Autosomal Dominant Disorders Flashcards
pleiotropy
when one gene effects multiple phenotypic traits and symptoms
age of onset of HD
typically 30-50 years old
progresses over 15 years and culminates in death
genetic abnormality of huntington’s disease (HD)
short arm of chromosome 4
mutation is a CAG expanded reapeat in the coding portion of hte gene
autosomal dominant
number of CAG repeats and Huntington’s Disease
Normal= 1-26
27-35 = unaffected
36+ = disease present, incomplete penetrance with 36-41
*** the larger number of repeats = earlier age of onset
protein affected in HD
huntingtin
involved in transport of vesicles in cellular secretory pathways
req. for normal produciton of BDNF
HD causes neuro degeneration of which areas in brain?
Basal ganglia (movement)
cortex (thoughts, memory)
Basal Ganglia
located on inner brain
control and coordination, muscle movement
HD specifically targets neurons of striatum (caudate nuclei and pallidum)
Cortex
outer surface of the brain
involved in perception, memory, and thought
Huntington’s disease pathophysiology
mutution in chromosome 4 causes increas in CAG repeats near huntingtin’s AA terminal
build up of CAG repeats causes production of abnormal huntingtin protein –> causes cell death
gain of function disease – over expression of abnormal huntingtin protein
HD imaging
loss of neurons on MRI
PET scan shows decreased glucose uptake in brain
clincial manifestations of HD
disease leads to brain weight loss (25% +)
- a progressive loss of motor control
- non-repetitive jerks; abnormal body movements that worsen over time
- psychiatric problems
- psychosis and schizophrenia
- cognitive abnormalities dementia
- behavioral disturbances
- aggression, outbursts
HD patients eventually won’t be able to walk. Aspiration pneumonia (difficulty swallowing) is what causes death most often. The clinical course of HD is protracted (drawn out: 15-18 years before death)
HD:
Loss of motor control results in excessive uncontrollable movements of the head, face, trunk and limbs, controlled by?
basal ganglia
HD
Alterations in thought, perception, and memory are controlled by?
Cortex
HD expression
95% of cases are inherited (5% spontaneous)
affected homozygots display same course as heterozygotes
larger number of CAG repeats = earlier onset of disease
Juvenile Huntington Disease
HD onset before 20 years of age
paternally transmitted
esp. large number of repeats (>60 CAG repeats)
maternal v. paternal expression of HD
when the father transmits the disease there is a tendency for greater CAG repeat expansion
HD penetrance
incomplete pentrance occurs between 36-41 repeats
full penetrance occurs at >41
HD treatment
no curative treatment
drugs are available to treat symptoms
most common form of muscular dystrophy in adults
Myotonic Dystrophy
Genetic abnormality in Myotonic Dystrophy
autosomal dominant
nucleotide repeat expansion of CTG in DMPK on chromosome 19
number of repeats determins the degree of severity
CTG repeats in MD
- 5 to 30 CTG repeats = unaffected individuals
- 50 to 100 CTG repeats = mildly affected
- 100 to 2000 CTG repeats = severely affected
myotonic dystrophy (summary)
- most common form of muscular dystrophy seen in adults
- characterized by progressive muscle deterioration.
- Caused by an abnormal nucleotide repeat expansion (CTG) in a non-coding region of DMPK gene on chromosome 19
protein affected in MD
DMPK
pathophys of MD
The mutation is an expanded CTG trinucleotide repeat
The number of these repeats is strongly correlated with severity of the disease (like HD with CAG).
affect multiple systems: skeletal m, cardiac arrhythmias, and cataracts.
clincial manifestation of MD
Onset is usually prominent in the 2nd or 3rd generation; lifespan is typically six decades
Muscle weakness and wasting in the arms and legs and myotonia (muscle spasms/stiffening) tends to be the 1st symptoms noticed.
expression of MD
number of repeates increases with suceeding generations (anticipation)
number of repeats correlated with severtiy of disease
can be seen in infancy
congential MD
inherited from the mother
presents in infancy
characterized by an inverted “V” shaped upper lip and c_ompromised respiratory function_ (what generally kills them)
MD penetrance
incomplete penetrance at 50-100 CTG repeats
full penetrance at 100-2000 CTG repeats
MD treatment
anti-seizure medicin to treat myotonia
requires lots of PT/OT to treat muscle weakness and wasting
HD general
- autosomal dominant
- a neurodegenerative disease that affects certain areas of the brain
- Onset is dependent on age
- typically 30-50 years old
- progresses over 15 years
- very rapidly, and culminates in death
- Specifically affects cells of the basal ganglia
- polyglutamine disease
- involves expanded CAG repeats in gene product
- affecting huntingtin protein
- chromosome 4.
Marfan Syndrome (general)
heritable disorder of connective tissue that affects fibrillin protein; it results in excessively “stretchy” connective tissue that allows for bone overgrowth to occur
genetic abnormality in Marfan syndrome
autosomal dominant
mutation located on chromosome 15 gene that encodes fibrillin
protein affected in Marfan Syndrome
fibrillin
connective tissue protien, major cmoponent of microfibrils
(suspensory ligaments of lens, aorta, and periosteum)
pathophys of marfan syndrome
mutated fibrillin gene = excessively stretchy connective tissue
body systems affected: skeleton, heart and vessels, eyes, nervous system, skin, lungs
skeletal clinical manifestations of Marfan
taller than average
chest wall deformiteis
steinberg thumb sign
clinical manifestations of marfans
cardiovascular
widening of ascending aorta
can lead to CHF (must montitor)
clinical manifestations of marfans
nervous
out poaching of dura in spinal cord = dura ectasia
clincial manifestations of marfan’s
eyes
dislocation of one or both lenses of the eye
clincial manifestations of marfan’s
skin
stretch marks
clincial manifestations of marfan’s
lungs
connective tissue abnormalities
makes lungs less elastic –> causes lung collapse
expression and penetrance pattern of marfan’s
40% of cases are spontaneous (60% inherited)
if parent has marfan, 50% risk they will pass gene to off spring
variable expression – same genotype can have large variety of phenotypes
Marfan’s treatment interventions
require annual evaluations to detect changes in spine/sternum
must monitor for changes in defects, adverse effects
reg. eye exam, no smoking, avoid exercise, pregnancy risk
Neurofibromitosis Type I
general
most common autosomal dominant
disturbs cell growth in nervous system
causes tumors to form on nervous tissue
Type 1 is 90% of cases, 50% of cases result from new mutation
Neurofibromitosis Type I
genetic abnormality
type I is mapped to a gene on chromosome 17q
lg. gene = mutation target (accoutns for high mutation rate)
type 2 is chromosome 22
Neurofibromitosis Type I
protein affected
encodes mRNA transcript and gene product: neurofromin
protein that acts as a tumor suppressor
pathophysiology
Neurofibromitosis Type I
affected individuals develop tumors
cutantous neurofibromas are classic symptom
Neurofibromitosis Type I
clincical manifestaitons
cutaneous neurofibromas (nodules/tumors on skin)
learning disabilities
lisch nodules (tumors on iris)
Cafe-au-lait (hyper pigmented skin)
NF1 is suspected if only 2+ present
tinnitus is present instead of iris nodules in NF2
Neurofibromitosis Type I
expression and penetrance pattern
highly variable expression
retinoblastoma (general)
most common childhood eye tumor
occurs during embryonic development when retinal cells are actively dividing/proliferating
Almost always presents by 5 years of age (40% familial/60% spontaneous mutations).
genetic abnormality Retinoblastoma
chromosome 13
autosomal dominant, sporadic and non hereitary
retinoblastoma protein affected
RB1 gene
Retinoblastoma
types and expression
Non-hereditary (60% are spontaneous) and sporadic (not transmitted)
affected individuals will transmit gene to half of offspring (familiar ones are multi focal and bilateral)
retinoblastoma
penetrance
reduced penetrance
not everyone with genotype gets phenotype because it requires a second hit in the same region of the DNA
retinoblastoma treatment interventions
treated with radiation, cryotherapy or laster photocoagulation
detected with the white light shown on the eye
Retinoblastoma reading assignment
There is reduced penetrance in inherited retinoblastoma because the normal RB1 allele requires a second hit in order for the tumor to develop.
The second hit has a low probability of occurring in any given cell.
Because the second hits are random events, a small fraction of persons who inherit the disease allele never experiences a second hit in any retinal cell and thus do not develop retinoblastoma.
The requirement for the second hit thus explains the reduced penetrance seen in the disorder.
Factor V Leiden
autosomal dominant condition that results in factor V protein variant that can not be degrated by aPC
blood clotting factor
can easily lead to thromboembolism
aPC
protein responsible for breaking down blood clot formed by factor V
Achondroplasia
aka dwarfism
disorder of bone growth
most common type of short-limbed dwarfism
unable to convert cartilage to bone, particularly in the long bones of the arms and legs
Achondroplasia
Genetic abnormality
mutation on the FGFR3 gene
Achondroplasia
protein affeted
protein made by FBFR3
receptor that regulates bone growth by limiting formation of bone from cartilage (ossification)
Achondroplasia
pathophys
FGFR 3 gene mutated
becomes overly active, interfearing with ossification and leads to disturbances with bone growth= short stature
bc this disease is in the long bones, it results in average size trunk
normal intelligence is seen with this disease
Achondroplasia
clinical manifestations
short arms and legs byt average size trunk
breathing disorder (apnea)
normal intelligence
Achondroplasia
expression and penetrance
trait appear in every generation
transmitted from either parent
similaries between HD and MD
autosomal dominant with anticipation and early onset form
longer the repeat, earlier the disease occurs
differences bt MD and HD
MD early form is from the mother, presents at birth
HD early form is paternal, presents in teens
HD mutation is on chromosome 4 with CAG repeats,MD mutation is chromosome 19 with CTG
HD fully penetrant at >41 repeats and affects huntingtin. MD is fully mutant 50-2000 repeats and affects and DMPK
