Wilson's disease neurology

1. WILSON’S DISEASE

2. Copper (Cu)
 Total body copper is about 100mg
 Sources :liver, fish, meat, lentils
milk is a poor source
 RDA: 1-3mg

3. Functions
 Mobilization of iron
Fe2+ Ceruloplasmin Fe3+
 Formation of enzymes
dopamine oxidase, serum ferroxidase,
ALA synthase, monoamine oxidase,
tyrosinase etc.

4. Functions of ATP7B
1) Binds Cu to Apoceruloplasmin
2) Packages Cu into vesicles for exocytosis in bile
Cu2+
• Absorption : from duodenum
• Metallothionein – facilitates
absorption
• Phytates, zinc and
molybdenum decrease Cu
uptake
Excretion of copper
90% Bile fecal Cu
10% urine

5. Excess of Cu
Initially bound to metallothionein, but as this storage capacity is
exceeded , liver damage begins
Cu2+ Cu2+ + *OH + -OH
H2O2
Free radical
Tissue damage

6. DEFINITION
 Wilson’s disease occurs due to a defect of
copper transport by the hepatic lysosomes.
 Genetic defect in excretion of Cu resulting
in excess deposition of Cu in body tissues.
 It is autosomal recessive disorder.

7.  Frequency of carriers ~1%
 Siblings of diagnosed patient have a 1 in 4
risk
 Whereas children of affected individual
have 1 in 200 risk.

8. ETIOLOGY
 Mutations in the ATP7B gene,
A membrane bound, copper transporting
ATPase.

9. WD-PATHOPHYSIOLOGY

10. LIVER
Slice of enlarged liver shows micro and macronodular cirrhosis.
Inset demonstrates copper deposits within hepatocytes on rubeanic
acid stain. Inset: Rubeanic acid

11. CLINICAL FEATURES
Broad age of presentation
Early twenties, extends to sixth decade.

14. APPROACH FOR EVALUATION
OF WD
Clinical
suspicion
Classical
Acute hepatitis
Unexplained jaundice
Hepatic features with
extrapyramidal manifestations
Family history
High degree of suspicion
Early/young onset extrapyramidal
Symptoms
Progressive behavioural symptoms
Multi-axial psychiatric involvement
psychiatric symptoms
poor scholastic performance
seizures
Recurrent pathological fractures
Unexplained haematological
abnormalities

15. Confirm
atory
work-up
Biochemical
Raised 24 hr urinary
Copper (>100mg/24hr)
Low serum cerruloplasmin
copper
Ophthalmic
Slip lamp confirmed
Kayser-Fleisher ring
Radiological
USG Abdomen
cirrhotic liver
portal hypertension
MRI Brain
bilateral basal ganglia changes
tectal plate changes
CPM like features and
combination of basal ganglia
Brainstem signal changes
Genetics
Genetic analysis
For mutations

16. INVESTIGATIONS
 Biochemical
◦ Serum ceruloplasmin ↓ <20mg/dL
◦ 24hr Urinary Copper >100micg/d
◦ Serum free copper >10micg/dL
◦ Liver Copper >250micg/g
 Ophthalmological
◦ Slit lamp KF ring
 Imaging
◦ X-ray Osteoporosis
◦ Ultrasound Cirrhosis
◦ CT Scan
◦ MRI
 Genetics

17. MRI in WD
a. ‘Face of giant panda’ sign;
b. MRSS: decreased NAA and therefore a
decreased ratio with other products
c. Bright lateral putamen or claustral sign;
d. Pallidal hyperintensity

19. Treatment Options
 Reduced Copper intake
◦ Low copper diet
 Reduce copper absorption
◦ Zinc
 Increase copper excretion
◦ Penicillamine
◦ Trentine
◦ Tetrathiomolybdate
 Liver Transplantation
 Gene Therapy

20. Manage
ment
Symptomatic
Medical Surgical
Symptomatic medical treatment
Of disabling symptoms
Surgical therapy for medically
Refractory symptoms
thalamotomy
splenectomy
Disease modifying
Medical Surgical
Penicillamine
Zinc
Trientine
Ammonium tetrathiomolybdate
Liver transplantation
For fulminant hepatic failure

21. Chelating agents: Penicillamine
and Trientine
intestine
Copper
Ceruloplasmin
Penicillamine/Trientine
urine

22. D-Penicillamine
 Dose
◦ Initial: 1-1.5 g/day adults or
20 mg/kg/day children
◦ Maintenance: 0.75-1 g/day
 Adverse effects
◦ Fever, rash
◦ Proteinuria
◦ Lupus like reaction
◦ Aplastic anemia
◦ Neurological Deterioration
occurs in 10%-20% during
initial phase
◦ Leukopenia
◦ Thrombocytopenia
◦ Nephrotic syndrome
◦ Degenerative changes in skin
◦ Hepatotoxicity

23. Trientine (triethylene tetramine
dihydrochloride)
 Dose: 1-1.2 g/day
 Adverse effects :
◦ Gastritis
◦ Aplastic anemia rare
◦ Neurological Deterioration 10%-15% during initial phase .

24. intestine
Copper
Albumin Ceruloplasmin
Zinc
metallothionein
Zinc Acetate/Sulfate

25. Zinc
Indication:
Following penicillamine
Penicillamine intolerance
Prophylactic to aymptomatic sibs
New cases (cannot afford Penicillamine)
Dose : Initial: 50 mg T.I.D (adults)
Adverse effects
 Gastritis
 Zinc accumulation
 Possible changes in immune
 ND can occur during initial phase

26. Monitoring
Family
Care giver education
Screening of siblings
Education regarding
Mode of transportation
Patient
Education
Clinical course
Copper restricted diet
24 hour urinary copper
Radiological improvement

27. Complications
 Hepatosplenomegaly
 Renal disease
 Hemolytic anemia

28. Prognosis
 Life long treatment is needed to control
Wilson’s disease.
 If not treated early, Wilson’s disease is fatal.