Lecture 4: Huntington's Disease & Parkinson's Disease Flashcards
(44 cards)
What is Huntington’s Disease?
Neurological disorder characterized by spasmodic involuntary movements of the limbs or facial muscles (Chorea)
Chorea→dance like
What are the clinical features of Huntington’s Disease (3)?
- Chroea → spasmodic involuntary movements of the limbs or facial muscles
- Autosomal dominant pattern of inheritance → mutation on chromosome (chromosome 4 exon 1) is an expansion of a polyglutamine repeat (≥ 39 repeats of CAG)
- Behavioral and Cognitive changes
What are the clinical features/characteristics of Huntington’s Disease (3)? What clinical feature is prominent in juvenile-onset of HD (3)?
- Most often hyperkinetic, choreiform (jerking/writhing movements)
- Dystonic, rigidity, and akinesia supervene later in the course
- Rigidity, bradykinesia (slow movements), and tremors can be prominent in juvenile-onset HD (<20 years of age)
What are the clinical features of incoordination in HD (4)?
- Motor sequencing → fine motor
- Bradykinesia → slow movements
- Dysarthria/Dysphagia → speech/swallow
- Gait instability and falls
Dysarthria → disorder of speech
Dysphasia → disorder of language
What is the average onset age of HD? and average survivial length?
- 40 years
- 15-20 years although varies
10% <20, 10% >60
What are the psychiatric conditions associated with HD (3)?
- Mood disturbances → depression, anxiety, mania
- OCD → mild obsessiveness can be seen
- Psychosis → hallucination rare, delusion more common but still rare
What is the suicidal attempt rate from depression associated with HD?
- Suicidal attempt → 7.3% - 12%
- Greater than average risk
What part of the brain does dementia from HD cause cognition to decline?
Subcortical
What are the factors that contribute to changes in behavior from HD (2)? What are the clinical presentations of behavior in HD (4)?
Factors
- Outbursts of temper → hunger, thirst, pain, inability to communicate, frustration with failing abilities, boredom, changes in routine
- Fits of despondency
Clinical Presentations
- Jealously
- Promiscuity/Paraphilias → voyeriusm, exhibitionism
- Alcoholism → 17% males, 6% females
- Smoking → high cardiovascular mortality
How does a brain affected by HD appear?
Marked atrophy of the caudate and putamen (striatum)
Which striatial neurons are the 1st to degenerate with HD?
Spiny I: GABA/Enk medium spiny neurons that project from putamen (striatum) to external globus pallidus
ON EXAM
What is the clinical presentation of a brain with early chorea in HD?
Loss of projections from putamen to external globus pallidus (GPex)
What is the clinical presentation of a brain with juvenile HD (rigidity and dystonia)?
Loss of projections from the putamen to both external (GPex) and internal globus pallidus (GPint)
What can cause sudden onset hemichorea-hemiballismus?
lesion in the brain from a stroke in subthalamic nucleus
ON EXAM
What genetically causes HD?
Mutation of chromosome 4 → causes an expansion of a polyglutamine repeat (≥ 39 repeats of CAG) on the Huntingtin protein (HTT gene)
Excessive glutamine in Huntington protein
CAG repeats may expand in paternal transmission via meiosis during spermatogenesis → instability in the repeat length
What is the normal, borderline, low abnormal, and abnormal levels of CAG?
- Normal: CAG 10-35
- Borderline: CAG 27-35 (may expand if passed by male)
- Low abnormal: CAG 35-39 (may develop disease)
- Abnormal: CAG >40 (will develop disease)
- Up to 26→normal never get the illness
- Up tp 36→most likely to get when older
What types of drugs are used for symptomatic therapy to treat HD (4)?
- Anti-depressants → serotonin uptake inhibitors, tricyclics
- Carbamazepine for aggressive outbursts
- Neuroleptics → eg butyrophenones-haloperidol or phenothiazines-chlorpromazine for control of chorea
- Monoamine depleters → tetrabenazine
What neuroprotective agents are used as therapy for HD (2)?
- CoQ10, creatine → recently shown to be futile as neuroprotective agents
- Other agents have been tried but failed as neuroprotectants → Remacemide, riluzole, minocycline
What is RNA interference as a therapy for HD?
a natural gene silencing mechanism mediated by double-stranded RNA
How was RNA interference clinically demonstrated as an option for therapy for HD (proof of concept)?
- The silencing of mutant HTT expression was demonstrated in a tetracycline-regulated conditional mouse mode of HD 10 years ago
- HD gene could be turned on and off in mice
- When the gene was on → cellular inclusions of HTT protein and motor dysfunction developed
- When the gene was off → inclusions disappeared and behavioral changes improved
How was the siRNA directed against the HD gene administered in animal experiments (2)?
- Direct infusion into the brain
- By infusion into the cerebrospinal fluid at the lower spine
What are the obstacles to human gene silencing in HD (4)?
- Find a non-invasive way to deliver drugs so that they reach all levels of the brain (not just the striatum) and can be used for decades
- Need for continuous expression of the siRNA against htt
- Requires direct infusion to stratum via a pump to deliver the gene for anti-htt siRNA or infusion into the CSF at the lower spine (intrathecal infusion pump)
- Avoid “off-target” effects → anti-htt siRNA may affect the normal HD allele
What was the Nanoparticles for “Direct Nose-to-Brain delivery of Gene Therapy” experiment?
C57/BL mice were given intranasal manganese-nanoparticles (Mn-NPs) loaded with a transgene (dsDNA encoding red fluorescent protein (RFP) )
What was the result of the Nanoparticles for “Direct Nose-to-Brain delivery of Gene Therapy” experiment?
Mouse brain sections showed expression of RFP (red fluorescent protein) in neurons of the olfactory bulb (OB), striatum (ST), and hypothalamus (HT) after 48 hours
