Huntington's disease Flashcards
What is Huntington’s disease?
Presentation?
Also known as Huntington’s chorea, is an inherited neurodegenerative disorder that results in death of brain cells.
The earliest symptoms are often subtle problems with mood or mental abilities. A general lack of coordination and an unsteady gait often follow. As the disease advances, uncoordinated, jerky body movements become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia.
Cannot be treated. Annual death rate = 1-1.5 million
Clinical onset?
The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, but can start at any age. The disease may develop earlier in life in each successive generation.
- Juvenile onset: 10% at 4-19 years, Westphal variant
- Early and midlife onset: 65%
- Late onset: 25%
Motor clinical features:
What are the less common clinical features?
What features they get that are similar to parkinson’s?
What are the pre-terminal events?
Chorea: Irregular unpredictable involuntary brief jerky movements that flit from one body part to another in a random sequence
“ Varies in severity
“ Affects whole body
“ May plateau later and be masked by rigidity
“ Can be minimal in juvenile-onset cases
“ Associated with clumsiness & in coordination
Dystonia: sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures.
Eye movement abnormalities
“ Early abnormality
“ Slow/inaccurate saccades (A saccade is a quick, simultaneous movement of both eyes between two or more phases of fixation in the same direction)
“ Initiation and suppression problems
Rigidity Bradykinesia (juvenile variant)
Less common: Cerebellar dysfunction, UMN signs, epilepsy, myoclonus
PArkinsonis, gait disturbance, bulbar dysfunction
Pre terminal events: Weight loss and dysphagia
Juvenile vs Adult HD
- mental deterioration
- Chorea
- Rigidity
- UMN/Cerebellar signs
- Myoclonus
- Epilepsy
- Inheritence
J v A
- Severe : Variable
- Sometimes absent : prominent
- yes : only in late stages
- common : uncommon
- sometimes : rare
- common : uncommon
- Father : either parent
What are the cognitive disorders in HD?
- Bradyphrenia (is the slowness of thought common to many disorders of the brain), attentional and sequencing impairments (executive dysfunction)
- Memory retrieval impaired, registration spared
o No signs aphasia, agnosia and apraxia (which is typical of AD)
o Insight and central language function generally preserve
do get early onset dementia
What are the psychiatric features of HD?
- depression (10% develop mania)
- psychosis (schizophrenic and delusional)
- Suicide (high for even those who dont develop disease)
- sexual disorders (hyper sexuality - reduction of inhibition)
Genetics of HD
- inheritance
- mutation
- correlation with onset
- anticipation
- AD inheritence by gene called huntingtin
- Due to expanded CAG trinucleotide repeat on chromosome 4: Normal 6-35, reduced penetrance 36-39, High penetrance >40
- There is an inverse correlation between (CAG)n and age of onset
- male patients with affected fathers progress fastest
Pathology of HD
Atrophy of caudate and putamen (similar to PD)
Loss of volume of cerebral cortex
Neuronal loss and astrocytosis
Nuclear and cytoplasmic inclusions containing aggregations of mutant hungtitin and polyglutamine
Which neuronal population is affected in HD?
Which neurones are sparred?
What neurotransmitters are affected?
It is the most affect neuronal population in HD:
- Striatal medium spiny neurons which express D1 and D2 receptors are preferentially lost in HD. In indirect pathway: decrease inhibition to thalamus, therefore increase stimulation to motor cortex causing chorea
- interneurons = sparred
- Reduced levels of neurotransmitters: GABA, Ach, Somatostatin, neuropeptide Y, NOS
What are the cellular mechanisms of HD
Protein -> gain of function:
Mutant hungtintin forms aggregates - Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neurone function.
- Increase Ca2+ from ER causing mitochondrial dysfunction
- Pathological Htt (mHtt) fragments have been found in the nucleus, where they may damage neurons by a transcriptional mechanism
What imaging can we use in HD?
CT/MRI: monitor increase in bi-caudate diameter, striatal volume loss correlated with CAG repeats
PET img: Decrease in flumazenil binding in caudate
Current management of HD
- non pharmocological
- pharmacological
- genetic counselling
- psychological support
- Respite care
Symptomatic relief:
- cognitive dysfunction
- sleep wake cycle disruption
- psychiatric dysfunction - antidepressants
- weight loss
- Chorea - Tetrabenazine and sulpiride but a lot of side effects
No disease modifying drugs
What are examples or future treatments? (2)
- Huntington’s disease antisense oligonucleotide hungtintin lovering (gene silencing) trial: ISIS-HTT-Rx phase 1
- HD patient post foetal striatal transplantation
