Neurology JC023: Unsteady Gait: Cerebellar Lesions, Movement Disorders, Parkinsonism

Question 1

Physiology of gait

Answer 1

3 levels of gait control:
1. Upper level (**Gait execution)
- Premotor cortex
- Motor cortex
- Regulatory system: **Extrapyramidal system (e.g. Basal ganglia)

2. Middle level (Subcortical centres: **Synergy of gait)
   - Midbrain locomotor region (MLR)
   - Spinal locomotor network (SLN)
   - Regulatory system: **Cerebellar system
3. Lower level (Force production)
   - Peripheral nervous system
   - Musculoskeletal system
   - Regulatory system: Spinal reflex pathways (Vestibular + ***Proprioceptive inputs)

Regulatory system: **Postural control + **Balance

Question 2

Gait disorders

Answer 2

1. Apraxic gait
   - **Motor cortex + Extrapyramidal system affected (Diffuse problem)
   - **Difficulty initiating walking, 行行下唔行
2. Parkinsonian gait
   - ***Extrapyramidal system affected
   - Hypokinetic gait, Small steps, Turn slowly
3. Ataxic gait
   - **Cerebellar system + Spinal reflex pathways affected
   - **Wide based, Truncal unsteadiness
4. Hemiplegic / Diplegic / Spastic gait
   - Upper level of gait centre affected (e.g. Stroke)
5. Antalgic gait
   - Musculoskeletal system affected (∵ pain)
6. Waddling gait
   - Musculoskeletal system affected

Question 3

Causes of Gait disorders

Answer 3

1. Motor deficits
   - UMN (spasticity)
   - LMN (amytrophy = muscular wasting)
   - Muscular disorders
2. Movement disorders (Extrapyramidal disease)
3. Sensory ataxia
4. Cerebellar ataxia
5. Vestibular disorders
6. Parkinsonian syndromes
7. Normo-pressure hydrocephalus

Question 4

Revision: Cerebellum

Answer 4

Cerebellum:
- Coordination / Fine-tuning of voluntary movements
- Control of equilibrium + muscle tone
- Responsible for ***ipsilateral side

Vermis / Other paramedian structures:
- **Truncal stability
- **Gaze fixation
- ***Gait
—> rely on integration of Sensory (Vision) + Vestibular + Motor (Proprioception) signals input

Question 5

Cerebellar disorders

Answer 5

Ataxia (共濟失調症):
- ***loss of coordination
- irregularity / disorderliness
- may result from:
1. Cerebellar disorders
2. Impaired sensory feedback (Sensory ataxia)

1. Limb ataxia / Ataxic gait
   - Dysmetria + Tremor + Dysdiadochokinesia
   - hard to test if weakness / sensory impairment
   - muscle tone is reduced but often not apparent
2. Scanning dysarthria (***specific for cerebellar disorder)
   - Explosive dysarthria (incoordination of speech / respiration —> speech volume / rate vary from word to word) + Cerebellar speech (slow + slurred)
3. Nystagmus
   - vestibulocerebellar pathway affected —> Ocular Dysmetria (jerkiness of smooth-pursuit eye-movements with disrupted fixation)
   - **Gaze-evoked + **Horizontal
   - unilateral lesion: fast-phase of nystagmus is towards the ***affected side
4. Dysmetria
   - errors in range + force of movements —> under / over-shooting of target: Finger-nose, Heel-shin test
5. Dysdiadochokinesia
   - decomposition of fine repetitive movements
   - NOT specific for cerebellar disorders
   - can be seen in ALL neurological conditions affecting motor control of limb
6. Hypotonia
7. Intention / Kinetic tremor
   - exaggerated by maximising range of movement tested
8. ***Pendular tendon reflexes

Question 6

Etiologies of Cerebellar disorders

Answer 6

Children:
- Congenital maldevelopment (Arnold-Chiari malformation, Dandy-Walker syndrome)
- Metabolic disorders
- **Infections (Chicken pox encephalitis)
- **Tumours (Medulloblastoma, Cystic astrocytoma)
- Hereditary degenerative disorders

Adult:
- Hereditary degenerative disorders (AD Spinocerebellar ataxias, Recessive Friedreich’s ataxia)
- Alcoholism
- **Cerebrovascular disease
- **Multiple sclerosis
- **Metabolic disorders (e.g. Hypothyroidism)
- **Drug overdose (e.g. Anticonvulsant, Antihistamine)
- ***Tumours (direct involvement / paraneoplastic syndrome)

Question 7

Ataxic gait

Answer 7

Result of Incoordination of movements + Unsteady balance of trunk

Features:
- **Wide based (to maintain balance)
- **Truncal unsteadiness (when asked to walk tandem)
- **Tendency to Jerk sideway
- **Walk relatively quickly
- Irregular length / synergy
- Greatly exacerbated during rapid postural adjustments e.g. Turning corners
- may combine with other gait disorders (e.g. Spastic gait in MS, High-stepping gait in Tabes dorsalis)

Question 8

Hemiplegic gait

Answer 8

• Arm adducted
• Internally rotated at shoulder
• ***Flexed at elbow
• Pronation of forearm
• ***Flexion of wrist and fingers
• Leg slightly flexed at hip
• ***Extended at knee
• Plantar flexion
• ***Inversion at foot

Question 9

Apraxic gait / Gait apraxia

Answer 9

• ***Difficulty initiating walking
• Disorganised walking skills
• ***Shuffling small steps
• BUT ***arm swing and posture are normal (vs PD: reduced arm swing, stooping posture)

Question 10

Cerebellum vs Basal ganglia

Answer 10

Cerebellum: Rapid (ballistic movement)

Basal ganglia: Slow (ramp, smooth movement)
1. Caudate nucleus
2. Putamen
3. Globus pallidum
4. Substantia nigra

Question 11

Extrapyramidal disorders (aka Movement disorders)

Answer 11

Disorders of Basal ganglia:
- affect slow (ramp) rather than rapid (ballistic) movements

Basal ganglia motor loop:
- complex network consisting of multiple nuclei
- D1: excitatory pathway
- D2: inhibition pathway
- normally balance out each other, imbalance: Movement disorders

Dyskinesia / Hyperkinetic disorders (Defect in D2 inhibition pathway)
- Chorea (舞蹈症)
- Ballismus (芭蕾舞症)
- Athetosis (手足徐動症), Choreoathetosis
- Dystonia (肌張力不全症)
- Tremor (顫抖症)
- Myoclonus (肌躍症)
- Tics (肌抽搐症)

Akinesia / Hypokinetic disorders (Defect in D1 excitatory pathway)
- Parkinsonism

Question 12

Chorea (舞蹈症)

Answer 12

Lesion in Striatum / related structures

Features:
- **Irregularity + **Randomness + Excessive + **Spontaneous + Jerky + Non-repetitive
- At different parts of body in random sequence
- **No weakness
- Gait: Tendency to sway + jerk
- ***Muscle tone ↓
- Patient may mask it by Quasi-purposive (seemingly on purpose)
- Irregular + Explosive speech

Causes:
- Huntington’s disease
- Cerebral palsy
- **Kernicterus (excessive bilirubin)
- Rheumatic fever (Sydenham’s chorea, reactivate as **Chorea gravidarum during pregnancy)
- SLE
- Structural lesions (e.g. Tumour, AV malformation)
- ***Wilson’s disease
(- Can be secondary to PD due to high Levodopa dose)

Question 13

Hemiballismus (單側芭蕾舞症) / Ballismus (芭蕾舞症)

Answer 13

Exaggerated form of Chorea / Proximal chorea

Etiology:
- Stroke —> Lesion affect **Contralateral Basal ganglia / Subthalamic nucleus unilaterally —> **Contralateral Hemiballismus

Features:
- Irregular, Non-repetitive
- ***Violent excursions of affected limbs (∵ proximal muscles affected)

Treatment:
- ***Tetrabenazine (block Dopamine reuptake)

Prognosis:
- usually disappear several weeks after onset

Question 14

Athetosis (手足徐動症)

Answer 14

Etiology:
- **Neonatal cerebral hypoxia
- **Kernicterus

Features:
1. ***Abnormal limb posturing
- Shoulder: Adducted + Internally rotated
- Elbow: Semi-flexed
- Wrist / MCP joints: Flexed
- IP joints: Extended

2. ***Slow, coarse, twisting writhing movements of extremities
   - Flexion / Extension of wrist, fingers, elbow
   - Retraction, Internal rotation at shoulder
3. Patient may grasp affected limb with normal hand to ***restrain movement
4. UMN signs may present
5. Lower limb less affected

Question 15

Dystonia (肌張力不全症)

Answer 15

Frozen Athetosis
***Abnormal posturing

Etiology (reversible):
- Focal brain lesion (involving Basal ganglia, Rostral midbrain)
- Wilson’s disease
- Drug-induced dystonia

Features:
- **Excessive muscular tone + contraction of antagonistic muscle groups
—> Sustained postural distortion of limbs + trunk (扭麻花, painful)
—> may be distorted by Repetitive spasmodic twisting movements
- **Posture / Action / Task-specific
- Sporadic / Familial

Types:
1. Focal Dystonia (more common)
- **Cervical dystonia (Spasmodic torticollis)
- **Blepharospasm
- Foot dystonia
- Writer’s cramp

2. Generalised dystonia

Treatment:
- **Anticholinergics
- Levodopa
- **Benzodiazepines
- Botox local injection

Question 16

Tremor (顫抖症)

Answer 16

• ***Rhythmic oscillating movement of a segment of limb / head
• ***Alternating / Synchronous contraction of antagonistic pair muscles —> Rhythmic oscillating movement
• Fixed periodicity
• Waveforms / Amplitudes can vary

3 types:
1. Resting tremor (esp. Parkinsonian)
2. Postural tremor
3. Intention / Kinetic tremor (esp. Cerebellar)
(4. Essential tremor)

Parkinsonian tremor:
- 4-6Hz
- in relaxed + supported limb
- occur when affected body parts are **at rest
- **subside with action

Postural tremor:
- enhanced physiologic (8-12 Hz) tremor on outstretched hand:
—> anxiety, exercises, sleep deprivation, drugs, alcohol, thyrotoxicosis, heavy metal poisoning

Cerebellar Kinetic tremor:
- ***3-6 Hz
- Terminal accentuation / Terminal dysmetria: ↑ in tremor towards target
- Past-pointing
- Treatment: No
- Pathology in Red nucleus: Severe Resting + Kinetic tremor

Physiological tremor:
- 8-12 Hz
- more obvious with old age, anxiety, thyrotoxicosis

Essential tremor:
- 5-10 Hz
- **action-induced
- resemble **exaggerated physiological tremor
- **not well-defined etiology
- worsen by stress / age
- some have positive family history (Benign essential tremor)
- alcohol can improve transiently
- Treatment: **β-blocker, ***Primidone (barbiturate)

Question 17

Myoclonus (肌躍症)

Answer 17

Very wide DDx

Features:
- **Sudden, Brief shock-like muscle contractions
- Variable intensity
- Repetitive / Paroxysmal jerk
- **Simple movement (not complex e.g. chorea / athetosis)
- ***Less rhythmic + Visible pauses (vs Tremor)

Types:
1. Focal (involving only a few muscles)
- Basal ganglia disorders (neck, arm, shoulder)

2. Generalised
   - types:
3. Physiological (nocturnal, hiccups)
4. Essential
5. ***Epileptic
6. Symptomatic
   - Abnormal Cerebral cortex activities
   —> Epilepsy syndromes
   —> Neurodegenerative diseases e.g. AD, CJD
   —> Mitochondrial diseases
   —> Cerebral anoxia
   - Spinal cord disorders

Treatment:
- Depend on etiological diagnosis / specific disease syndrome
- **Benzodiazepines
- Piracetam
- **Anticonvulsant e.g. Na Valproate

Question 18

Differentials of myoclonus

Answer 18

• ***Epilepsy with myoclonus seizures
• ***Secondary myoclonus
• ***Dystonia myoclonus / chorea-related
• Basal ganglia disorders
• Stiff-person syndrome
• Essential myoclonus
• Periodic movements of sleep
• Brainstem, spinal myoclonus

Question 19

Tics (肌抽搐症)

Answer 19

Etiology:
- **Gilles de la Tourette’s syndrome
- **Compulsive behaviour
- Obsessive ruminations
- ADHD

Features
- **Brief, Rapid
- **Coordinated movements, **Stereotypic (vs Chorea: irregular, random)
- Repeated at irregular intervals
- Ability of **voluntary suppression, but ***inner urge to make movement (vs Chorea: involuntary)
- Can be trivial
- Not uncommon

Persistent multiple simple tics:
- begin before 15 yo
- associated with vocal tics
- complete remission can occur in adulthood

Chronic multiple motor + vocal tics:
- Gilles de la Tourette’s syndrome
- **Male
- Treatment: **Clonidine (α2 agonist), ***Haloperidol (typical antipsychotic)

Prognosis:
- Symptoms begin in childhood, Worst during late adolescence
- Resolve spontaneously after 20 yo (majority)

Question 20

Drug-induced movement disorders

Answer 20

1. Acute dystonic reactions
   - ***Anti-dopaminergic drugs (in young patients after a few hours) (Prochloperazine, Metoclopramide)
   - Cranial, Cervical, Axial muscles
   - Oculogyric crisis

Treatment:
- **IV Anticholinergics (Procyclidine, Benztropine, Diphenhydramine)
- **Benzodiazepines

2. Tardive dyskinesia:
   - Elderly taking long-term antipsychotic
   - may be due to Dopamine receptor ***hypersensitivity
   - Continuous stereotypic oro-lingual movements
   —> Lip-smacking
   —> Chewing
   —> Rolling of tongue in mouth, pushing against cheek, periodic protrusion
   - Gait unaffected

Treatment:
- Difficult
- Withdrawal (abruptly may paradoxically cause Tardive dyskinesia)

(Extrapyrimidal symptoms of Anti-psychotics:
1. Akathisia
2. Dystonia
3. Parkinsonism
4. Tardive dyskinesia)

Question 21

Parkinson’s disease

Answer 21

A Clinicopathological entity

Etiology:
- Mostly **Sporadic (only a few Familial)
- Idiopathic degeneration of **Substantia nigra
- Presence of Intraneuronal ***Lewy bodies on microscopy

Parkinsonism:
- Clinical features of PD (reflecting loss of dopaminergic neurons)

Pathology:
- Loss of neurons in Substantia nigra (Melanin-containing, Dopaminergic)
- Loss of neurons in Brainstem, Pallidum, Putamen
- Lewy bodies inclusions (PD)

Parkinsonian syndromes:
- big family of syndromes that present with Parkinsonism
- PD one of them (but commonest Parkinsonian syndrome)

Question 22

Other causes of Parkinsonism

Answer 22

1. Secondary parkinsonism
   - **Antipsychotic (i.e. Neuroleptics e.g. Phenothiazine) / Other dopamine-depleting drugs (e.g. Metoclopramide)
   - **Wilson’s disease (must be excluded in early-onset Parkinsonism)
   - Lithium
   - Toxins: MPTP, CO poisoning, Cu, Mn
   - Trauma (e.g. Punch drunk syndrome)
   - Microvascular disease (HT, Atherosclerotic)
   - **Normal pressure hydrocephalus
   - Post-encephalitis lethargica
   - AD, **Lewy body dementia, CJD
   - Leucodystrophies
   - Hallevorden-Spatz disease
   - Westphal variant of Huntington’s disease
   - Denatao-rubro-pallido-luysian atrophy
   - Guam variant of motor neuron disease
2. Other neurodegenerative disease involving Basal ganglia
   - **Diffuse Lewy body disease
   - **Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)
   - ***Multiple system atrophy
   - Corticobasal ganglionic degeneration
   —> called Parkinsonism “Plus” syndromes (have other features apart from Parkinsonism ∵ more widespread disease process)

Question 23

Epidemiology of PD

Answer 23

• 80% of Parkinsonian syndromes
• Prevalance: 160/100,000 population
• Incidence: 20/100,000 per year
• 1% population >65 yo
• Onset: 40-70 yo, peak in ***6th decade
• Onset before 30 yo: ~1%
• Onset before 50 yo: ~10%
• M:F = 3:2

Question 24

Natural history of PD

Answer 24

• Degenerative condition
• Insidious onset
• Gradual progression
• Average survival from onset ***13 years
• Mortality rate 2-5x of age-matched population

***“Hoehn and Yahr” staging
Stage 1: Unilateral (3 years)
Stage 2: Bilateral (6 years)
Stage 3: Bilateral + Postural imbalance (7 years)
Stage 4: Severe, need help (9 years)
Stage 5: Chair / Bedbound (14 years)

Question 25

Risk factors of PD

Answer 25

Likely multi-factorial 1. Aging - Nigral cells 425,000 reduced to 200,000 by 80 yo (30% of age-matched subject to start with —> early emergence of motor dysfunction) 2. Genetics - family history - specific mutation 3. Environment (less clear)

Question 26

***Clinical features of PD

Answer 26

Parkinsonism (TRAP): 1. Resting Tremor - Resting (↓ with action, ↑ with rest) - Begins in hand / foot - Flexion + Extension of ***fingers (usually little movement above wrists) - Exacerbated by stress - ***Coarse (4-6 Hz) - ***“Pill-rolling” 2. Rigidity - ***↑ Resistance to passive movements (***Lead-pipe / Cogwheel) (vs Spasticity: distribution + velocity-dependent) - ↑ Muscle tone equal in flexor / extensor - Uniform throughout range of movement - ***Cogwheel rigidity (combination of Tremor + Hypertonia) - ***Fatigue, muscle ache (∵ sustained muscle contraction) 3. Akinesia / Bradykinesia - ***Slowness in voluntary movements - ***↓ Automatic movements (e.g. Arm swinging) - Gait disturbance —> ***Flexed, Stooping posture —> Slow —> ***↓ Arm swing —> Poor foot clearance —> Poor gait initiation —> ***Small steps, Shuffling (Marche a petit) —> Turning difficulty —> Falls —> Difficulty in initiation —> then advances rapidly with small steps to catch up with shift in centre of gravity (***Festinating gait) - Lack of facial expression + blinking (***Facial amimia) - Clumsiness in rapid repetitive movements (***Dysdiadochokinesia) - Blepharospasm, sustained blink responses (***Myerson’s sign) - Small hand writing (***Micrographia) - ***↓ Voice, monotonous speech 4. Postural instability - Tendency to fall backwards (***Retropulsion) Other S/S apart from Motor symptoms: 1. Psychiatric - Panic, Anxiety - Depression - Paranoia, Hallucinations (more prone to SE of anti-parkinsonian drugs) 2. Sensory - Paresthesia - Pain 3. Autonomic dysfunction - Tachycardia - Sweating - Constipation - Belching - SOB - Postural hypotension - ***Detrusor instability 4. Cognitive decline - Slowness in thought - Poor memory - Lack of motivation

Question 27

Clinical red flags to differentiate Parkinsonism Plus vs PD

Answer 27

1. ***Rapid progression, early instability and falls 2. ***Poor treatment response to Levodopa (PD has excellent response to Levodopa) 3. ***Early + prominent dementia 4. ***Pyramidal signs, Cerebellar signs, Autonomic dysfunction, ***Gaze palsy 5. Young onset with strong family history

Question 28

Diagnosis of PD

Answer 28

Clinical diagnosis: - ***Klawans principle: Presence of S/S of PD + without S/S not consistent with PD - ∵ ***NO reliable in-life markers UK PD Society Brain Bank Clinical Diagnostic Criteria Step 1: Diagnosis of Parkinsonian syndrome (S/S of PD) - Bradykinesia - >=1 of following —> Muscle rigidity —> 4-6 Hz rest tremor —> Postural instability not caused by primary visual, vestibular, cerebellar, proprioceptive dysfunction Step 2: Exclusion criteria for PD (without S/S not consistent with PD) - S/S with Parkinsonism Plus syndrome Step 3: Supportive prospective positive criteria for PD (only 80% specificity) - Progressive disorder - Persistent asymmetry affect side of onset most - Excellent response (70-100%) to Levodopa - Severe Levodopa-induced chorea - Levodopa response >=5 years - Clinical course of >=10 years Other investigations: 1. DaT (Dopamine transporter) scan (123I-β-CIT and 123I-FP-CIT SPECT) 2. 18F-dopa, 11C-Raclopride PET scan —> can still be positive in Parkinsonism Plus syndromes 3. TC-US midbrain for Fe deposition in SNc (substantia nigra pars compacta) 4. MRI (DWI, DTI, ADC map)

Question 29

Genetics of PD

Answer 29

- Sporadic - Positive family Hx: Double risk of PD - >10 genetic loci implicated in Parkinsonian syndromes: PARK, SNCA, LRRK etc. (although most of them related to Parkinsonism Plus syndromes) - Gene mutation: ***α-synuclein, ***Parkin - ***LRRK2 associated with 1. Familial PD 2. Sporadic late-onset cases (0.5-2%)

Question 30

Treatment of PD

Answer 30

NOT exist in PD: 1. Restorative therapy (reverse disease process) 2. Neuroprotective therapy (arrest / slow down disease progression) Only available in PD: 3. Symptomatic / Palliative therapy - Dopaminergic (replenish dopamine deficiency from Nigral cell degeneration) - Anti-inhibitory Drug therapy: - ***Levodopa + Carbidopa (peripheral DOPA decarboxylase inhibitor) (Gold standard) Early stage: - ***Anticholinergic (Benzhexol) - ***MAO-BI (Selegiline) Adjunct: - ***Dopamine agonists (Bromocriptine, Ropinirole, Apomorphine, Pergolide) - ***COMT inhibitor (Entacapone, Tolcapone) - Amantadine Surgery: - ***Pallidotomy - ***Thalamotomy - ***Deep brain stimulation - Cell transplantation Others: - Physical therapy - Daily living aid

Question 31

***Dopaminergic therapy

Answer 31

1. Levodopa - converted to Dopamine in remaining Nigral cell - combined with peripheral Dopa-decarboxylase inhibitor / Transferase inhibitor —> achieve higher CNS concentration - Problems with long term use: —> ***Loss of efficacy (only for ~5 years, ∵ gradual loss of dopaminergic terminals) —> Drug-induced ***Choreiform Dyskinesia (Motor fluctuations, End-of-dose wearing off, Unpredictable on-off response) —> ***Psychiatric complications (Hallucinations, Psychosis) —> Can add ***Atypical antipsychotics with low propensity for inducing extrapyramidal SE (e.g. Clozapine, Olanzepine, Quetiapine) 2. MAOI (Monoamine oxidase B inhibitor) - ↓ breakdown of dopamine 3. Dopamine receptor agonist - ↑ sensitivity of dopamine receptor

Question 32

Anti-inhibitory therapy

Answer 32

Surgical treatment 1. Lesioning specific D2 nuclei e.g. Pallidotomy, Thalamotomy - Down-regulate D2 inhibitory pathway 2. Deep brain stimulation (current) - Overdrive pacing of STN (subthalamic nucleus) with electrodes —> blockade effect

Question 33

Treatment flow of PD

Answer 33

Early disease, impaired ADL —> ***Tremor predominant: Selegiline, Anticholinergic, Levodopa —> ***Other features dominant: Selegiline, Amantadine, Dopamine agonist, Levodopa —> Good response: Lowest dose that maintains control —> Poor / No response: ↑ Dose, Consider other diagnosis Moderate impairment of ADL —> Levodopa —> Wearing off: Smaller + more frequent doses, Carbidopa Levodopa, Add Dopamine agonist, COMT inhibitor (Entacapone) —> ***Dyskinesia: ↓ Dose, Add Amantadine —> ***Non-motor adverse effects: ↓ Dose, Add Quetiapine, Clozapine Consider surgical options for severe, pharmacologically unaddressable detriments

Question 34

Other structures affected by PD

Answer 34

Apart form Substantia nigra pars compacta 1. Ventral tegmental area 2. Locus ceruleus 3. Raphe nuclei 4. Substantia innominate 5. Intermediolateral column 6. Olfactory bulb

Question 35

Parkinsonism

Answer 35

- Occurs in all ethnicities groups - related to aging - clinical signs

Question 36

Other notes

Answer 36

Other notes

Question 37

Huntington’s disease

Answer 37

- Manifest 30-50 yo - Chorea —> Dementia Pathophysiology: - Neuronal loss in ***Striatum + ***Cerebral cortex Genetics: - ***Autosomal dominant - ***Chromosome 4, repeat GAG Behavioural problems: - personality change - affective disorders - frank psychosis Prevalence: 5-10 / 100,000 MRI / CT: - Cortical + Caudate atrophy Treatment: - No cure - ***Symptomatic (Haloperidol: atypical antipsychotic) Clinical features: - Marching the knee reflex Prognosis: - Death within 10-12 years

Question 38

Wilson’s disease (Hepatolenticular degeneration)

Answer 38

- ***Autosomal recessive - Defect in copper-transporting ATPase coded on chromosome 13 (ATP7B gene) + Low Ceruloplasmin / Cannot incorporate Cu —> ***Cu accumulation in Liver + ***Basal ganglia —> Neurological manifestations in childhood / young adulthood —> Dyskinesia / Parkinsonism / Psychiatric problems Features: - Kayser-Fleischer rings (Cerebral involvement) Prognosis: - Untreated: die from ***Cirrhosis / ***Neurological complications within 10 years Treatment: - ***Penicillamine (Cu chelation) - Liver transplantation (Cu removal) Prevention: - Family screening to detect presymptomatic cases —> treat with ZnSO4