Lecture 9: Huntington’s Disease (HD) Flashcards
Define chorea
neurological disorder characterized by jerky involuntary movements affecting especially the shoulders, hips, and face
How is HD classified
- Movement/Cognitive/Psychiatric disorder
- Average age of onset usually by 40 years (range 2- >80 years)
- Symptoms usually start between 30 to around 50 years of age
- Progression over 10-25 years
Describe the prevalence of HD
- Incidence= >1 in 10,000
- ~10x more prevalent in Western Europeans compared to African and Asian populations
- ~2X higher in Tasmania compared to rest of Australia
- > One HD individual settling in Tasmania many years ago +passing mutation on
- Venezuela- highest incidence= 700 per 100,000 people
Describe and explain the clinical features of HD
- Physical features:
- Involuntary (choreic) movements-twitching
- Weight loss
- Abnormal gait (manner of walking), balance problems and slowing of voluntary movements
- Speech & swallowing difficulties
- In juvenile HD and in late stages of HD, rigidity and dystonia (uncontrollable muscle contraction= twisted + repetitive movements)
- Juvenile HD- rare + occurs early in life - Cognitive dysfunction
- Problem solving
- Cognitive flexibility
- Short term memory
- Visuospatial Functioning
- Progression to a global subcortical dementia
- >HD often misdiagnosed as dementia
- Most damage in corpus striatum
- some patients lose 25% of total brain weight
- Brain atrophy (waste away due to nerve degeneration)
- > loss of striatal neurones
- Secondary brain atrophy of globus pallidus
- Atrophy throughout cortex
- > especially frontal+ parietal lobes
- Small neurone loss-> leads to larger neurone loss
- Neurones using GABA + enkephalin or substance P preferentially lost
- Dilation of lateral + third ventricles + fibrially gliosis
- Changes in white matter more drastic than grey matter for HD + pre-HD
3. Psychiatric Manifestations - Personality changes: -> first noticed as symptom of HD
- Aggression
- Depression (~30%)
- Apathy and irritability
- Impulsive behaviour
- Early onset dementia
- Affective/mood disorders-> depression, bipolar, anxiety
- Rarely psychoses
- Increased alcohol use in early stages
- Increased suicide rate
Describe the progression of symptoms caused by HD throughout life
Transitional phase:0-3yrs
- mood swings
- behavioural disturbances
- hyperreflexia
- memory impairment
- increased clumsiness
- impairment of voluntary movements
- eye movement abnormalities
Early: 3-5 yrs
- dysarthria
- chorea
- gait abnormalities
Middle: 8-10 yrs
- bradykinesia
- rigidity
- global dementia
- dystonia
- dysphagia
Late: 15-25 yrs
- incontinence
- wasting
- aspiration
- bed ridden
- death
Explain the prognosis of HD
Once symptoms begin:
- Progressive cognitive, motor and psychiatric impairment
- Death at average of 18 years after onset of symptoms
- Cause usually infection, pneumonia, heart failure or choking
Most common cause of death is pneumonia:
- Unable to clear their lungs properly; problems with swallowing so food and liquid enter lungs
- Second most common cause of death is heart failure-> problems with chest movement + breathing
- Suicide rate: 5-10x higher than general population
Outcome:
- Eventually require total nursing care
List the requirements for diagnosis of HD
- Medical history
- Family history
- Neurological examination
- Brain imaging test (MRI, CT, PET)
- Laboratory tests
- Genetic test (if necessary)-> fully confirms diagnosis
Explain the mode of inheritance for HD
- Altered gene is passed from parent to child
- No evidence of sex linkage
- Developing HD ->conditional on having inherited the gene
- Autosomal dominant disorder –> children of parent with defective HD gene have a 50:50 chance of inheriting the gene from affected parent
- Juvenile Huntington’s occurs in ~16% of all cases of HD
- 80% of cases with onset before 20 years of age (juvenile HD) are due to paternal transmission
Explain how HTT gene was found
- Father suffered from HD
- Led a research team into a remote part of Venezuela where HD is prevalent
- Medical history + blood samples collected ->key to locating the gene
- Developed a chromosomal test - identify carriers of HD
Describe the mutation of HTT gene
- HD= Repeat Expansions
- Trinucleotide repeat: type of short tandem repeat
- Size of repeat region varies between individuals
+ polymorphic in normal individuals - Some trinucleotide repeats: when the number of repeats exceeds a certain threshold
= neurological disease
Describe the structure of HTT gene
- The HTT gene location= short arm of chromosome 4 = 4p16.3.
- CAG codon codes for glutamine A series
= chain of glutamine =polyglutamine tract /polyQ tract - The repeated part of the gene= the PolyQ region
- Usually - <36 repeated glutamines in the polyQ region
- 21 CAG repeats= normal HTT
Explain how mHTT gene can be found in patients
- Forward primer: attaches to start codon on template DNA strand of original DNA used in PCR
- Reverse primer attaches to stop codon on complementary DNA strand of original DNA used in PCR
- Need pos. + neg. control for PCR
- > Pos.= actual sample containing DNA in well-> known that the DNA sequence of interest is present + a band will definitely be produced
- > Neg.= water filled in a well= blank-> DNA missing =no bands are expected
- 2 bands present from each well-> allele for HTT inherited from each parent
- Band above threshold or cut off= allele inherited from affected parent
- Some HD patients with a de novo CAG repeat expansion
Describe the correlation between age of onset and no. CAG repeats
- More repeats-> more affected- symptoms show earlier
Give the classification, disease status + risk to offspring for each repeat count
- <26- normal -not affected-non
- 27-35-intermediate- not affected- elevated«50%
- 36-39- reduced penetrance- may/may not be affected - 50%- later onset + slow progression of disease
- 40+- full penetrance-affected- 50%- early onset
State why 36 repeats is the threshold
- ≥36 glutamines= altered protein
- mutant HTT (mHTT) - increases decay rate of certain types of neurons ->mostly in corpus striatum
Why is it important to know about trinucleotide repeat disorders
- Over 15 genetic different disorders
- Makes up significant proportion of inherited neurological disease
- Most common cause of inherited mental retardation in males (Fragile X syndrome)
- Molecular diagnosis is now available for:
- diagnostic confirmation
- predictive testing
- prenatal testing
- preconception testing
- preimplantation diagnosis
- Genetic counselling and ethical issues are complex
Give the mode of inheritance, age of onset and cause for: Friedreich Ataxia, spinocerebellar ataxia, mytonic dystrophy, fragile X syndrome
FA
- Autosomal recessive progressive neurological disorder
- < 25 years
- expansion of GAA repeat in intron of FXN gene
SA
- Autosomal dominant progressive neurological disorder
- 3rd or 4th decade
- Expansion of CAG repeat in coding exons of SCA genes
MD
- Autosomal dominant progressive neurological disorder
- Variable expression and anticipation
- expansion of 3’ UTR region of DMPK gene
FXS
- X-linked recessive mental retardation syndrome
- expansion of CGG repeat in 5’ UTR region of FMR1 gene
Describe the Major Features of Most Trinucleotide Repeat Disorders
- Neurological/cognitive symptoms
- Many are autosomal dominant with variable expression
- Later age of onset
- Meiotic and mitotic instability with some degree of anticipation in many of the conditions
- > Anticipation: Increasing severity and/or decreasing age of onset of an inherited disease in successive generations within a family
- Can involve expansions of repeats in coding and non-coding regions of the gene
Explain the folding of mHTT protein
- In nucleic acids triplet repeats can form hairpin structures-> self- complementary
- In Protein, when polyQ (glutamine tract) exceeds a certain length (~ 35)
= abnormal conformation
Explain how the different species of mHTT protein are formed
- > monomers and oligomers of full-length mHTT
- > truncated N-terminal fragments - oligomers or fibrils
- Efficient proteolytic cleavage of full-length mHTT ->releases N- terminal polyQ-containing fragments
- Truncated mutant HTT exon-1 (mHTTex1) fragment formed continuously by mRNA splicing
- mHTT monomeric, oligomeric and fibrillar form dynamic structures that can interconvert
- Eventually deposited into cells as large inclusion bodies
List the cellular processes that are affected by the interaction of mHTT proteins
- > Initiation of autophagy
- > Mechanistic target of rapamycin (mTOR) signalling
- > Vesicle transport along microtubule
- > Fission of mitochondria
- > Transport of mitochondria along microtubules
- > Palmitoylation of synaptic proteins
- > Regulation of gene transcription
Explain how mHTT protein effects gene transcription regulation
- CAG repeats found in coding region
- mHTT protein with a run of glutamine residues (Q)
- PolyQ regions binds to basal TF, co-activators + co-repressors =stopping normal function of transcription
Explain how mHTT can cause Disruption of extracellular ion homeostasis and glutamate uptake by astrocytes
- Extracellular ion homeostasis + glutamate uptake by astrocytes at the synapse changed by mHTT
- Alters expression of potassium channel Kir4.1 + glutamate transporter 1 GLT1/SLC1A2
= causes increased MSN (medium spiny neuron) excitability and activation - Neuroinflammation caused by mHTT protein
-> aberrant immune activation of peripheral and central nervous system cells
Explain how mHTT is neurotoxin and how this was discovered
- mHTT causes dysfunction in multiple critical cellular processes
- leading to toxicity->over time causes neurodegeneration in a cell autonomous and non-cell autonomous manner
- cell autonomous: an action within or by a single cell, not requiring any other cells
- mHTT gene injected into normal nerve cells+ effects observed
- Effect= Dying nerve cell with loss of fingerlike processes
- Phenotypic rescue occurs when function HTT added = dying cell rescued
Explain how haploinsufficeincy was ruled out as a cause of HD
- Wolf-Hirschhorn Syndrome has microdeletion on 4p= HTT gene lost
- Causes:
- Growth retardation with abnormal facies
- Cardiac, renal, and genital abnormalities
- However:
- Basal ganglia intact
- No movement disorders
- Rules out haploinsufficiency as cause of HD
- > not caused by loss of normal protein
- > caused by neurotoxicity of mHTT protein
Explain the additional roles of HTT
Huntingtin interacting proteins – suggest other roles for Huntingtin protein:
- HIP1 (homologous to yeast gene with cytoskeletal functions) - affinity to normal sized tracts
- HIP2 - encodes an ubiquitin conjugating enzyme
- HAP1 - affinity to larger polyglutamine tracts
- GADPH - direct affinity for polyglutamine tracts GADPH involved in several key cellular functions including cellular metabolism
- EGF receptor complex- huntingtin binds to SH3 domains of Grb2 and Ras-GAP suggesting role in the EGF signaling pathway
