 Jul 18;301(5631):386-9. Influence of life stress on depression :

moderation by a polymorphism in the 5-HTT gene. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R. + Science vol 30118 july 2003 Getting the Short End of the Allele–Constance Holden

•  2) Psychol Med. 2005 Jan;35(1):101-11. The relationship between stressful life events, the serotonin transporter (5-HTTLPR) genotype and major depression. Gillespie NA, Whitfield JB, Williams B, Heath AC, Martin NG.

•  3) Arch Gen Psychiatry. 2005 May;62(5):529-35.The interaction of stressful life events and a serotonin transporter polymorphism in the prediction of episodes of major depression: a replication.Kendler KS, Kuhn JW, Vittum J, Prescott CA, Riley B.

•  4) Arch Gen Psychiatry. 2006 Sep;63(9):989-96.Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression.Jacobs N, Kenis G, Peeters F, Derom C, Vlietinck R, van Os J.

•  5) British Journal of psychiatry (2006), 188 , 210-215 Life events, first depression onset and the serotonin transporter gene Wilhelm K, PhilipB. MItcell,HeatherNiven,Adam Finch,Lucinda Wedgwood,Anna Scimone, Ian P. Blair,Gordon Parker,Peter R. Schofield

•  6) Am J Psychiatry. 2006 Sep;163(9):1588-93. Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. Zalsman G, Huang YY, Oquendo MA, Burke AK, Hu XZ, Brent DA, Ellis SP, Goldman D, Mann JJ.

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•  7) Curr Psychiatry Rep. 2006 Dec;8(6):452-7. The interaction of serotonin transporter gene polymorphisms and early adverse life events on vulnerability for major depression.Vergne DE, Nemeroff CB.

•  8) Psychosomatic Medicine 69:762–768 (2007) Serotonin Transporter Gene Polymorphism (5-HTTLPR) and Anxiety Reactivity in Daily Life: A Daily Process Approach to Gene-Environment Interaction. Katheleen C.Gunthert,Tamlin S.Conner, Stephen Armeli, Howard Tennen, Jonathan Covault, Henry R. Kranzler.

•  9) J Psychopharmacol. 2007 Jul;21(5):538-44. Epub 2007 Apr 19.Review: Serotonin by stress interaction: a susceptibility factor for the development of depression?Firk C, Markus 10). Psychosom Med. 2008 Jan;70(1):32-9. Epub 2007 Dec 24.Childhood socioeconomic status and serotonin transporter gene polymorphism enhance cardiovascular reactivity to mental stress.Williams RB, Marchuk DA, Siegler IC, Barefoot JC, Helms MJ, Brummett BH, Surwit RS, Lane JD, Kuhn CM, Gadde KM, Ashley-Koch A, Svenson IK, Schanberg SM.

•  11) Am J Med Genet B Neuropsychiatr Genet. 2008 Jan 5;147B(1):128-30.Dissocial behavior, the 5HTTLPR polymorphism, and maltreatment in women with bulimic syndromes.Steiger H, Richardson J, Joober R, Israel M, Bruce KR, Ng Ying Kin NM, Howard H, Anestin A, Dandurand C, Gauvin L.

•  12) Behav Genet. 2008 Jan;38(1):34-43. Epub 2007 Oct 23.Effects of environmental stress and gender on associations among symptoms of depression and the serotonin transporter gene linked polymorphic region (5-HTTLPR).Brummett BH, Boyle SH, Siegler IC, Kuhn CM, Ashley-Koch A, Jonassaint CR, Züchner S, Collins A, Williams RB

•  13) Physiol Behav. 2008 Mar 18; 93(4-5):807-19. Epub 2007 Dec 4. Polymorphisms in the serotonin reuptake transporter gene modify the consequences of social status on metabolic health in female rhesus monkeys.Jarrell H, Hoffman JB, Kaplan JR, Berga S, Kinkead B, Wilson ME.

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•  14) Int J Mol Med. 2008 Apr; 21(4):499-505. Association between serotonin transporter gene polymorphisms and depressed mood caused by job stress in Japanese workers. Katsuyama H, Tomita M, Hidaka K, Fushimi S, Okuyama T, Watanabe Y, Tamechika Y, Otsuki T, Saijoh K, Sunami S.

•  15) J Stud Alcohol Drugs. 2008 Nov; 69(6):814-23. A serotonin transporter gene polymorphism (5-HTTLPR), drinking-to-cope motivation, and negative life events among college students.Armeli S, Conner TS, Covault J, Tennen H, Kranzler HR.

•  16) Novartis Found Symp. 2008; 293:48-59; discussion 59-70. Use of monozygotic twins to investigate the relationship between 5HTTLPR genotype, depression and stressful life events: an application of Item Response Theory.Wray NR, Coventry WL, James MR, Montgomery GW, Eaves LJ, Martin NG.

•  17) J Affect Disord. 2008 Nov;111(1):1-12. Epub 2008 Jun 4.Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene-environment interaction. Brown GW, Harris TO.

•  18) Int J Psychophysiol. 2008 Dec 14. [Epub ahead of print]Aggression and 5HTT polymorphism in females: Study of synchronized swimming sport stress and control groups. Sysoeva OV, Maluchenko NV, Timofeeva MA, Portnova GV, Kulikova MA, Tonevitsky AG, Ivanitsky AM.

•  19) Am J Med Genet B Neuropsychiatr Genet. 2009 Jan 16.Genetic variation in 5HTTLPR is associated with emotional resilience (as the ability to maintain healthy and stable levels of psychological functioning in the wake of stress and trauma) .Stein MB, Campbell-Sills L, Gelernter J

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•  20) Am J Epidemiol. 2009 Feb 19. [Epub ahead of print] Modification of the Association Between Serotonin Transporter Genotype and Risk of Posttraumatic Stress Disorder in Adults by County-Level Social Environment.Koenen KC, Aiello AE, Bakshis E, Amstadter AB, Ruggiero KJ, Acierno R, Kilpatrick DG, Gelernter J, Galea S.

•  21) Psychoneuroendocrinology. 2009 Feb 25. [Epub ahead of print]Sex-specific association between the 5-HTT gene-linked polymorphic region and basal cortisol secretion.Wüst S, Kumsta R, Treutlein J, Frank J, Entringer S, Schulze TG, Rietschel M.

•  22) Leg Med (Tokyo). 2009 Feb 27. [Epub ahead of print] 5HTT polymorphisms are associated with job stress in the Japanese workers. Katsuyama H, Tomita M, Okuyama T, Hidaka K, Watanabe Y, Tamechika Y, Fushimi S, Saijoh K.

•  23) Neuroimage. 2009 Apr 1;45(2):275-9. Epub 2008 Dec 24. The relationships between daily life events and the availabilities of serotonin transporters and dopamine transporters in healthy volunteers--a dual-isotope SPECT study.Yeh TL, Lee IH, Chen KC, Chen PS, Yao WJ, Yang YK, Chiu NT, Lu RB.

•  24) Brain Res. 2009 Aug 25;1286:84-93. The roles of sex and serotonin transporter levels in age- and stress-related emotionality in mice.Joeyen-Waldorf J, Edgar N, Sibille E.

•  25) Horm Behav. 2009 Jul 24. Resilience and vulnerability are dose-dependently related to neonatal stressors in mice.Macrì S, Granstrem O, Shumilina M, Antunes Gomes Dos Santos FJ, Berry A, Saso L, Laviola G.

•  26) J Child Psychol Psychiatry. 2009 Oct 7. Chronic and acute stress, gender, and serotonin transporter gene-environment interactions predicting depression symptoms in youth.Hammen C, Brennan PA, Keenan-Miller D, Hazel NA, Najman JM

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•  27) Psychoneuroendocrinology. 2009 Aug;34(7):972-82. Sex-specific association

between the 5-HTT gene-linked polymorphic region and basal cortisol secretion.Wüst S, Kumsta R, Treutlein J, Frank J, Entringer S, Schulze TG, Rietschel M.

•  28) Mol Psychiatry. 2009 Jul;14(7):681-95. Epub 2009 Jan 20. Mol Psychiatry. 2009 Jul;14(7):648-9.Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.Gatt JM, Nemeroff CB, Dobson-Stone C, Paul RH, Bryant RA, Schofield PR, Gordon E, Kemp AH, Williams LM.

•  29) Int J Psychophysiol. 2009 May;72(2):173-8.Aggression and 5HTT polymorphism in females: study of synchronized swimming and control groups. Sysoeva OV, Maluchenko NV, Timofeeva MA, Portnova GV, Kulikova MA, Tonevitsky AG, Ivanitsky AM.

•  30) Brain Behav Immun. 2009 Feb;23(2):286-93. T-cell phenotypic and functional changes associated with social subordination and gene polymorphisms in the serotonin reuptake transporter in female rhesus monkeys.Paiardini M, Hoffman J, Cervasi B, Ortiz AM, Stroud F, Silvestri G, Wilson ME.

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contraddizioni?

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Conclusion This meta-analysis (by PhD) yielded no evidence that the SERT genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined. JAMA, June 17, 2009—Vol 301, No. 23 2462-2471

(PhD review)

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ISTITUTO SUPERIORE DI SANITA‘ Com. n. 3 del 24/04/2009

Dai gemelli, evidenze sull'origine genetica dell'attitudine positiva verso sé stessi, la vita ed il futuro su Behavior Genetics, coordinato dall'ISS (reparti di Epidemiologia, Genetica e Salute Mentale del CNESPS), in collaborazione con i Dipartimenti di Psicologia delle Università "La Sapienza" di Roma, "Bicocca" di Milano e con l'Università di Stanford (California - USA).

•  La ricerca ha coinvolto 428 coppie di gemelli, monozigoti e dizigoti, tra i 23 e i 24 anni, iscritte al Registro Nazionale Gemelli. Le stime di "ereditabilità" dei tratti considerati, sono state del 73% per l'autostima, del 59% per la soddisfazione di vita e del 28% per l'ottimismo. Un'elevata correlazione genetica e una bassa correlazione ambientale riscontrata tra autostima, soddisfazione di vita e ottimismo (parametri utilizzati per definire la DM).

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Prim Care Companion J Clin Psychiatry. 2009;11(3):93-102. Clinical implications of genetic variation in the

serotonin transporter promoter region: a MD review. –  Luddington NS, Mandadapu A, Husk M, El-Mallakh RS.Department of Psychiatry

and Behavioral Sciences, University of Louisville School of Medicine, Kentucky. –  OBJECTIVE: To determine the state of the art in understanding the

role of genetic variation in the serotonin transporter (5-HTT) promoter region (5-HTTLPR) in the development of a depressive episode and in its response to treatment. DATA SOURCES: PubMed and Ovid were used to search for articles published prior to December 2007 utilizing the key words serotonin transporter, 5-HTT, 5-HTTLPR, serotonin transporter gene, and SLC6A4. STUDY SELECTION: All studies were reviewed, but case reports and small case series were excluded. DATA EXTRACTION: All relevant articles were read by at least 2 of the coauthors and notes regarding study design, measures, data analysis, and findings were later used to construct the review. DATA SYNTHESIS: A common genetic variant, the short allele, in which 44 base pairs are missing from the promoter of SLC6A4, is associated with a greater risk for developing a major depressive disorder in patients following exposure to adversity. This association appears to be most important in the early stages of the depressive disorder. Additionally, the likelihood of a positive response to antidepressant treatment may be reduced in these patients in terms of delayed response, greater adverse event load, or, in bipolar patients, mania induction and rapid cycling.

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Genomic and epigenetic evidence for oxytocin receptor deficiency in autism (BMC Medicine2009) Simon G Gregory et al. Background: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. Methods: .. genome-wide … 119 probands from multiplex autism families. ... We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). Results: .. may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. Conclusions: Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the autism .

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OSPEDALE “CRISTO RE” CORSO di SPECIALIZZAZIONE in PSICOTERAPIA PSICOSOMATICA

L’IMPULSIVITÀ COME ENDOFENOTIPO Candidata: Dott.ssa Daniela MINEA

Relatore: Prof. Francesco BORGHINI Correlatore: Prof. Andrea CASTIGLIONE HUMANI

ANNO ACCADEMICO 2007-2008 •  Conclusioni Dai risultati ottenuti possiamo concludere che esiste una significativa

correlazione tra la presenza dei polimorfismi S/L,S/S del gene 5HTTPLR SLC6A4 e la presenza del tratto impulsività nei disturbi di personalità. Dal momento che la probabilità di tale correlazione risulta del 90%, il rimanente 10% potrebbe essere giustificato dall’influenza del fattore epigenetico; un ambiente particolarmente favorevole potrebbe aiutare infatti a gestire in modo diverso la realtà e, in chiave epigenetica, ad esercitare un certo controllo sul proprio patrimonio genetico…

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La Sindrome di Asperger Compromissione dell’interazione sociale, meno

intensa rispetto all’autismo, senza compromissione cognitiva e disturbi del comportamento adattativo.

Il linguaggio, talora precocemente evoluto, è spesso non comunicativo, non prosodico e stereotipato.

Preoccupazione ossessiva per interessi limitati, anormali per contenuto ed obiettivo, per intensità e settorialità, con adesione compulsiva a rituali disfunzionali.

Sviluppo motorio rallentato, goffo, disprassico. Compromissioni cognitive nelle prove non verbali

(con prove verbali normali).

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La Sindrome di Asperger

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•  Actas Esp Psiquiatr. 2007 Sep-Oct;35(5):338-41. •  Asperger's disorder in adulthood: a case report. •  Alonso Y, Miralles MC, Mulet B, Serret V.Rehabilitation Hospital Unit, Hospital

Psiquiátrico Universitario Institut Pere Mata, Reus, Tarragona, Spain. alonsoy@peremata.com

•  Abstract •  Asperger's disorder is a pervasive development disorder. It involves

qualitative disorders in social relationship and communication as well as restricted and repetitive interests and activities, with no delay in language acquisition. Although Asperger's disorder is an illness that begins in childhood, its diagnosis may frequently not be done until later stages. The case presented is about a 21 year old man with a diagnosis of schizoaffective disorder who, after several admissions, was sent to the Rehabilitation Hospital Unit for stabilization and diagnostic study given the atypical features of his case. The psychopathological examination showed disorders in social relationships, psychomotricity and communications that had begun in his childhood. All these data, and the results of the biomedical and psychological diagnostic tests oriented us towards the presence of a dual diagnosis of Asperger's disorder and schizoaffective disorder. The presence of common symptoms between the AD and other psychiatric diseases as well as the possible existence of comorbidity may lead to an incorrect or late diagnosis.

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•  Dtsch Arztebl Int. 2009 Jan;106(5):59-64. Epub 2009 Jan 30. •  Asperger's syndrome in adulthood. •  Roy M, Dillo W, Emrich HM, Ohlmeier MD.Klinik für Psychiatrie, Sozialpsychiatrie und

Psychotherapie, Zentrum für Seelische Gesundheit, Medizinische Hochschule Hannover, 30625 Hannover, Germany. roy.mandy@mh-hannover.de

•  Abstract •  INTRODUCTION: Asperger's syndrome is one of the autism spectrum disorders.

Affected individuals display considerably impaired capacity for social interaction, unusual special interests, and a tendency towards ritualized behavior.

•  METHODS: The etiology, symptoms, diagnosis, and treatment of Asperger's syndrome in adulthood are outlined on the basis of a selective literature review via Medline and information in relevant reference books. Furthermore, the authors report their personal experience at a special clinic for adults.

•  RESULTS: Asperger's syndrome in adulthood can be diagnosed by thorough anamnesis, heteroanamnesis-with emphasis on childhood-and painstaking clinical examination. The considerable psychosocial impairments affect the patients' professional, social, and private lives. The precise etiology is still unknown, but a multifactorial origin with genetic, neurobiological, and psychosocial components appears probable. Although no specific, empirically tested treatment concepts have yet been established, psychotherapeutic elements (structuring and directive interventions) seem to be helpful, together with pharmacotherapy-if indicated-in the presence of comorbidity.

•  CONCLUSIONS: Asperger's syndrome should be included in the differential diagnosis of adults who display the corresponding symptoms. The etiopathogenesis and treatment of Asperger's syndrome in adulthood should be further investigated.

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•  Adv Med Sci. 2011 Oct 29:1-9. [Epub ahead of print] •  Predictive models for subtypes of autism spectrum disorder based on single-nucleotide

polymorphisms and magnetic resonance imaging. •  Jiao Y, Chen R, Ke X, Cheng L, Chu K, Lu Z, Herskovits EH. •  Source •  Key Laboratory of Child Development and Learning Science, Southeast University, Ministry of

Education, Nanjing, China State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

•  Abstract •  Purpose: Autism spectrum disorder (ASD) is a neurodevelopmental disorder, of which Asperger

syndrome and high-functioning autism are subtypes. Our goal is: 1) to determine whether a diagnostic model based on single-nucleotide polymorphisms (SNPs), brain regional thickness measurements, or brain regional volume measurements can distinguish Asperger syndrome from high-functioning autism; and 2) to compare the SNP, thickness, and volume-based diagnostic models.Material and Methods: Our study included 18 children with ASD: 13 subjects with high-functioning autism and 5 subjects with Asperger syndrome. For each child, we obtained 25 SNPs for 8 ASD-related genes; we also computed regional cortical thicknesses and volumes for 66 brain structures, based on structural magnetic resonance (MR) examination. To generate diagnostic models, we employed five machine-learning techniques: decision stump, alternating decision trees, multi-class alternating decision trees, logistic model trees, and support vector machines.Results: For SNP-based classification, three decision-tree-based models performed better than the other two machine-learning models. The performance metrics for three decision-tree-based models were similar: decision stump was modestly better than the other two methods, with accuracy = 90%, sensitivity = 0.95 and specificity = 0.75. All thickness and volume-based diagnostic models performed poorly. The SNP-based diagnostic models were superior to those based on thickness and volume. For SNP-based classification, rs878960 in GABRB3 (gamma-aminobutyric acid A receptor, beta 3) was selected by all tree-based models.Conclusion: Our analysis demonstrated that SNP-based classification was more accurate than morphometry-based classification in ASD subtype classification. Also, we found that one SNP-rs878960 in GABRB3-distinguishes Asperger syndrome from high-functioning autism.

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Il Disturbo Disintegrativo dell’Infanzia è un raro disturbo con iniziale sviluppo

normale. Tra i 2-4 anni ed i 10 anni, vi è una perdita massiccia delle capacità acquisite nel linguaggio, nel gioco, nelle abilità sociali, nell’adattamento all’ambiente, nel controllo sfinterico, nelle abilità motorie.

DPS non altrimenti specificati Forme atipiche per insorgenza oltre i 3 anni, o

per sintomatologia sottosoglia, pur con compromissione di interazione sociale, linguaggio e gioco simbolico.