Huntington's Disease Overview

Huntington's Disease

• A familial neurodegenerative disorder
• Autosomal dominant inheritance
• Average onset at 40 years old
• No cure

Inheritance

• Genetic trait passed from parent to child
• One mutated gene from one parent can cause the condition
• Child with a parent with the mutated gene has a 50% chance of inheriting it
• Men and women have equal likelihood of having the mutation
• Sons and daughters have equal likelihood of inheriting the mutation

Symptoms (Motor)

• Involuntary twitching
• Excessive restlessness
• Rigidity
• Spasticity
• Decreased coordination
• Voluntary movement abnormalities

Symptoms (Psychiatric)

• Depression
• Aggression
• Irritability
• Apathy
• Impulsivity
• Antisocial behaviour

Symptoms (Cognitive)

• Planning/organising problems
• Memory loss
• Inattention
• Dementia

Chorea

• Brief, involuntary, unpredictable irregular movements
• Flowing from one muscle to the next, like a dance
• Interferes with speech, swallowing, posture, gait
• Disappears in sleep

Stages of HD

Early Stage

• Functional: work, drive, handle money, live independently
• Symptoms: minor involuntary movements, subtle loss of coordination, difficulty with complex thought processes

Middle Stage

• Lose ability to work, drive
• Can perform Activities of Daily Living (ADLs)
• Prominent chorea
• Increasing difficulty with voluntary tasks, problems with swallowing and balance

Late Stage

• Require assistance with all activities
• Often nonverbal
• Bedridden
• Some comprehension may remain
• Severe chorea, rigidity, dystonia, bradykinesia

Speech Impairments

• Slow progression
• Hypophonic/explosive voice
• Impaired articulation
• Decline in voluntary control of lips/tongue/mouth movement
• Worsening speech intelligibility

Cause of HD

• Inherited trinucleotide repeat disorders
• Most common: repeat mutant genes expressed throughout the body (Friedreich's ataxia, Spinocerebellar Ataxia)

Huntington Gene/Protein

• Chromosome 4
• CAG (glutamine residue) repeated up to 30 times
• Codes for the protein Huntington (htt)
• Involved in cellular transport, protein processing, synaptic function
• High expression in brain neurons

How Huntington Gene Causes Neuronal Cell Death

• Unknown mechanisms; proposed mechanisms include:
  • Impaired protein trafficking
  • Polyglutamine aggregation
  • Excitotoxicity
  • Oxidative stress
  • Programmed cell death (apoptosis)
• Abnormal levels of GABA and dopamine

Symptoms Onset

• Higher the number of CAG repeats, earlier the onset of symptoms

Brain Regions Affected

• Basal ganglia (caudate nucleus, putamen)
• Widespread neuronal loss initially in striatum, extends to other regions
• Accumulation of huntingtin protein
• GABA neurons are lost

Neurotransmitter Pathways Affected

Dopamine

• Functions: reward, pleasure, motor function, compulsion, perseveration

Serotonin

• Functions: mood, memory processing, sleep, cognition

• Striatal GABAergic neuron degeneration can cause hyperactivity of dopaminergic systems

• Reducing dopaminergic activity might help restore neurotransmitter balance

Risk Factors

• Parent with HD mutation has a 50% chance of passing it to their children

Diagnosis

• Physical and neurological exam
• Medical and family history
• Clinical rating scales to assess symptom severity and frequency
• Genetic testing
• Prenatal testing (amniocentesis, chorionic villus sampling)

Treatment

• Symptomatic drug treatment
• Addresses motor symptoms

Future Therapies

• Gene therapy
• Htt aggregation blockers
• Anti-apoptotic drugs
• Antioxidants
• Neurotrophic factors
• Transplantation