Huntingtons Disease

Lecture 12

What type of disorder ? Affects what ?

A typical motor disorder - affects the basal ganglia (control of movement occurs here)

What is HD ? Discovered when ? By who ? Prevalence ? Average age ? Cure ? Cause ?

• First described in 1872 - By George Huntington ( a neurologist) at the age of 8

• “On Chorea”

• Familial neurodegenerative disorder - degeneration of neurons

• Autosomal dominant inheritance - inherited

• Prevalence is 1 in 10,000 people

• Average age of onset is 40 y.o (can be seen @ age 20 but that is rare

• No cure - results in death of patients

Autosomal Dominant Inheritance: What is it ? How does it happen ? A child ? Likelihood based on gender ? Nowadays ?

• Autosomal dominant inheritance is a way a genetic trait or condition can be passed down from parent to child.

• One copy of a mutated (changed) gene from one parent can cause the genetic condition

• A child who has a patient with the mutated gene has a 50% chance of inheriting that mutated gene

• Men and women are equally likely to have these mutations and sons and daughters are equally likely to inherit them (not located on a fixed chromosome, x or y chromosome)

• Nowadays, there is a hope for these patients, partners (where one has a gene for PD) can do IVF, sperm is sequences, they reselect sperm for fortification duirng IVF treatment in order to prevent children have this disease.

What are the symptoms of HD ? (3) which is the classic symptom ? (6)(6)(4)

Motor (classic symptom):

• Involuntary twitching

• Excessive restlessness

• Rigidity

• Spasticity

• Decreased coordination (+ balance which causes falls)

• Voluntary movement abnormalities

Psychiatric

• Depression

• Increased agression

• increased irratability

• Patients switch from irritability to apathy

• Impulsivity

• ANtisocial behaviour (the partener becomes severly affected. cannot participate in family life @ later stage of the disease as doesnt know social behaviour)

Cognitive

• Problems with planning and organising

• Memory loss (similar to alzeimers. @ early stages - short-term memory is affected, @ later stages: long-term memory is affected

• Innattention - problems focusing on one task

• Dementia

Chorea: Can observe in what ? Have to have condition ? What is it ? Appear ? What does chorea mean ? Affect what ? Previously called what ?

• Can oberve in children

• Dont have to have the disease, can be caused by infection in brain. Bacteria or antibodies will affect basal ganglia.

brief, involuntary, unpredictable, irregular

movements

• appear to flow from one muscle to the

next. = 'dance-like' movements

• term chorea is derived from the ancient

Greek χορεία "dance” as the movements

of the body is comparable to dancing.

• can affect various body parts, and interfere

with speech, swallowing, posture and gait,

disappears in sleep

• Previously called Chorea Huntingtons disease but then it was discovered that at later stages there is severe psychiatric and cognitive symptoms

Is HD the same throughout the time you have the disease ? When does it start ? What is the first thing that happens ? As the disease progresses ?

No there is stages

• Usually disease starts at age 40-45

• Usually what they have first is the motor impairment (chorea-like symptoms), a few cognitive problems

• As disease progresses, there is functional inability to perfrom their daily life tasks. More motor impairment, severe dementia, cognitive impairment, severe chorea - hinders dressing, talking, moving

Early stage: What age ? 5 symptoms ?

• 40 years old

• Bit of balance + coordination

• Signs of depression

• signs of memory formation problems

• bit chorea

• can be independent with proper support

Middle stage (4)

• Lose ability to walk

• Cannot drive because of chorea

• Increased Ax in eating + dressing

• Ax in moving - not wheelchair bound yet

Later stage: (3)

• restricted to bed / wheelchair

• severe problems with speech, dressing, walking, eating

• severe chorea

What will happen the patients eventually ?

Patients with the disease can eventually lose the ability to talk, eat, walk, drink + care for themself

Speech Impairment : (4) Impairment of what ?

Speech: impairments in movement of the tongue

• Becomes slower with disease progression (at early stages)

• voice may become hypophonic or explosive

• Articulation of speech becomes impaired when voluntary control of lips, tongue and mouth declines, becomes more impaired as disease progresses

• The coordination of speaking and breathing declines, and the intelligibility of speech deteriorate (at end stage)

What happens often in patients ?

Patients commit suicide, becasue of the permanent illness of this disease and because fate is very severe.

What causes HD ? Belongs to what ? Include (3) All do what ?

HD belongs to a family of inherited trinucleotide repeat disorders which includes:

1. Friedreichs ataxia (affects balance)

2. Type 1 Spinocerebellar Ataxias (8 types) - affects the cerebellum + basal ganglia

3. Spinal + bulbar muscular dystrophies

All inherited disorders, all impair movement.

What does Trinucleotide repeat disorders mean ?

CAG - 3 basis in repetition. genes play an important role in regulation of nervous system + homeostasis

• are the most Common repeat mutant gene expression throughout body, but primarily affects the brain.

Huntington gene and protein: Located where ? Codes for what ? What is it involved in ? High what ? When the protein is mutated ?

• Huntington gene on chromosome 4, where the DNA sequence CAG (glutamine residue) is repeated up to 30 times.

• Codes for the protein hungton (Htt)

• Htt is involved in cellular transport, protein processing in neurons, vesicle function, transcription, mitochondrial function

• High expression in neurons in the brain, predominant in neurons

• When the protein is mutated, leads to dysfucntion of neuron then cell death of neuron.

HD is caused by a mutation in the Huntington Gene: a mutation of what ? How much cause it ? What happens ?

• A mutation in the huntington gene which causes an expanded stretch of CAGs (polyglutamine) - usually one one CAG

• Expansions beyond 36 CAGs cause the disease

• When there is more than 1 CAG, causes mutations in protein, leads to cell death of neurons. As the disease progresses more neurons die - this leads to symptoms patients experience.

How does Huntingtin gene cause neuronal cell death ? Propssed mechanism ((5) ?

results ? Which causes what ?

• How the mutated huntingtin gene causes neuronal cell death is unknown

Proposed mechanism

• Impaired protein trafficking which interferes with synaptic transmission (protein accumulates in the neurons)

• Polyglutamine aggregation

• Excitotoxcitity in neurons (release a lot of ions which causes cell death)

• Prpgrammed cell death (apoptosis)

Results in abnormal levels of the neurotransmitter GABA + dopamine - leads to the psychiatric symptoms the patients experience.

Hypothesis for intracellular effect of mutant htt ?

Protein (mutated huntingtin) accumulates in the cell body of the neurons, it will be sent to alteration in the signal of the neurons.

Age of symptom onset ? How does early onset occur ?

• In general, the higher the number of CAG repeats, the earlier onset of symptoms (this is why it effects younger patients)

• Age of symptom onset is usually 40-45

What are the brain regions that are affected in HD ? Same as what ? What can you see in the brain ? (3)

Same as PD.

• Basal Ganglia - particularly caudate nucleus, putamen.

• Widespread neuronal loss initially in striatum + eventually all of the basal ganglia and later in the cerebral cortex

• Accumulation of huntingtin protein aggregation in neurons of striatum + cerebral cortex

• GABA neurons are lost in the striatum - inhibitory, particularly lost in striatum, can explain chorea symptoms

Which neurotransmitter pathways are affected ? What does this cause ?

1. Dopamin: Starts in the striatum in the basal ganglia, neurons project to frontal cortex, becomes often first affected in HD. Dopamine plays a big role in many disorders of the NS, for eg. Depression, PD, regulation of reward, motivation, pleasure, role in fine control of movement. Important in role of compulsion (later stages), important role in preservation of movement.

2. From striatum to frontal cortex to parietal cortex. Important for regualtion of mood, memory processing, regulation of cognition + sleep. Have sleep problems @ later stage of disease.

• Degeneration of striatal GABAergic neurons can cause hyperactivity of dopaminergic systems

Risk Factors ?

There is actually no risk factors for HD because it is a genetic disorder

A parent with a mutation in the HD gene has a 50% chance of passing on the disease to their children.

Diagnosis ?

• Physical + Neurological Examination: Medical + family history, Clinical rating scales to Ax severity + frequency of symptoms.

• Genetic testing: genetic counselling

• Prenatal testing: Amniocentesis, Chorionic villus sampling

Treatment of HD ? (3) What did you learn about dopamine ?

Symptomatic (mainly) drug treatment for HD

Motor

• Tetrabenazine - reduces dopmaine activity

• Baclofen - GABA receptor agonist (increases inhibition in the brain)

Psychiatric

• Neuroepileptics (target GABA, increase inhibition in brain, less psychiatric symptoms)

• Antidepressants

Cognitive

• Not usually treatable

• Can be given memantine - NMDA receptor agonist. Helps slow down cognitive impairment in these patients

Degeneration of striatal GABAergic neurons can cause hyperactivity of dopaminergic systems.

• reduces dopaminergic activity might help restore balance of neurotranmitter function.

Non-Drug Therapies for HD ? (4)

• SLT

• Physio

• OT

• Psychological therapies

Future therapies ? (6)

• Gene therapy:( is tested in humans used in animals. Where gene is replaced)

• Htt aggregation blocker (used in mouse models, injected into basal ganglia, blockage of HD in neurons has side effects)

• Anti-apoptotic drugs ( prevent apoptosis has side-effects)

• Neurotrophic factors - in mouse models side effects can also cause brain cancer

• Transplanation - of neurons into basal ganglia - most promising

• Antioxidants