NPch. 22-23 Huntington's Disease & Multiple Sclerosis Flashcards
Huntington’s Disease
Huntington’s Disease
Introduction
1- what is it characterized by?
2- what is the progression in life?
1- progressive motor impairments, cognitive decline and mood and behavioural changes
2- symptoms noticeable during 30-50 y.o.
- Juvenile Huntington’s disease if symptoms visible during childhood
- duration is average 15-20 years (till death)
- cannot be prevented, cured or delayed but multidisciplinary approach for relief of symptoms
Huntington’s Disease
Statistics
- genetic testing is available
- positive test predicts disease onset in 10-18 years
- chance of inheritance: 50%
- no cures or treatments to prevent disease progression
Huntington’s Disease
Historical Context
- first medical documentation in 1872 by George Huntington (22yo)
- known for description of Huntington’s
- highlighted motor dysfunction, cognitive decline, psychiatric symptoms as core aspects of disease
- noted tendency of disease to run in families (inheritance)
- 1993 genetic mutation that causes HD was discovered
Huntington’s Disease
Diagnosis
- clinical evaluation (description of symptoms - motor impairments), family history and genetic testing for CAG expansion in HTT gene
- MRI and CT not required (can help to see extent of damage)
- increasing focus on cognitive factors for diagnosis to determine onset
> motor impairments sometimes absent in beginning (“pre-manifest mutation carrier”)
Huntington’s Disease
Differential Diagnosis
- autosomal dominant genetic conditions (similar; genetic testing to see whether it’s HD)
- non-progressive extrapyramidal disorders (not caused by single gene mutation)
Huntington’s Disease
Prevalence & Epidemiology
- 1 in 7,300 affected in western populations (2015)
- 1-7 per million in Taiwan, Hong Kong and Japan
> difference in ethnicities probably due to variations in normal distributions of CAG repeats - higher rates in populations of european descent (endemic to all populations but related to genetic lineage)
Huntington’s Disease
Inheritance
- autosomal dominant disorder
- can be inherited from either parent
> independently from sex (autosomal)
> one defective copy is enough (dominant)
> passed on even if one parent - every son/daughter has 50% chance of developing HD
- DNA test to determine whether patient is mutation carrier
> impossible to predict age of onset and initial symptoms
Huntington’s Disease
Genetics - mutations
- mutation: excess of repeats of basis CAG on chromosome 4
- DNA → mRNA → aminoacid = CAG → glutamine
- HD: abnormal huntingtin protein (mHtt) with more than 36 glutamine residues
- <36 repeats: healthy individual
- 27-35 repeats: possible de novo HD
- 36-39 repeats: mild symptoms (maybe healthy until old)
- > 40 repeats: clinical HD
! the more CAG repeats, the lower the age of onset
! number of repeats linked to severity/course
Huntington’s Disease
What is the role of Huntingtin?
- HTT gene encodes for the protein Huntingtin
- huntingtin important for:
> nervous system
> BDNF production (brain-derived neurotrophic factor - important for brain growth and development)
> cell adhesion
! normal function not completely understood
!! regulates glial cells and neurons’ typical functioning
Huntington’s Disease
what type of disease is HD?
- toxic gain-of-function disease
> focus on conformational changes in protein structure
> if mutation happens, new function it didn’t have before
> change shape and accumulation in cells (Htt)
> (different pathways of dysfunction) - expanded poly-Q huntingtin can form large, visible inclusions
Huntington’s Disease
Neurodegenerative patterns
- higher expression of HTT in neurons compared to glia
- earliest and most severe neural loss (atrophy) in striatum (caudate nucleus and putamen) → higher expression of HD
- progressive thinning and loss of neurons in cerebral cortex
- overall reduction in brain volume as disease progresses (shrinkage)
! prodromal HD: before motor symptoms
Huntington’s disease
what are the most common neurological changes in HD?
- basal ganglia → striatum → caudate nucleus and putamen
- subcortical and cortical atrophy
- fewer dopamine receptors in striatum
- changes in glucose metabolism
- later stages→ damage in other brain areas (cerebral cortex, hippocampus, cerebellum, hypothalamus, thalamus)
Huntington’s Disease
Clinical Features - how do the impairments progress?
(see graph!)
- 45 y.o.: medium onset for motor diagnosis
- motor diagnosis: when symptoms are severe enough
- if no motor diagnosis → “carrier”
1. from presyntomatic to advanced
> functional abilities: constant decline
2. from prodromal to advanced
> motor impairment: rapid increase
> cognitive impairment/dementia: less steep increase
> chorea (involuntary movements): slower and less steep increase
! death: complications in motor impairments (e.g. breathing)
Huntington’s Disease
Motor symptoms
- Chorea (involuntary movements; start in extremities)
> not repetitive or rhythmic; “dance”-like - Hypokinesia (decrease in spontaneous movements)
+ slowness of movement, impaired muscle tension, rigidity, eye movement, difficulty swallowing, balance problems - walking becomes difficult
- severe motor impairments in later stages (no more walking)
Huntington’s Disease
implications for motor symptoms
- striatal degeneration (coordination) and impaired motor neurons
→ involuntary movements, tremors (shaking) and poor coordination
Huntington’s Disease
Cognitive symptoms
- cognitive difficulties can manifest years before motor symptoms
- cognitive decline is gradual (severe in later stages)
- can remain mild until later stages or rapidly transform into dementia
- attention, mental flexibility, planning and emotion recognition (! also changes in emotion regulation)
- similar symptoms to Alzheimer’s disease in later stages
Huntington’s Disease
Implications for cognitive symptoms
- cortical atrophy and selective vulnerability for specific neurons
→ impaired memory, reasoning, executive functions
+ emotional and behavioral control
Huntington’s disease
what are general cognitive symptoms?
- intelligence
> usually not until later stages
> earlier deterioration in nonverbal performance - memory
> even at early stages
> problems with encoding and retrieving new information
> seem to be linked to attention impairment - speed of information processing
> slow thinking in early stages - attention and executive functioning
> less self-control and inhibition
> problems with initiating activities and discussions
> focusing and dividing attention
> inflexibility and perseverance of thouhgts - (no) disease awareness
> bc of executive impairments, coping mechanism or no subjective experience of motor impairments - perception and spatial recognition
> difficulty in distinguishing and matching different shapes - language and speech
> deterioration in loudness of speech (hypophonia)
> problems with articulation (dysarthria) - emotion and social cognition
> difficulty recognizing negative emotions
> worse theory of mind
Huntington’s Disease
TRACK-HD study findings
- longitudinal observational study to identify earliest detectable changes
- 10/12 cognitive outcomes showed deterioration early on
- pronounced differences compared to controls
> through Symbol digit modalities test, Circle tracing test, Stroop word-reading test - tests most affected had significant motor or psychomotor component (imagining movements)
→ shows link between motor and cognitive issues in Huntington’s disease
Huntington’s Disease
Psychiatric features
- Depression (50% of HD patients)
- Frontal Lobe Syndrome (premanifest stage)
> inappropriate remarks, lack of insight on behavior, overeating, … - Irritability and Apathy (late stages)
- Psychosis or Delusions (less common)
