Published on February 28, 2014
Genomic and Proteomic markers in Forensic Psychiatry Adonis Sfera, MD With input from Mario Mendez MD, PhD
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
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)
From cellular to molecular level mid 1980s Protein mass spectrometry Confocal laser scanning microscope Multiphoton microscope
Cellular biomarkers Cellular connectomics (neuroimaging and electrophysiology). *Human Connectome Project *Brain cells are organized in networks: neuronal, glial, neuronal-glial and complex cellular networks.
Molecular biomarkers -Genomic markers -Proteomic markers
2003- the holy grail of genetics
Gene mining “gold rush”
Genes – more questions than answers
From the sovereignty of genes to the sovereignty of proteins
Origami – the art of folding
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
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
Fragile X syndrome- cellular level
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.
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."
Talking about genomic markers…
The neurobiology of morality
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
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.
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.
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
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)
Where in the world is insula?
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
The salience network of the brain
Empathy and compassion The neuro-moral network processes: -moral emotions -moral drives -avoidance of harm to others -the need for fairness -punishment of violators.
Disorders of the neuro-moral network Focal lesions or frontotemporal dementia (FTD), disturb personal, intrinsic moral emotions and decision making
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.
Developmental and acquired sociopathy . Sociopathy Antisocial personality disorder
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.
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
Phineas Gage: aquired sociopathy
Connectomics and Phineas Gage
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
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
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
Insula degeneration in bvFTD Insular atrophy is one of the earliest structural biomarkers in behavioral variant FTD (bvFTD)
Insular VEN degeneration in bvFTD A cluster of dysmorphic right Insula VENs
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.
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.
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.
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).
Tauopathies - misfolded tau protein
Axonal microtubules and tau protein
Remembering the memory – quick reminder Synapses or microtubules controversy
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”.
Memory nano-machines Electronic conductance Access to logic gates
Traditional computing vs. quantum computing (Bit vs. Qubit) Bit 0 or 1 Qubit 0 and 1
Quick reminder of genomics and proteomics
Genes are the blueprints of life Proteins are the building blocks of life. The blueprint of life confused with life itself
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
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
Myth # 1 We are different because our genes are different
Fact # 1 Two unrelated human beings share 99.9% of their genomic sequence, and could be considered almost genetically identical. Variability 0.1%
Myth # 2 All genes in our genome code for proteins
Fact # 2 -Only 1.1% to1.4% of the genome's sequences code for proteins. -Human body contains over 100,000 proteins.
Myth # 3 Genes are structural units.
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.
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.
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.
Proteins – conformational dynamics Humans have 23,000 genes 1.1% to1.4% code for proteins Over 100,000 proteins in human body
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).
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