Genetics of Movement Disorders

Question 1

What are Movement Disorders?

Answer 1

Group of neurological conditions
that cause abnormal movements. MDs are the consequence of damage or dysfunction of the brain areas that affect movement.

Question 2

General Symptoms

Answer 2

Question 3

Affected brain areas

Answer 3

Question 4

Affected movement types

Answer 4

• Voluntary
• Involuntary

Abnormal:
- Increased (Hyperkinesia)
- Decreased (Hypokinesia)

Question 5

Aetiology

Answer 5

Genetic risk factors

Environmental risk factors

Question 6

Types of MDs

Answer 6

Question 7

Essential Tremor - Clinico-pathological features

Answer 7

• Affects 5% of the population over 65 y/o
• Clinical manifestation: progressive bilateral tremor affecting the upper extremities. Can affect head/neck and vocal cords
• Pathological manifestation: alteration or loss of Purkinje cells (inhibitory GABAergic neurons helping with coordination), impaired cerebello-thalamo-cortical circuitry. Some patients have Lewy Bodies.

Question 8

Essential Tremor - Genetic features

Answer 8

• > 50% (and up to 90%) of the cases are familial, i.e. can be inherited in families, in an autosomal dominant way.

Question 9

Essential Tremor - Therapeutics

Answer 9

• Propranolol: a beta-blocker used to reduce tremors. It can be effective in up to 50-70% of patients.
• Primidone: an anti-seizure medication, primidone is effective in many ET patients, either alone or in combination with propranolol
• Deep Brain Stimulation (DBS): implanting electrodes in the thalamus
  . The electrodes deliver electrical
  impulses to regulate abnormal activity, reducing tremor symptoms. Highly
  effective in patients with severe tremors who do not respond to medications, but requires surgery and regular follow-up, with risks such as infection and bleeding.

Question 10

Parkinsons’ Disease - Clinico-pathological features

Answer 10

• Affects 1% of the population >60 years, 4% of the population >80 years
• Clinical manifestation: Tremor, Rigidity , Akynesia, Postural Instability
• Pathological manifestation: loss of dopaminergic neurons in the substantia nigra pars compacta
  (SNpc) & Lewy Bodies
• Non-motor symptoms including mild memory and thinking problems, sleep disturbances, pain, anxiety and depression.
• 90% Sporadic & 10% Familial

Question 11

Parkinson’s Disease - Therapeutics

Answer 11

Question 12

Multiple System Atrophy (MSA)

Answer 12

• Rare and progressive adult-onset neurodegenerative disorder (faster progression than PD)
• Clinical features: autonomic dysfunction in combination with
  parkinsonism that responds poorly to levodopa and/or cerebellar ataxia
• Pathology: neuronal loss and gliosis in multiple areas of the central nervous system, oligodendroglial accumulation of misfolded and aggregated α-synuclein

Question 13

Progressive Supranuclear Palsy (PSP)

Answer 13

• Clinical features: alterations in movement, gait, balance, speech, swallowing, vision, eye movements,
  mood, behaviour, and cognition
• Pathology: 4R-tau accumulation in different brain area
• Initially suggested to be sporadic, but causative genes and risk factors identified

Question 14

Synucleinopathy vs Tauopathy

Question 15

Huntingdon’s Disease

Answer 15

• Most common autosomal dominant neurodegenerative condition, slowly progressive
• Clinical manifestation: motor, cognitive, and psychiatric
  symptoms, generally appearing during mid-life (around 40 years of age), chorea
• Pathology: cortical and striatal neurodegeneration, protein aggregation
• Caused by a CAG repeat expansion in the first exon of the HTT gene, which encodes a mutant huntingtin
  protein.
• Anticipation: Huntington’s Disease
  phenotypes become more severe
  from one generation to the next

Question 16

Amyotrophic Lateral Sclerosis – Lou Gehrig’s disease

Answer 16

• Separate classification as a motor neuron disease (the most common).
• Clinical manifestation: muscle weakness and respiratory failure due to motor neuron degeneration. Fatal and fast progressing (usually death within 5 years). Usually begins with unilateral lower motor neuron symptoms (i.e., unilateral upper extremity weakness), and then progresses predictably to include lower motor neuron and bulbar symptoms
• Complex Pathology
• No cure

Question 17

Amyotrophic Lateral Sclerosis - Genetics

Answer 17

• 10% familial
• 90% sporadic (not inherited)
• Most common genes associated with ALS are SOD1, FUS, and TARDBP