What dz is this?:

PRINCIPLES
Variable expressivity
Genetic heterogeneity
Gene dosage
Toxic gain of function
Risk modifier
 
MAJOR PHENOTYPIC FEATURES
Age at onset: middle to late adulthood
Dementia
-Amyloid plaques
Neurofibrillary tangles
Amyloid angiopathy
 

Alzheimer's

-What is the Inheritance (2 types)

-what % is sporadic?

-Early onset is usually inherited?

-MOST is MULTIFACTOR...some is autosomal dom (rare)

-75%

-Yes often called early-onset familial

-What protein is involved in neuronal dysfunction and death observed with AD?

-What genes are associated with beta-amyloid (there are 3)

-Which of these causes the most rapid progression and earliest onset?

-Beta-Amyloid

-Beta-amyloid 1) precursor protein gene (APP), preseniline 1 gene (PSEN1), and the presenilin 2 gene (PSEN2)

-PSEN1

-What 3 neurological areas are mostly degenerated in AD?

-Degeneration leads to Tangles and plaques

-what do these plagues/tangles do?

-When APP is cleaved abnormally, it makes A42, 

-AD is a central neurodegenerative disorder, especially of cholinergic neurons of the hippocampus, neocortical association area, and other limbic structures.

-True

-

What is Beta-APPs role in AD?

-What is the neurotoxic constituent of improperly cleaved Beta-APP?

-What 3 enzymes cleaves BetaAP

-which cleaves 90%and has no role in dz

-Which cleave to form Beta-40 (nontoxic) or Beta 42 (toxic) forms?

-ABeta-42...(neurotoxic form of amyloid)

-Alpha-secretase, beta/gamma secretases

-alpha secretase

-beta/gamma secretases both.  

-are social etiquette and superficial conversation systems retained?

-What do AD people usually die from?

-What are some inheritance risks for AD?

-T/F...aging process is deccelerated in AD?

-Yes

-Death usually results from malnutrition, infection, or heart disease.

-Old age, family history, female gender, and Down syndrome are the most important risk factors for AD.

False...it is accelerated

Both familial AD and sporadic late-onset AD are strongly associated with allele Epsilon-4 at the  _____ gene

-what is the mechanism for this type of AD?

-apolipoprotein E (APOE) ...this is a dose-dependent type onset

-Unclear as to what APOE's role is.

Goss: Muscle

Muscle tone Afferent signal motor neurons located where?

-For muscle tone...what is the sequence of events? (there are 3)

-DRG

-1) Muscle stretches
2) Afferent neuron carries impulse to spinal cord
3) Motoneurons cause muscle to contract
 

-hemi=

-paresis=

-______ motor neurons

-In the brain and spinal cord

-Send axons out of the spinal cord
 

 -UMN Damage

-LMN Damage

-fasciculations

-hypotonia...flaccid paralysis.

-The site of contact between the axon and the muscle fiber

-What is neurotrans here?

-Fast FIBERS: White, rapid but short movements

-What is decreased in NMJ with botulism?

- Two dzs that cause this:Decreased acetylcholine effects on muscle cell

-NMJ

-ACh

 -Type-II

 -Acetylcholine release from neuron

-Curare and MG (autoAb to Ach receptors)

-What type of repeats are involved with Fragie X SYndrome?

-How many repeats correspond to a premutation

-how many for a mutation?

-CGG repeats (causes hypermethylation of CGG repeat sequences and the adjacent FMR1 rpomotor...this causes a loss of FMRP expression)

-59-200

-more than 200

-The length of an unstable CGG repeat increases each generation if it is transmitted by a female, therefore, increasing numbers of affected offspring are usually observed in later generations of an affected family; this phenomenon is referred to as?

-genetic anticipation

-AGG

-How many males exhibit fragile X

-How many females?

-Patients with fragile X syndrome have a _____ life span.
 

-All

-Half (X inactivation of affected fragile X)

-normal

What am I?

causes moderate mental retardation in affected males and mild mental retardation in affected females.
Most affected individuals also have behavioral abnormalities, including:
hyperactivity
hand flapping or biting
temper tantrums
poor eye contact
autistic features

-_____ have a long face with prominent jaw and forehead, large ears, and macro-orchidism. Because these clinical findings are not unique to fragile X syndrome, the diagnosis depends on molecular detection of mutations.

-What is the curative Tx for Fragile X?

-Males

-There are none.

-What does MERFF stand for?

-

The MTTK mutations associated with MERRF reduce the amount of charged tRNAlys in the mitochondria by ___ to ___% and thereby decrease the efficiency of translation such that at each lysine codon, there is a ___% chance of termination.

-mtDNA is strong subject to selective pressures?

-50% to 60%

-26%

-True

-who do we inherit our mitochondrial DNA from?

-what gene is responsible for Myoclonic Epilepsy (mito gene)

-What does this gene code for?

-MERRF patients are nearly always ________ for the mutant mitochondria.
 

-MOM

-MTTK GENE

-tRNA^lys

-heteroplasmic

Myoclonic Epilepsywith Ragged-Red Fibers (MERFF)

Myoclonic Epilepsy MTTK mutations:

-_____ accounts for 80% and _____ with 8363G>A together account for an additional 10%.

-Ultimately what is compromised with MERFF?

-What if you don't find ragged-red fibers in a muscle biopsy?

8344A>G

8356T>G

-Oxidative phosporylation.  

-Doesn't rule out MERFF

-The MTTK mutations associated with MERRF reduce the amount of charged tRNAlys in the mitochondria by ___ to ___ % and thereby decrease the efficiency of translation such that at each lysine codon, there is a 26% chance of termination.

-Any Tx?

-50% to 60%

-Supportitve...try to maximze oxidative phosphorylation with Coenzyme Q and Carnitine SUPPLEMENTS.

-What is the risk of a male having a child with MERFF?

-What about a female...?

-What if we have a hugely positive maternal blood sample for MERRF?

-Zero

-Can't be calculated due to the nature of mitochondrial replication

-Doesn't predict dz severity in child becaseu of REPLICATIVE SEGREGATION...you never know how child's replicative segregation may work out. 

ACHONDROPLASIA:

-what kind of inheritance is this?

--Gain-of-function mutations in the _____ gene

-Two mutations, _____ (∼98%) and 1138G>C (1% to 2%), account for more than 99% of cases 

-Mutation of guanine at position 1138 accounts for nearly ____ of achondroplasia; 

-What is the de novo mutation rate for this?

-Autosomal semidominant

-FGFR3 gene

-1138G>A

-100%

-80%

Achondroplasia

-________ is associated with shortening of limbs due to premature differentiation of cartilage in the growth plate into bone.

-How is Intelligence affected in Achondroplasia?

-Achondroplasia

-It is not

-what is the risk of two achondroplasic parents having a normal sized baby?

-What would teh mother have to have in this case?

-De novo mutations of FGFR3 guanine 1138 occur exclusively in the ____ germline and increase in frequency with advanced paternal age 

-25%

-Cesarean section

-father's

-What does the FGFR3 do, in general?

-how does it cause Achondroplasia?

-a transmembrane tyrosine kinase receptor that binds fibroblast growth factors

-FGFR3 activation inhibits proliferation of chondrocytes within the growth plate and thus helps coordinate the growth and differentiation of chondrocytes with the growth and differentiation of bone progenitor cells.

___ at position 1138 is one of the most mutable nucleotides in ANY GENE.

-__% have de novo mutations at 1138?

-What causes dental crowding in Achondroplasiacs?

-T/F...de novo mutations in the mothers germline occur with greater frequency over the age of 35?

-GUanine. 

-80%

-Midface hypoplasia.

-False...its is the father's germ line that has new mutations at 1138.

-What is the predominant type of DMD mutation?

- Oogenesis or Spermatoenesis arise with comparable freq in each...the de novo large deltions occur in which...the de novo Nucleotide changes arise in which

-What causes the Intellectual impairment of these kids?

-Large deletions (60-65%)

-Large deltions..Oogenesis

-Nuc Changes...Spermatogenesis.

-We don't know yet.

-are teh dystrophin abnormalities in smooth muscle?

-DMD pts have an IQ that is __ std dev below the mean.

-Females are less affected then males due to

-However most females still have what SS?

-Yes, but they rarely cause complications.

-One

- X inactivation

-cardiac abnormalities like DILATED CARDIOMYOPATHY,  LV DILATION, and EKG changes

-If a mother is a carrier...which has a 50% chance of INHERITING the gene (daught/son?)

-Dystrophin proteins that normally stabilize the muscle cells during contraction are defective
Plasma membranes are torn apart by muscle contraction, causing death of muscle tissue

-How will their calves look?

-By __ years of age, most patients are confined to a wheelchair and have or are developing contractures and scoliosis.
 

-Duchenne Muscular Dystrophy

-Huge ( due to the replacement of normal muscle tissue with connective tissue and fat _

-12

-Most DMD pts die of what?

-Any diff in intelligence?

-What chromosome is associated with DMD?

-what does DMD gene encode?

-Most patients die of impaired pulmonary function and pneumonia; the median age at death is 18 years.

-Yes..most are 1 std dev from mean IQ

-X chromosome

-the protein, Dystrophin

-What kinds of muscle is DMD expressed in?

-What types of DMD mutations usually occur?

- What is the DMD manuever..used mostly by age 5

-all card, smooth, skeletal and some  BRAIN NEURONS

-include large deletions (60% to 65%), large duplications (5% to 10%), and small deletions, insertions, or nucleotide changes (25% to 30%) 

-Dowers

What is the median age of death for DMD folks?

-_______ therapy can slow the progression of DMD for several years.

 -_____ muscular dystrophy (BMD) is also due to mutations in the DMD gene.
-BMD results from mutations that to a complete loss of dystrophin as seen in DMD patients ?

-18

-Glucocorticoid

-Becker

-False, lead to deficient or defective dystrophin ONLY

In both DMD and BMD, female carriers may develop dilated cardiomyopathy in the absence of apparent weakness?

-ARMD: Early signs occur in 30% of all individuals older than ____ years

-True

-75 years

-50% of genetic risk is due to a polymorphic varient Tyr402His in ___ ___ __ gene.

 -What varients may reduce your chances of getting AMD (2 of em) ?

-Early AMD is usually WET?

-_____ are localized deposits of extracellular material behind the retina in the region of the macula.

-Complement factor H (CFH) GENE

- Complement Pathway Factor B (CFB) and Complement component 2 (C2)

 -False...DRY

-Drusen

-In about ___of patients, retinal pigment epithelium remodeling occurs at the site of large, soft drusen.

-(neovascularization) occur here that grow in from the _____.

-What causes wet AMD?

-____ is a negative regulator of the alternative complement cascade and the Tyr402His variant is less capable of inhibiting complement activation, which is likely to predispose to AMD

-10%

-Choroid.

-These vessels are fragile, break, and bleed in the retina, resulting in wet AMD.

-CFH 

Although it is clear that environmental factors contribute to AMD, the only nongenetic risk factor identified to date is ______.

 -For wet-type AMD, thermal laser photocoagulation, photodynamic therapy, and intravitreous injection of a vascular endothelial growth factor inhibitor (______) may slow the rate of visual loss.

-smoking

-pegaptanib (Macugen)

- is a progressive degenerative disease of the macula, the region of the retina responsible for central vision, which is critical for fine vision (e.g., reading).

-Approximately 50% of the population-attributable genetic risk is due to a polymorphic variant, Tyr402His, in the ___ ____ _ gene.
 

-ARMD

-complement factor H (CFH)

-Ectopic Pregnancies are usually?

-Placenta attatching to the myometrium (middle uterine wall)

-Placenta attatching to the cervix?

-In the fallopian tube (95%)

-Placenta Accreta

-Placenta Previa

-Toxemias result in an abnormal amount of what ion retained?

-What is preeclampsia plus seizures?

-Are these common?

-Sodium...leads to Preeclampsia (triad of HTN, edema, proteinuria)

- Eclampsia (edema leads to seizures)

-Yes 6% of pregnancies (1st trimester, usually mild)

-What do Ependymomas in CNS dz secrete?

-Where do these occur mostly in the CNS?

-Meningiomas are mostly malignant?

-CSF.

-Filum Terminale

-No mostly benign  (EXCELLENT PROGNOSIS)...Usually located midline at teh Base of the brain.  You will see epileptic seizures or motor deficits.

 -divide to form the other bone cells

-lay down the extracellular matrix

 live in the mature bone and maintain the extracellular matrix

-: break down the extracellular matrix
 

 -Osteogenic Cells

- Osteoblasts

-Osteocytes

-Osteoclasts

-PTH (helps to release calcium from bone...tells kidneys to reabsorb Ca...Vit D is told to be excreated by Intestine)

-Where is Vit D activated (2 places)

-Liver..then Kidney

Vit. D

What am I?

-Released by thyroid when blood calcium is too high
-Inhibits the release of calcium from bone
-Reduces osteoclast activity
-Inhibits vitamin D activation in the kidney
-Inhibits calcium reabsorption by the kidney
 

Calcitonin

-a form of dwarfism caused by abnormal enchondral bone formation in the growing long bones; caused by mutation of the gene for the fibroblast growth factor receptor 3

-What is the best way to Dx this?

 -Achondroplasia

-X-ray

What are these features of?

Shortened, stubby fingers
Trident Hand
Separation between middle and ring fingers

-What is longer in Achondroplasias....arm or forearm?  thigh or leg?

 Achondroplasia

-Forearm, and lower leg

-What type of spinal problem do Achondroplasias have?

-Humpbacks?

-Lordosis (delayed walking and bowed legs)

-in childhood...dissapears after walking

-t/f?  People who inherit FGFR3 mutations from both parents have a severely decreased life expectancy than those who inherit the mutation from one parent

-Name some weird complications of Achondroplasia?

-Can we cure Achondroplasia?

-True dat

-Resp infections, jaw abnormalities, HYDROCEPHALUS, EAR INFECTIONS

Osteogenesis Imperfecta

OI is caused by an error called a mutation on a gene that affects the body’s production of the ____ found in bones, and other tissues.

-How do we test for OI?

-collagen

-a skin sample or a blood sample are used to study the amount of Type I collagen or to do a DNA analysis.
 

OI Type__ is the mildest and most common form of the disorder. It accounts for 50 percent of the total OI population. It is characterized with mild bone fragility, relatively few fractures, and minimal limb deformities. The child might not fracture until he or she is learning to walk.

-Do bones still fracture after bone growth is complete?

-I

-No.... After growth is completed, the incidence of fractures decreases considerably.
Blue sclerae are often present.
 

OI Type ___is the most severe form.
At birth, infants with this have very short limbs, small chests, and soft skulls. Their legs are often in a frog-leg position.

-How long do infants with this type of OI usually live?

-  II

-Weeks

 What am I:

Infection of bone
-Direct contamination
-Contamination through blood (hematogenous)
-Miliary tuberculosis
-Contamination from skin lesions
 

Osteomyelitis

Who does osteomyelitis affect when it only affects long bones where it damages arteries of the bone?

-who is it affecting when it affects vertebrae, sternoclavicular and sacroiliac joints (pubic symphysis) AND joint spaces.

Children

Adults

Osteoporosis...primary cause...Unknown

Secondary...do to another related dz

-Softening of bones as a result of inadequate mineralization of the organic matrix (osteoid)
Caused by deficiency of vitamin D, inadequate metabolic processing and activation of vitamin D, or disturbances of phosphate metabolism

-What is this called in Children?

Osteomalacia...caused by insufficient Calcium OR Phosphate levels

-Rickets (bowlegs, widented costochondral jct, Craniotabes, Delayed DENTITION)

Common chronic disease of unknown etiology characterized by irregular restructuring of bone and subsequent thickening and deformities of bones

-What are the 3 phases?

-Give me 4 common SS of Paget's Dz

 -Paget's (Regions of excessive bone turnover
New bone is disorganized
Deformation and fracture common)

-Destructive, Mixed, Osteosclerotic

-Deafness, kyphosis, bowlegs. THICK SKULL

Upper Motor Neuron Damage

-Destruction of muscle fibers is characterized by a release of ______ _____.

-Muscles are very susceptible to infection?

-MG: more common in men?

-A young person with MG will also have?

-What do MG muscles look like histologically.

-What is reduced in MG?

-creatine kinase (CK)

-False, they are resistant

-False...women

-Enlarged Thymus

-Normal striated cells

-Surface receptors for ACh (these peeps have autoAbs against teh surface receptors.)

-What would a electromyography of an MG pt. look like?

-how do you cure MG?

-What do CK levels do in Musc Dystrophies?

-Most common muscular dystrophy
Caused by deficiency of dystrophin
 

-Less and less reactivity with consecutive electrical stimulation of affected muscles.

-You don't....treat symptoms. 

-Go up

-Duchenne-Type (X-linked)

-What does dystrophin do?

-how is Duchenne inherited?

-What is form of Duchenne called (10x less common...and is less severe...)

-When do Sx first appear in Ducheene?

-holds together other structural proteins, linking them to the cell membrane of skeletal muscle...it's absense leads to muscle wasting.

-X-linked recessive (so it affects boys)

-Becker's Dystrophy

-Preschool (they may make it to 20...Beckers-35)

-How are Duchenne-type and Becker's cognitively?

-Some mental retardation

-Myotonic dystrophy

-Extremities

-Soft tissue sarcomas occur in about __% of adult CA.

-Name the 5 cell types referred by to  soft tissue sarcoma

-Name some clin features of Mito Disorders?

-3 organs most affected by Mito disorders

- 1%

 -fat tissue, bone tissue, cartilage, smooth and skeletal muscles

 - Lactic acidosis, short stature, sensorineural hearing loss, ragged red fibers (muscles), spongy degeneration of brain

-HEART, Skeletal muscle, and brain are most affected (most metabolically active and need mito the most)

Osteoarthiritis

-OA:Damaged joint cartilage tries to heal itself
Creating _____ or spurs

-Cartilage contains more ___, less collagen

-Joint spaces narrowed?

-Osteophytes

-Water

-No, they are widened

RA

- _____ are deposits containing monosodium urate crystals

-______ (swelling and pain of first metatarsophalangeal joint of the foot)
 

-Tophi

-Podagra

What if taken during pregnancy can reduce the occurance of Dysraphic disorders such as spina bifida, ancephaly, and meningocele?

-What gender is more affected by MS?

-What is the lab test proving MS?

-..what other immune compents will be in teh brain?

-Folic Acid

-Women 2x...(MS is a demylinating dz)

 -Oligoclonal bands of IgG in CSF .

-Oligoclonal T-cell populations

What is another word for Alcoholism?

-What kinda nutritionaly deficiency is going on here?

-Wernicke-Korsakoff Syndrome

Uncoordinated movements
Progressive mental deterioration, loss of memory, inability to concentrate, irritability
Subdural hematoma, pontine myelinolysis
Delirium tremens

-Not enough Vit B1

-Which Neurological nutritonal dz am I? causes....dermatitis, diarrhea, delirium)

-which am I?:  uncoordinated movements, sensorimotor peripheral neuropathy, signs of spinal cord disease, abnormal gait, psychiatric symptoms)

-Nicotinic Acid Deficiency

-Vit. B12 Deficiency

-What two parts of the cortical brain are affected with Alzheimers?

-In AD-The brain appears atrophic and shows narrowing of the ___ and a widening of the ___.

-Carriers of what gene develop AD at a 90% rate?

-Temporal and frontal areas.

-gyri....sulci

-mutated apoE4 gene on Chromosome 19 (3% of us have this)

-what do AD and Trisomy 21 have in common?

-Aside from plaques what are 2 other neuropathologic features of AD?

-identical neuropathologic chnages in which brain contains deposits of amyloid beta derived from a precursor protein, APP (AMYLOID PLAQUES)

-Neurofibrillary tangles
Decreased acetylcholine production
 

-T/F...the amyloid beta proteins produced in AD are water soluble?

-which stage of AD am I? Second: confusional stage
Disorientation, lack of insight, impaired hygiene and language use, sundown syndrome

-What else causes dementia and must be rulled out?

-False...they aren't and thus stick together to make fibrils ...then plaques.

-Second

-Alchoholism, HD, and microinfarcts.

T/F...most PD pts get dementia?

-What will we see histologically (2things)?

-Grossly what appears pale?

-What neurotransmitter is depleted?

-False only 10%...may get depressed tough

-Loss of melanin-rich neurons
Lewy bodies

-SN

-DA. (treat with l-dopa at first)

-Where is the gene for Huntington's? located? (huntingtin gene)

-how are mutations inherited?

-what is teh sequence repeat encoded by huntingtin protein?

-WHere does loss of neurons occur in the non-cortical areas?

-In the cortical regions?

-Chromosome 4

-Autosomal Dominant

-CAG repeat

 -Caudate and Putamen

-Motor Cortex of FRONTAL LOBE

Amyotrophic Lateral Schlerosis (slurred speech but mentally these people are sound)

What is degenerated with AMyotrophic Schlerosis?

-Deadly?

-T/F...metastasizing tumors from teh brain are deadly?

-T/F...benign tumors of the brain are deadly?

-Loss of motor neurons in the spinal cord, midbrain, and cerebral cortex

-Yes... Incurable, progressive disease that leads to death over a period of a few years

-False, brain tumors do not metastisize

-True...cause encephalocele.

ASTROYCYTOMAS

Glioblastomas are rare?

-WHere do they attack...

-What are teh unique gross exam features?

-False...most common CNS tumor

 -Lateral Hemispheres

-Highly variegated gross appearance
Parts of the tumor are necrotic and yellow
Parts are hemorrhagic red, and parts are white
Irregularly shaped
Poorly demarcated
Butterfly-like appearance
 

What causes the multitude of GM gross appearances?

-Which glial tumor may become GM?

-Where do these hit?

 -Common?  

-T/F...well circumscribed...partially cystic

-Highly anaplastic Astocytic cells

-Oligodendrogliomas.

-Cerebral hemispheres

 -No, only about 10% of all gliomas

-True

-Where do Ependymomas occur in children?

-in adults?

-can they occur in the lower back?

-Here teh papillary tumors form what?

-Ventricles

-Spinal Cord

-Yes at the filum terminale....

-Rosettes (flower like tumors)

Meningiomas are mostly malignant?

-what are some S/S

-how is the prognosis?

-False, mostly benighn

-Seizures, motor deficits

-EXCELLENT! YAY Dr. N :)

-tumors that metastasize to teh brain usually come from what 3 CA types?

-How common are tumors of nerve cells themselves?

-Lung, Breast, Melanomas

-rare (and mostly benign when they do occur_

Hyperpathia

Paresthesias

Dysesthesia

Hypalgesia

Analgesia

Allodynia

-4 types of HA discussed in class?

Neuropathic Pain Syndrome.

Fragil X syndrome is an __-linked mental retardation caused by muations in the _____gene on ______ (what segment of what chromosome)?

-What kind of mutation within this gene is it?

-Affects only boys?

-X-linked

-FMR1 Gene

-Xq27.3

-Trplet expansion

-Boys and girls.  (all boys who inherit get it...only 40-50% of females)

Fragile X is most common form of moderate mental retardation?

-99% of FMR1 mutations are expansions of what specific sequence?

-What is normal FMR1 CGG repeat number?

-Dz causing repeats will number in the ?

-True

-CGG

-6-50

-anything over 200.

-Premutations represent __-___ repeats.

 -paternally or maternally premutations better?

-Alleles with more than 200 CGG repeats have ______ of the CGG sequence and the FMR1 promotor causing an overall loss of FMRP EXPRESSION

-If ___ triplets are embedded in teh CGG repeats the expansion is inhibted.  

-60-200

-Paternally inheritated premutations don't usually lead to full mutations.

- AGG

-What are some of the behavioral problems of Fragile X?

-Life expectancy?

-hyperactivity
hand flapping or biting
temper tantrums
poor eye contact
autistic features

-Full lifespan

-Males with Fragile X look how?

-People with mosaicism have a higher degree of retardation

-Inheritance....___% for sons...25% for daughters, but it depends on teh size of the premutation.

Long nose, huge jaw, forhead,ears and HUGE BALLS

-False...they are less special as not every cell has teh disorder.

-50%