ICM/Genetics 2

• leading
• yes/no
• double
• open-ended (best)

• silence
• facilitation
• confrontation (only use when the patient is lying on purpose)
• direction

• *allocate time (10 minutes)
• address important issures
• assure patient's understanding
• negotiate further testing/treatment/follow-up
• be concrete

(name) a (age) year old (race, occupation, and marital status) male/female. A history of (major, pertinent illnesses or surgeries), presents with (patients own words) for the past (time).

• "When was the last time you were perfectly well?"
• listen first, then direct and facilitate

time, quantity, location, aggravating/alleviating factors, quality, setting, associated symptoms, inconstate dimensions

• significant illnesses: childhood illnesses, serious infections, anything requiring lifestyle modification or absence from school/work
• Surgeries: in/outpatient, obstetrical deliveries, significant injuries
• Hospitalizations:
• Disease exposures: TB/HIV
• Medications: prescriptions, OTC, herbs, home remedies
• Allergies/Sensitivies: describe and date reaction; antibiotics, penicillin, eggs, shellfish, nuts, environment

• job
• marital status/kids
• education
• tobacco/alcohol/drug use
• diet
• exercise

• F - Faith: "Do you consider yourself to be a religious/spiritual person?"
• I - Influence: "Does your religion influence the way your care for yourself/illness?"
• C- Church: "Are you a part of a congregation/spiritual community?"
• A- Address: "How would you like me to address these issures with you?"

• include: ALL first degree relatives (ideally a 3-generation history --> genogram)
• record: age/health if alive or age/etiology of death; all major illnesses (CV disease, DM, HTN)

• **appropriate for age and circumstance
• immunizations
• PAP smear
• breast exam/mammogram
• colon cancer screening
• special circumstances (ophthalmology, CXR, exercise stress test)

cover chief symptoms referable to each system

• what: cc; age/sex,; HPI; pertinent PMH, HF, SH, ROS
• determine potential diagnoses and think about organ systems or chronic conditions that accompany the diagnosis

• V: vascular
• I: infection/inflammatory
• T: trauma/toxin
• A: autoimmune
• M: metabolic
• I: idiopathic
• N: neoplastic
• C: congenital

• appearance: grooming, hygiene, older/younger than stated age, appropriate wardrobe, disfigurations/scars/tattoos
• behavior: cooperative, agitated, disinhibited, disinterested, acute distress? eye contact?

Abnormal movements (tremors, slow mvmts, lip smacking, tongue protrusions), gait, posturing, pacing, hand wringing, tics, restlessness

• fluency
• amount
• rate
• tone
• volume

best used by describing the patient's own words

• expression of mood during interview
• flat (nothing) --> blunted --> constricted --> full range (normal)

• describes throughs occurring to the patient
• obsessions
• paranoia: "Do you ever feel like peopler are out to get you?"
• suicidal thoughts/intentions/plans
• homicidal thoughts
• delusions: incorrect processing --> fixed ideas not shared by others; can have normal thought processes, but delusional content

• abnormal thought process
• rapid shifting from one through to another with logical connections

• abnormal thought process
• over-inclusion of nonrelavent details, and eventually returning to answer the question
• listener can follow train of thought

• abnormal thought process
• irrelevant thoughts, only related in a minor way, never returning to original question

• abnormal thought process
• impossible to see the connection between the sequential thoughts
• words make sentences, but they don't make sense

• abnormal thought process
• repeatedly coming back to the same topic

• abnml thought process
• unable to complete the thought --> stop speaking in the middle of the conversation
• no recall of events

• abnormal thought process
• new words or combinations that are not really words; not easily understood

• abnormal thought process
• confused language, mixure of words/phrases with not apparent meaning

• abnml thought process
• thoughts associated by the sound of words rather than the meaning

• abnml thought process
• senseless repetition of a word/phrase

• auditory are most predominant in the US, visual are more predominant
• also tactile, gustatory, and olfactory

• illusion: misperception of real external stimuli (hearing tree rustling and thinking someone's called your name)
• depersonalization: feeling that one is not oneself
• derealization: feeling that the environment has changed

• name, date, locations, and situation
• also current events

• calculations
• "world" backwards
• 5 things that start with a particular letter
• seriel 7's or 3's
• calculations

• immediate: digit-span (repeating 6 figures to and from examiner)
• recall: immediately repeat 3 words, and then 3-5 minutes later
• recent: past few months or days
• long term/remote: childhood data

• Proverb explanations
• Similarities/Differences

• ability to understnad the outcome of behaviors/ capacity to make/act on good decisions
• test with hypothetical situations

• reliability: consistency of exam under different variables
• validity: how a test measures that which it is intended to measure

• intelligence/cognitive testing
• achievement testing
• neuropsychological testing
• personality testing

• fluid: capacity for learning and problem solving that is independent of education/experience
• crystallized: interaction of fluid intelligence and culture; abstract

• determines verbal knowledge => informal/formal education
• define words, how are words similar?

• ability to form relatively abstract concepts/relationships w/o words (i.e. visuals, manipulation of concepts, relationships)
• use pictures to fill the last spot (as shown in class)

• tests auditory short-term (sequencing skills, attention, and concentration)
• Remember and repeat these numes and say in ascending order 2-3-1

Ability to perform simple tasks, maintain focused attention/concentration ~ 2 minutes

• a composite number to describe intelligence, but doesn't reflect areas of strength and weakenss
• perceptual reasoning, verbal comprehension, memory, working memory, processing speed

• assesses achievement in academic areas (reading, spelling, writing, arthmetics)
• expressed as a standard score (IQ) or grade equivalents

• determines the degree to which the areas of the brain and neurologically driven areas of skill are intact
• for localization of disease processes or strength/weakness areas for rehab planning

• diagnosing both enduring personality traits and acute psychiatric conditions
• objective: checklists/forms --> empirically generates norms; 500 true/false statements (assess depression, schizophrenia, anxiety, ADHD, mania, and personality disorders)
• projective: patient's response to an ambiguous stimulus, so the pt projects his internal state one the ambiguous stimulus (Roschach Inkblot tests)

a type of personality testing allowing the patient to tell a story based on an illustration

face-to-face, quite/private room, leaving lots of time

• determine what the patient knows to prepare them for the possibilities throughout the diagnostic process and their understanding of health and disease
• recognize that the patient may not want to know all of the information, or designate someone else to communicate on their behalf

• do plan the most appropriate next step and offer if to the patient, but remember their right to refuse
• set a firm date for a follow-up (short interval)
• ask about the patient's safety in the context of their emotional state
• discuss potential sources of support

• legal obligation to obtain informed consent from the patient
• honesty with a child --> trust
• ask the family *why* they don't want the news given (fear? previous experiences? person/cultural/religious context)
• offer to talk to the patient together

• affective: tears, anger, sadness, love, anxiety, relief
• cognitive: denial, blame, guilt, disbelief, fear, loss, shame, intellectualization
• basic psychophysiologic: fight or flight

• listen quietly and attentively
• encourage descriptions of feelings

• use a skilled translator, but avoid family members
• consider telephone translation services
• *speak directly to the patient

• some patients want a plan and details, others want reassurance
• avoid precise answers regarding timing
• *reassure availability*

maintain common chart or log book with goals, treatment choices, emergent situations, likes/dislikes, contact information

• allows identification of individual chromosomes and determination of any structural abnormalities
• FISH is the most common staining technique

• a labeled probe is hybridized to a chromosome to test for missing/additional chromosome material and/or rearrangments
• multiple probes can be used for multiple colors

• metacentric
• submetacentric
• acrocentric

• polyploidy: complete set of extra chromosomes (triploidy or tetraploidy)
• aneuploidy: cells that are missing/ have extra of a single chromosome (monosomy, trisomy, or tetrasomy), typically => nondisjunction

• nondisjunction during a meiotic division (either I or II)--> different chromosome numbers in gametes
• monosomy is almost always lethal, but some trisomy is compatible with life

• most common aneuploid condition (90% from mother)
• --> heart defects, strabismus/eye problems, hypothyroidism, hearing loss, developmental disabilities, SC injuryies in older pts d/t vertebral weakness, GI obstruction

• 2nd most common autosomal trisomy live births
• prenatal growth deficiency, VSDs, severe developmental delays, 5% reach 1yr, predisposition to infections and apnea

• least common autosomal trisomy live birth
• oral-facial clefts, small/malformed eyes, CNS defects, heart defects, renal abnormalities, 5% reach 1st year, *are* able to developmentally progress

• dramatic increase in risk of chromosomal problems after 35 years
• *check age of mother at due date

• 45, XO (70% maternal origin)
• short stature, sexual infantilism, webbed neck, broad chest, heart/kidney defects

• 47, XXY (50% paternal meiosis I)
• tall/thin, gynecomastia, hypogonadism, no secondary sexual characteristics

• crossing-over regions between X and Y
• could possibly include the SRY region (located just centromerically)

• => two breaks on different chromosomes --> exchange of material
• carriers have normal phenotypes, but posisbly partial trisomy or monosomy in children

• balanced: no gain or loss of chromosomal material
• unbalanced: gain/loss of chromosomal material

agents that --> chromosomal breakage during mitosis and meiosis

• the p arms of nonhomologous chromosomes are lost and the q (long) arms will fuse together (esp common w/ acrocentric chromosomes)
• phenotypically normal if the p arms have no genetic material and it's a live birth, but only have 45 chromosomes/cell
• typically involving chromosomes 14 and 21
• can --> 3 copies of 21q --> Down's Syndrome

• deletions: single chromosomal break --> loss of genetic material (either terminal or interstitial); on 5p --> Cri-du-chat syndrome,
• microdeletions: < 5Mb deletions, usually determined by FISH, 4p --> Wolf-Hirschhorn; 7q (elastin allele)--> Williams

• microdeletion on 22q
• --> tetralogy of Fallot, palatal abnormalities, learning difficulties

• one parent contributes two copies of a chromosome and the other parent contributes none => parental or zygotic nondisjunction
• deletion on 15q --> Prader-Willi (paternal) or Angelman (maternal)

• unequal crossing over
• --> less serious consequences than deletions in the same region

• => deletions of the telomers --> end fusion --> ring
• possible for 46,X,r(X) --> Turner's syndrome

• => two breaks in the chromosomes followed by backwards reinsertion of teh fragment
• pericentric: involves the centromere
• paracentric: doesn't involve the centromere
• can interfere with meiosis --> offspring abnormalities
• Chromosome 8q --> mental retardation, heart defects, seizures,

• => chromosome dividing latitudinaly (perpendicular to normal axis of division)
• --> i(Xq) w/ Turner Syndrome symptoms

• recognizable chromosome syndrome features
• unrecognizable pettern of ≥2 malformations
• ambiguous genitalia
• ID/developmental delay in children w/ multiple anomalies
• parents with chromosome abnalities
• stillborn infants w/ malformations
• females w/ short stature and primar amenorrhea
• males w/ small testes or gynecomastia

usually autosomal recessive, with no morbidity in the carrier state

• most common monogenic disorder of carbohydrate metabolism
• poor sucking, failure to thrive, jaundice, cataracts (10%)
• (untreated) --> sepsis, hyperammonemia, shock
• (chronic) poor growth, mental retardation, ovarian failure

• fructokinase: asymptomatic fru in urine *most common
• Hereditory fru intolerance: poor feeding, hepatic/renal insufficiency, failure to thrive (FTT), death
• F16BPase deficiency: impaired gluconeogenesis, hypoglycemia, severe acidemia

• **most common error of carbohydrate metabolism
• --> DM1/2 or maturity-onset-diabetes of youth (MODY)

• 5-90% depending on the population
• lactose intolerance is common in tropical/subtropical countries
• --> nausea, bloating, diarrhea

• impaired synthesis or degradation
• esp damaging to liver (heaptomegaly) and skeletal muscle (unable to release glu --> hypoglycemia)

• Phe: --> PKU; --> fetal birth defects, growth retardation, microcephayl, and mental retardation if hyperphenylalaninemia during gestation
• Tyr: --> hereditary tyrosinemia type 1 (HT1) --> neurological, kidney, and liver dysfunction
• BCAAs: --> Maple Syrup Urine Disease (MSUD), --> ketaoacid accumulation --> neurodegeneration and death

• => defect in cholesterol biosynthesis
• --> brain/heart/genitle/hand defects at birth (rarely seen with metabolic disorders)

• most common error of fatty-acid metabolism
• --> episodic hypoglycemia, comiting, lethargy (esp p minor illness and dec intake), cerebral edema/encephalopathy
• variability - acute illness, chronic, sudden death, or asymptomatic with mutation

• => cortisol synthesis defect
• --> masculinization of the genitalia in females, and premature virilization in males

• => accumulation of substrate from undegraded molecules
• --> (mucopolysaccharidoses, GAG breakdown defects), hepatosplenomegaly, short stature, hearing/vision loss, C/V dysfunction, andseizures (Hurler Syndrome --> crouched stance, thickened digits, protuberant abdomen)
• --> (degradation problems) visceromegaly, organ dysfunction, earth death

• most types are autosomal recessive, but ornithine transcarbamylase is X-linked recessive
• --> lethargy, coma,

• complicated b/c of the varying energy demands for each system
• --> hypotonia, hepatomegaly, non-ketotic hypoglycemia, and metabolic acidemia

--> cystinosis (Cys is the least soluble AA)--> FTT, renal glomerular damage (p Cys crystals), cystinuria, HTN

• autosomal recessive disorder of iron accumulation in liver, kidney, heart, joints, and pancreas (associated diseases)
• earlier penetrance in men b/c women lose iron during menstruation, gestation, and lactation (~40 y/o for men)

• Wilson's disease (WND): autosomal recessive; accumulation of Cu --> liver disease and neurological abnormalities
• Menkes' disease (MND): X-linked recessive; lack of Cu, --> kinky hair, mental retardation, seizures, and early death

scaly, red rast around mouth, genitals, buttocks, and limbs

• genetic: looking at inheritance patterns in families and establishing the order on the chromosomes
• physical: tag the chromosomes w/ physical markers to est position/ DNA sequences on the chromosomes

• synteny: two genes are on the same chromosomes (physical location)
• linkage: two genes are so close that they are likely to be inherited together *must* be syntenic; cM ≤ 50

• the distance between two loci on a chromosome (probability, not physical distance)
• 1cM ~ 1% recombination frequency (theta)

• linkage likelihood/ likelihood of no linkage (theta = 50cM)
• ratios > 1.0 = favor of linkage
• ratios < 1.0 = odds against linkage

LOD: logarithm of linkage ratio, LOD >3.0 = linkage, LOX <-2.0 = not linked

• the nonrandom association of alleles at linked loci, but it will diminish over time as a result of recombination
• helps us map disease genes

• Digenic inheritance: inherited as AD, AR, XLR or mitochondrial; > 21 different gene mutations w/ 24 additional chromosomal regions that are symptomatic (*locus heterogeneity*)
• --> rdxn in daytime vision p rod photoreceptor death

• linkage: positions of loci on the chromosomes that will be transmitted togehter within families
• association: statistical relationship between two traits in the population

• ossification of discs/joints/ligaments in the spinal column
• associated with mutation of the HLA gene (for human leukocyte antigen)
• *association*

• GWAS: SNP (single nucleotide polymorph) analysis to test for association or linkage disequilibrium between a disease and a marker by testing thousands of markers across teh genome
• --> quick identification of candidate disease genes or chromosomal regions of the disease

• a gene whose (known) protein produce makes it a likely candidate for the disease in question (collagen genes for Marfan syndrome)
• analysis = positional candidate approach (much faster)

• recognize general features of invading microorganisms
• phagocytes: engulf and destroy microorganisms
• NK cell: specialized lymphocytes that respond to tumor cells and viruses
• complement system: performate a microbes' membrane and attract phagocytes

• T lymphocytes: interact with infected cells to kill them; aid B cell response
• B lymphocytes: --> antibodies for specific antigens

• macrophages and dendritic cells engulf microbes, digest in the phagolysosome, and present peptides on their surface = "antigen-presenting cells"
• costimulatory molecules: displayed on the surface of the cell encounteriing foreign pathogens that stimulate the T helper cells to secrete cytokines and promote immunoglobulins from B lymphocytes that can bind the invading microbe
• final step: stimulated B cells --> somatic hypermutations during mitosis --> altering the receptors --> mature plasma cells (secretes 10 million antibodies/hour)

• permit a faster/more vigorous response to a second exposure to the same pathogen
• this is what vaccinations promote

• MHC I: present the proteins being made by the cell in questions (viral or cancer proteins); expressed on all cells' encoded by HLA-A, -B, and -C loci on chromosome 6; --> transplant rejection
• MHC II: present what the cell eats and digests in the phagolysosome; expressed only on APC cells; heterodimers => chromosome 6

• Th1: T helper cell --> stimulate more cytotoxic T cells to respond to an infection
• Th2: T helper cell --> stimulate B cells to respond
• memory T cells: ensure rapid response to a second exposure from the same pathogen
• regulatory T cells: prevent the immune system from attacking the body's own cells

• innate system: quick reactions
• humoral system: prevents extracellular pathogens (bacteria and viruses) from taking hold
• cellular immune system: intracellular infections (parasites and viruses)
• **overlaping

• heavy chains: one pair of identical chains - gamma, mu, alpha, delta and epsilon
• light chains: one pair of identical chains - kappa and lambda
• both heavy and light chains have Constant, Variable, and Joining regions (with a Diversity region on the heavy chain)
• **each region on each chain is expressed by the genes and the cell chooses the combination that it want and becomes a constant for that particular B cell!**

• multiple germline immunoglobulin genes:
• Somatic recombination (VDJ regions): deletion of the unwanted sections
• junctional diversity: the way in which the different regions come together vary
• Somatic hypermutation: the secondary differentiation by B cells have a VERY high mutation rate for antibody diversity (not used for T cells)
• multiple combinations of heavy/light chains: randome combos are possible

• only able to respond to MHC presented peptides
• same regions (Variable (V), Constant (C), Joining (J), and Diversity (D)) as immunoglobulins

• MHC I present: --> inhibition of NK cells
• MHC I absent: --> activation of NK cells

• inter-individual variation: KIR and MHC genes (b/c they're part of a gene family)
• intra-individual variation: immunoglobins and T-cell receptors

• --> mononucleosis, hemoytic anemia, etc
• infected cells destroy cutotoxic T cells by downregulating MHC I molecules and expresses an inactive analog

fetal MHC I cells would express paternal molecules, but the MHC I cells are downregulated and the cells present HLA-G on the surface -x-> T cell response or NK cells

• HIV infections send RNA to the nucleus of macrophage and helpter T cells to incorporate into the cell's chromosomes
• CCR5: the gene for the cytokine receptor through which HIV likes to invade; individuals who are homozygously lacking the receptor are HIV resistant

• Rh negative mother and Rh positive daughter --> mother's antibodies attacking the baby
• Mother must be given Rh immune globulin (Rhogam) to prevent the reaction

• intrinsic defect with B or T cells, MHC, complement system or phagocytes => genetic alterations
• agammaglobulinemia, SCID, Zap70 kinase deficiency, purine nucleoside phosphorylase deficiency, bare lymphocyte syndrome, DiGeorge, ataxia telangiectasa, Wiskott-Aldrich, Chediak-Higashi, Leukocyte adhesion deficiency, chronic granulomatous disease

• 1 in 30 - 1 in 50
• 2-3% are recognizable

• axis formation: anterior/posterior, ventral/dorsal, etc
• pattern formation: spatial location of cells --> differentiation
• organogenesis: differentiated cells --> organ systems

• **regulate development!!
• Fibroblast Growth Factor (FGF): cartilage/bone formation
• Hedgehog family: axis specification, motoneuron placement, and limb patterning
• Wingless (Wnt) family: est polarity; abnormalities --> tumors
• Transforming Growth Factor beta (TGF-beta): --> homo/heterodimers --> BMPs --> bone, etc

• FGFR3: restrains chondrocyte proliferation and differentiation; inactivation --> cartilage proliferation and inc long bone growth, overexpression --> short bones and skeletal defects
• FGR1, 2, and 3 mutations: --> hypochondro/achondroplasia (depending on the area/domain of mutation), short status, mid-face hypoplasia, hearing loss, skeltal disorders

• HOX, PAX, SOX families, etc
• control the transcription of genes, so a mutation here could have many different effects (pleiotropic effects)

function: collagens/fibrills/proteoglycans as scaffolds for tissues and organs, also serve to separate adjacent groups of cells during development

• neural crest cells do not migrate --> enteric nervous system --> bowel hypomotility, obstruction, and gross distention
• Down's Syndrome or Waardenburg --> HSCR
• => inactivation of RET (rearranged during transfection) gene, EDNRB or -3(endothelin-B or -3),

• Induction: cells of one embryonic region influence the differentiation of a second embryonic region
• Neurulation: initiates organogenesis and induces the neural tube/neural crest cells to form

• formation of the three germ layers
• endoderm --> digestive/respiratory tract lining, visceral organs and lungs
• mesoderm --> skeleton, UG system, limbs
• ecoderm --> neural tube/ CNS, epidermis, and neural crest cells

• determines the anterior/posterior axis
• HOX gene

• unpaired structures develop in the midline and lateralize (heart), or the partner may regress (blood vessels),
• genes: Sonic hedgehog (Shh) and zinc-finer protein of the cerebellum (ZIC3), d adn eHAND TFs,
• situs inversus: a L/R reversal of organ position
• situs ambiguous: L/R randomization

• => neural crest cells
• HOX genes determine fate of ncc's
• mutations in FGFR and GLI3 --> defects

• => lateral plate and somatic mesoderm
• apical ectodermal ridge, progress zone, and zone of polarizing activity
• TBX gene mutations --> Ulnar-Mammary and Holt-Oram Syndromes w/ hypoplasia of limbs

• *coordination of multiple processes* esp between the epithelium and mesenchym
• mediated by multiple signaling molecules, conduct signals, and TFs

• 5-10% are inherited (germline mutations)
• 100% of cancers are acquired changes (somatic mutations)

environmental facors --> mutation in somatic cells (so not passed on)

• one copy of a mutant gene is inherited, which paves the way for a second, environomental mutation to happen --> tumor
• e.g. retinoblastoma

• encode products controlling cell growth
• mutated proto-oncogene --> oncogene (dominant gain-of-function mutation) --> de-regulation of vell cycle control
• can be inserted by retroviruses

• => defects in DNA repeair
• --> widespread mutations, chromosome breaks, and aneuploidy

• telomeres shorten after 50-70 divisions
• tumors activate telomerase to help the cells escape cellular senescence

• --> TF that induces apoptosis p damaged DNA
• somatic TP53 mutation is found in most tumors

• autosomal dominant, germline mutation
• --> numerous, large polyps develop in 20's,
• 1/20 Americans are diagnosed with colon cancer,

• normally a tumor supressor
• mutations --> hyperproliferative colon epithlium (DNA hypomethylation *epigenetic*) --> activation of KRAS, and loss of SMAD4 and TP53 genes --> tumors
• assoc w/ majority of colon cancer cases, also one of the earliest alteraions

• inherited mutations on any 6 genes w/ DNA mismatch repair
• microsatellite instability

• inherited breast cancer (esp early onset)
• mutations --> truncated protein and loss of function
• *BRCA = suppressor genes*

• autosomal dominant; highly penetrant, variably expressive
• characteristics: early onset, multiple affected family members, *bilaterality*, multiple tumors, rare cancers
• **take a complete family history with each visit and pay attention to any changes

• Tumor suppressor genes: BRCA1/2, APC, RB
• Proto-oncogenes/oncogenes: RET
• DNA mismatch repair genes: MSH2, MLH1

• sporadic: 75-85%, different sides of the family
• familial: 10-15%, same side of the family, but not very common
• hereditary: 5-10%, autosomal dominant transfer

Retinoblastoma, FAP, Neurofibromatosis, Li-Fraumeni, Con-Hippel Lindau disease, Wilms tumor, melanoma, breast/ovarian cancer, Cowden, Ataxia telangiectasia, Gorlin, HNPCC