This document provides an overview of genomic and proteomic markers in forensic psychiatry. It discusses various topics including: - Genomic markers for fragile X syndrome and their role in the courtroom - The neurobiology of morality and disorders that impact moral behavior - Proteomic markers like misfolded proteins that can cause neurodegenerative diseases - How disorders like frontotemporal dementia can result in acquired sociopathy due to neurodegeneration impacting moral processing centers in the brain - The importance of understanding these biological factors for clinicians working in forensic psychiatry

1. Genomic and
Proteomic markers in
Forensic Psychiatry
Adonis Sfera, MD
With input from Mario Mendez
MD, PhD

2. Outline
 Genomic
markers for fragile X syndrome
 Molloy v Meier - genomic markers in the courtroom
 Neuro-moral network
 Myths and facts about genes
 Proteins – the building blocks of life

3. Levels of brain organization

Neurobiology can be studied at two levels of organization:
-cellular (cell-cell or cell-ECM interactions)
-molecular (molecular networks enmesh the entire CNS)

4. From cellular to molecular level
mid 1980s
Protein mass spectrometry
Confocal laser scanning microscope
Multiphoton microscope

5. Cellular biomarkers
Cellular connectomics (neuroimaging and electrophysiology).
*Human Connectome Project
*Brain cells are organized in networks: neuronal, glial,
neuronal-glial and complex cellular networks.

6. Molecular biomarkers
-Genomic markers
-Proteomic markers

8. 2003- the holy grail of genetics

9. Gene mining “gold rush”

10. Genes – more questions than answers

11. From the sovereignty of genes
to the sovereignty of proteins

12. Origami – the art of folding

13. Misfolded proteins: neurodevelopmental
and neurodegenerative diseases
HUNTINGTIN PROTEIN =
Huntington’s
ALPHA-SYNNUCLEIN = Lewy body
dementia, Parkinson’s
TAU = frontotemporal dementia
AMYLOID BETA PROTEIN =
Alzheimer’s
PRION PROTEIN = Creutzfeld-Jacob
DISC 1 PROTEIN = Schizophrenia

14. Fragile X syndrome-molecular level
FMR1 gene
CGG triplet repeat,
is expanded in the
FMR1 gene
fragile X mental retardation 1
protein (FMRP)
misfolded FMRP

15. Fragile X syndrome- cellular level

16. Genetic markers in the courtroom
 Some
neurodevelopmental and neuropsychiatric
conditions such as Fragile X syndrome, velocardio-facial syndrome or Huntington’s disease
biological markers are accepted in court.

17. Molloy v Meier-genomic markers and duty
to warn

Dr. Meier, a pediatrician, treated Mrs. Molloy's minor daughter for developmental delays.

Mrs. Molloy informed Dr. Meier that her half brother was mentally retarded.

Dr. Meier ordered chromosome testing on Mrs. Molloy's minor child.

She did not, however, recommend testing for Mrs. Molloy. Nor did the testing that she ordered
specifically test for Fragile X syndrome. The results of the chromosome tests were negative.

Later, Mrs. Molloy gave birth to another child, who was similarly disabled as the sister.

Mrs. Molloy and the two children then underwent genetic testing, which identified all of them
as carriers of the genetic mutation associated with Fragile X syndrome.

Mrs. Molloy sued Dr. Meier, alleging that she failed to properly order and interpret genetic
testing, and that she failed to provide adequate genetic counseling to the parents.

The lawsuit further alleged that the parents would not have conceived another child had they
known that their first child had Fragile X syndrome, and that the mother was a carrier.

The Minnesota Supreme Court ruled that "a physician's duty regarding genetic testing and
diagnosis extends beyond the patient to biological relatives who foreseeably may be harmed
by a breach of that duty."

18. Talking about genomic markers…

19. The neurobiology of morality

20. The neurobiology of moral behavior

Humans have an innate moral sense based in a neuromoral network
centered in the ventromedial prefrontal cortex and its connections including
anterior insula (AI) and anterior cingulate cortex (ACC).

The neuromoral network works through moral emotions and moral drives,
such as the avoidance of harm to others and the need for fairness and
punishment of violators.

Disorders of this region, such as focal lesions or frontotemporal dementia,
disturb personal, intrinsic moral emotions and decision-making.

Clinicians must recognize and manage “acquired sociopathy” and other
dysmoral behaviors associated with disorders of the neuromoral network.

Patients with these disorders pose a special problem for forensic
neuropsychiatry.
Mario F. Mendez, MD, PhD. The Neurobiology of Moral Behavior: Review and Neuropsychiatric Implications. CNS
Spectr. 2009 November; 14(11): 608–620. PMCID: PMC3163302 NIHMSID: NIHMS296407

21. A universal normative morality

Philosophers since pre-Socratic times have long pondered the
existence of a universal normative morality in addition to the
descriptive codes proposed by each society, religion, or legal
system.

22. The neuro-moral network in higher mammals
.
Studies with apes and
other social animals
describe moral emotions:
-empathy
-gratitude
-a sense of fairness
-emotional reciprocation
-consolation
-group loyalty.
De Waal FB. How animals do business. Sci Am. 2005;292:54-61.
Haidt J. The emotional dog and its rational tail: A social intuitionist approach to moral judgment. Psychol Rev. 2001;108:814-834.

23. Where is the moral brain?
A
neuro-moral neuronal network was described
consisting of right VMPFC and its connections to
ACC and INS.
Mario F. Mendez, MD, PhD. The Neurobiology of Moral Behavior: Review and Neuropsychiatric Implications. CNS Spectr. 2009
November; 14(11): 608–620. PMCID: PMC3163302 NIHMSID: NIHMS296407

24. Von Economo Neurons (VEN)
The cells of empathy?
*Human: 82,855
*Gorilla: 16,710,
*Chimpanzee: 1,808
Found in anterior insular cortex (AI) and anterior cingulate cortex (ACC)

25. Where in the world is insula?

26. Anterior Cingulate Cortex (ACC)
Santillo AF, Mårtensson J, Lindberg O, Nilsson M, et al. (2013) Diffusion Tensor Tractography versus Volumetric Imaging in the
Diagnosis of Behavioral Variant Frontotemporal Dementia. PLoS ONE 8(7): e66932. doi:10.1371/journal.pone.0066932
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0066932

27. The salience network of the brain

28. Empathy and compassion
 The
neuro-moral network processes:
-moral emotions
-moral drives
-avoidance of harm to others
-the need for fairness
-punishment of violators.

30. Disorders of the neuro-moral network
 Focal
lesions or frontotemporal dementia (FTD),
disturb personal, intrinsic moral emotions and
decision making

31. Sociopathy

Functional neuroimaging studies demonstrate frontotemporal
hypometabolism, hypoperfusion, or changes in spectroscopy
in murderers pleading not guilty by reason of insanity and in
violent psychiatric inpatients.

A reduction in prefrontal gray matter volume associated with
reduced autonomic arousal in violent offenders.

The smaller the volume of prefrontal cortex, the greater the
tendency towards sociopathic behavior in sociopaths.
Sapolsky RM. The frontal cortex and the criminal justice system. Philos Trans R Soc Lond B Biol
Sci. 2004;359:1787-1796.
Veit R, Flor H, Erb M, et al. Brain circuits involved in emotional learning in antisocial behavior
and social phobia in humans. Neurosci Lett. 2002;328:233-236.

32. Developmental and acquired
sociopathy
.
Sociopathy
Antisocial personality disorder

33. Developmental sociopathy
-lack moral emotions, empathy, conscience, or remorse and guilt for their acts
-normal moral knowledge and reasoning.
-instrumental (cold-blooded and goal-directed) aggression with decreased sympathetic
arousal.
-minimal alterations in heart rate, skin conductance, or respirations when they are subjected
to fear, stressful or unpleasant pictures,
-reduced autonomic responses to the distress of others, as well as reduced recognition of
sad and fearful expressions.
Tiihonen J, Rossi R, Laakso MP, et al. Brain anatomy of persistent violent offenders: more rather than less. Psychiatry Res. 2008;163:201212.

34. Genomic markers of developmental sociopathy

DRD2 contains two alleles A1 and A2. A1 allele is associated with involvement in acts of
serious physical violence and aggression.

DRD4 located on chromosome 11 has a polymorphism in the 3rd exon consisting of 7repeat allele associated with extreme violence and aggression.

5HTTLPR located on chromosome 17 has a polymorphism that contains low and high
expressing alleles. The low expressing allele was associated with antisocial personality
disorder.

COMPT located on chromosome 22, has a polymorphism consisting of a single
nucleotide difference (methionine replaced by valine). Carriers of met allele display
signs of violence and aggression including antisocial personality disorder.

MAOA has two polymorphisms low and high activity alleles. The low activity allele is
associated with violence and aggression.
Christopher J Ferguson, Kevin M Beaver. Natural Born Killers: The Genetic Origins of Extreme Violence . Aggression and Violent
Behavior Volume:14 Issue:5. September/October 2009 Pages:286 to 294

35. Phineas Gage: aquired sociopathy

36. Connectomics and Phineas Gage

37. Frontotemporal dementia
behavioral variant (bvFTD)







The second most common dementia
Young onset (midlife)
Behavioral changes usually misdiagnosed as psychiatric d/o
20-50% of cases are hereditary
15% autosomal dominant
TAU protein misfolded, but not amyloid beta protein
VENs are specifically and selectively attacked (reduced by
an average of 74%)
John M. Allman, Nicole A. Tetreault, Atiya Y. Hakeem, Kebreten F. Manaye, Katerina Semendeferi, Joseph M. Erwin,
Soyoung Park, Virginie Goubert, and Patrick R. Hof. The von Economo neurons in the frontoinsular and anterior
cingulate cortex. ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, ISSN 0077-8923

39. FTD: acquired sociopathy
 transgression
of social norms including
sociopathic behavior
 loss
of empathy or appreciation of the feelings of
others, disinhibited, compulsive acts
 often
commit criminal violations while retaining
the ability to know moral rules and conventions.
Mario Mendez. The Unique Predisposition to Criminal Violations in Frontotemporal Dementia. J
Am Acad Psychiatry Law. 2010; 38(3): 318–323. PMCID: PMC31395

40. Signs and symptoms of bvFTD
Unsolicited sexual approach or touch
Traffic violations including “hit-and-run accidents
Physical assaults
Shoplifting
Deliberate non-payment of bills
Pedophilia
Indecent exposure in public
Urination in inappropriate public places
Stealing food
Eating food in grocery stores stalls
Breaking and entering into other’s homes
Mario Mendez. The Unique Predisposition to Criminal Violations in Frontotemporal Dementia. J Am Acad Psychiatry Law. 2010;
38(3): 318–323. PMCID: PMC31395

41. Insula degeneration in bvFTD
 Insular
atrophy is one of the earliest structural
biomarkers in behavioral variant FTD (bvFTD)

42. Insular VEN degeneration in bvFTD
A cluster of dysmorphic right Insula VENs

43. Why is this important for clinicians?

When patients present with dysmoral behavior for the first time, as
a change from a prior pervasive pattern of behavior, clinicians
need to consider a possible, causative brain disorder.

Family and friends need education as to the significance of the
patient’s behavior, and the question of whether their dysmoral
behavior is their “fault” may need frank discussion.

Medications can be useful in controlling related behaviors such
as impulsivity, but do not selectively suppress dysmoral behavior.

Selective serotonin reuptake inhibitors, beta-blockers, and mood
stabilizing antiepileptic agents (such as valproate,
carbamazepine, and lamotrigine) could be of help in this regard.

44. bvFTD and forensic psychiatry

Patients with FTD with disturbed volition have committed crimes and
been arrested.

The US federal insanity defense hardens the original M’Naughton rule,
requiring the defendant to prove, by “clear and convincing evidence,”
that “at the time of the commission of the acts constituting the offense,
the defendant, as a result of a severe mental disease or defect, was
unable to appreciate the nature and quality or the wrongfulness of his
acts” (18 U.S.C. § 17).

Without the restraint of intuitive moral emotions bvFTD patients may not
be able to deter an impulse to act in an unacceptable manner, even as
they know right and wrong and understand the nature of their acts.

These considerations demand a reappraisal of the how we view
culpability and criminal violations among brain-injured patients.
Markowitsch HJ. Neuroscience and crime. Neurocase. 2008;14:1-6.

45. Not Guilty by Reason
of Brain Damage?
 Sapolsky
(Phil Trans R Soc London B 2004;
359: 1787-1796) suggests that the insanity
defense (not knowing right from wrong)
should be expanded to consider impaired
volition – diminished impulse control.

46. Genomic markers of bvFTD
 GGGGCC
hexanucleotide repeat in the C9ORF72
gene in bvFTD and amyotrophic lateral sclerosis
(ALS).
 microtubule-associated

protein tau (MAPT) gene
progranulin gene (GRN).

47. Tauopathies - misfolded tau protein

48. Axonal microtubules and tau protein

50. Remembering the memory – quick reminder
 Synapses
or microtubules controversy

51. Synaptic Darwinism
Where are memories stored?
 Neurons
that fire together wire together.
 Memory is attached to synapses (plasticity).
Donald Hebb 1949 “The Organization of Behavior”.

52. Memory nano-machines
Electronic conductance
Access to logic gates

54. Quantum memory?

56. Traditional computing vs. quantum computing
(Bit vs. Qubit)
Bit
0 or 1
Qubit
0 and 1

58. Quick reminder of genomics and proteomics

59. Genes are the blueprints of life
Proteins are the building blocks of life.
 The
blueprint of life confused with life itself

60. Myths and facts about genes
BAD NEWS FIRST: genetics we all learned in
college is not valid for the conditions we are
treating and studying.
GOOD NEWS: forget genes, study proteins

61. Rare vs. common diseases
 Rare
diseases (mendelian transmission) -cystic fibrosis, Huntington’s disease,
muscular dystrophies, fragile X, etc.
 Common
diseases (non-mendelian
transmission)--diabetes, asthma, obesity,
coronary artery disease, most cancers,
schizophrenia, bipolar d/o

62. Myth # 1
 We
are different because our genes are
different

63. Fact # 1
 Two
unrelated human beings share 99.9%
of their genomic sequence, and could be
considered almost genetically identical.
 Variability 0.1%

64. Myth # 2
 All
genes in our genome code for proteins

65. Fact # 2
 -Only
1.1% to1.4% of the genome's sequences
code for proteins.
 -Human body contains over 100,000 proteins.

66. Myth # 3
 Genes
are structural units.

67. Fact # 3
 Genes
are functional units.
 Definition of a gene: A group of nucleotides that
code for one single protein.
 Genes can contain from 1,000 to more than 1.5
million nucleotides.

68. Myth # 4
 Identical
twins always have identical proteins
Hum Mol Genet. 2011 Dec 15;20(24):4786-96. doi: 10.1093/hmg/ddr416. Epub 2011 Sep 9.
Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder.
Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T, Murray
RM, Mill J.

69. Fact # 4
 Expression
 Identical
of genes may differ in identical twins.
twins convergent for schizophrenia 48%
 ST6GALNAC1promoter
on chromosome 17- different
in identical twins discordant for schizophrenia.
Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, Kalidindi S, Picchioni M, Kravariti E, Toulopoulou T, Murray
RM, Mill J. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol
Genet. 2011 Dec 15;20(24):4786-96. doi: 10.1093/hmg/ddr416. Epub 2011 Sep 9.

70. Proteins – conformational dynamics
 Humans
have 23,000 genes
 1.1% to1.4% code for proteins
 Over 100,000 proteins in human body

71. Biomarkers: Ethical considerations

Genetic variants predisposing to diseases or predicting drug response may
have medico-legal implications (ex, access to genetic data by employers
and insurance companies may lead to discrimination of individuals with an
unfavorable genetic constitution or who would only tolerate expensive
drugs (Koo, 2006)(Vijverberg, 2010).

The Genetic Information Nondiscrimination Act (GINA) was passed into law
on 21 May 2008. However, genetic non-discrimination laws only provide the
illusion of protection against potential risks of discrimination (Van
Hoyweghen, 2008).

A study reviewed the definitions of genetic testing used by 65 organizations
and entities throughout North America and Europe, such as genetics
professional organizations, insurance companies, pharmaceutical
companies, legal firms, and found extreme variability (Sequeiros, 2005).