Transcript Document

WILSON’S DISEASE
Ben Winrow
How to use this SDL
This SDL is designed to be informative and interactive
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
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Every time you see words that are underlined you can click on these to
get an explanation of what the word means, then click on ‘back to
presentation’ to return to the SDL
At the end of the SDL there are a set of questions so be sure to read and
remember the information that is contained in the following slides
Use the content finder on the left to revert to any section of the SDL
Wilson’s is not a common disorder, but it is the severity of the condition
if left untreated which prompted design of this SDL
Learning objectives
• To understand what Wilson’s disease is
• To be aware of its prevalence
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
• To understand the genetic factors leading to Wilson’s disease
• To understand the molecular processes that lead to the symptoms of
Wilson’s disease
• To have an appreciation of the presentation of Wilson’s in the young
patient and in the older patient
• To have an awareness of the ways in which Wilson’s disease is
diagnosed
• To understand the role of genetic analysis in the diagnosis of first
degree relatives of a Wilson’s patient
• To be aware of current treatment of Wilson’s disease
• To understand the shift in treatment options
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• To know the recent advances in treatment
Definition
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
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An inborn error of copper metabolism –
characterised by an increase in copper accumulation in tissues of the
liver (1), brain (2), cornea (3), skin (4), joints (5) and kidney (6), as a
result of decreased hepatobiliary excretion of copper. It is also known
as lenticular degeneration.
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Aetiology
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1.
Title page
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How to use this SDL
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Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
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Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
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Questions
14.
References
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•
The cause of Wilson’s has only recently been deduced but the exact
mechanism is always changing. The ATP7B gene product is a P-type
ATPase transporter, which is part of the trans-Golgi network.
The ATP7B gene itself is around 80kb long and has 21 introns.
The mutated gene leads to a faulty gene product and this causes the
pathologies seen in Wilson’s disease. The gene is responsible for
incorporation of copper into caeruloplasmin and its excretion into bile.
In Wilson’s disease copper is not bound to the caeruloplasmin, causing
toxicity. Characteristically, there is also low serum caeruloplasmin due
to poor synthesis. It is known that copper stimulates caeruloplasmin
production but the exact mechanism of poor synthesis is not fully
understood.
The lack of transportation of copper into the bile leads to accumulation
of copper in the hepatocytes
When hepatocyte storage capacity is reached, free copper is slowly
released into the blood stream causing an accumulation of copper in
extra-hepatic tissue.
Rarely, a massive release of copper can lead to haemolysis and
fulminant hepatic failure
Genotype-Phenotype relationship is still unknown, however mutations
that limit the function of the gene product seem to be related to an early
onset of symptoms of the disease.
Epidemiology
The prevalence of Wilson’s in Northern European Caucasian
population is 1/30,000
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
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Presentation of disease
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Diagnosis
10.
Genetic diagnosis
11.
Treatment
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Summary
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Questions
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References
Even though this makes the disease quite rare it is speculated that
1/90 people carry a defective ATP7B gene
In some areas of the world the prevalence can be as high as 1/5000,
and certain mutations in the gene are associated with these pockets
of increased prevalence
The areas highlighted below have an increased prevalence:
Iceland
China
South Korea
Sicily
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Northern India
Genetics
Patients are usually
homozygous or compound
heterozygous, this can make
There are around 300 known mutations
it difficult to obtain a
the most common being His1069Gln
diagnosis by mutation
analysis
The pattern of inheritance is Autosomal
recessive
Mutations are either
nonsense, missense or
With 2 carrying parents the child has a
frameshift, the most
¼ chance of having the disease
common mutation found on
the gene being missense.
Chromosome 13 carries the gene which
causes Wilson’s
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
8.
Presentation of disease
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Diagnosis
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Genetic diagnosis
11.
Treatment
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Summary
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Questions
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References
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The site of the mutation
determines the severity of
the disease
Presentation [1]
Hepatic presentation
The presentation of hepatic disease due to Wilson’s is diverse.
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
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Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
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Questions
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References
Most patients that present hepatically are young. Typically symptoms will
become apparent at around 6 years of age.
At this age slit lamp examination may not show Kayser-fleischer (K-F)
rings
One of the first signs that pathology is present is persistent asymptomatic
hepatomegaly or the elevation of serum aminotransferases (as seen in the
young patient presenting with Wilson’s, sometimes misdiagnosed as
hepatitis)
Jaundice with no apparent cause is often a presenting complaint
Acute hepatitis is another presentation with positive non-specific
autoantibodies and raised serum IgG
Non-alcoholic fatty liver disease can also be misdiagnosed as steatosis can
often occur
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A majority of patients however present with chronic liver disease having
been undiagnosed and therefore have small, scarred livers, ascites and
splenomegaly.
Presentation [2]
Hepatic presentation
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
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Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
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Treatment
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Summary
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Questions
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References
Fulminant hepatic failure is the ultimate progression, giving rise to
characteristic features– renal dysfunction (due to haemolysis by the free
copper in the blood stream causing renal tubulopathy), low amino
transferases and low alkaline phosphatases. Due to this presentation the
diagnosis is often wrong (acute hepatitis), which can be life threatening as
the only treatment is liver transplantation.
Due to the nature of the presentation it is often confused with other, more
common disease processes e.g. viral hepatitis
A high index of suspicion is needed to diagnose Wilson’s- if left untreated
the copper can deposit in extra hepatic tissues and cause irreversible damage
to the brain, causing neurological problems; the kidney, causing tubulopathy;
and the joints, causing early onset osteoarthritis.
Fig. A liver with acute
hepatitis
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Presentation [3]
Neurological presentation
The patient that presents with neurological pathologies tends to be older
(>35 years) and symptoms can often mimic other disorders
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
8.
Presentation of disease
9.
Diagnosis
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Genetic diagnosis
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Treatment
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Summary
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Questions
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References
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The majority of patients presenting neurologically will have movement
disorders (e.g. tremor)
Rigid dystonia can also be a presenting feature and this can be confused
with a parkinsonian disorder (drooling, slow walking)
There is a deficit in the patient’s handwriting (small and illegible) and
unusual clumsiness for age can be shown using direct questioning or
specific intelligence testing (mainly testing fluid intelligence)
Some patients present with the following symptoms:
Dystonia
Dysarthria
Dysphagia
Presentation[4]
Neurological presentation
20% of patients present with a psychiatric disorder, usually in adolescence,
and this can be misdiagnosed as many other mood or affective disorders.
1.
Title page
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How to use this SDL
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Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
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Diagnosis
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Genetic diagnosis
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Treatment
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Summary
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Questions
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References
Severe depression and neurotic behaviour patterns predominate
In the adolescent presenting in this way, attention may be limited and a short
temper is usually seen. There may also be an unexplained drop in the level of
intelligence and deterioration in school work.
Due to this children are often diagnosed as having Attention deficit
hyperactivity disorder (ADHD) or, in some cases, as being a ‘problem child’
It is important to diagnose these patients quickly as the damage that is
caused in the brain is largely irreversible
Basal ganglia damage
due to Wilson’s
disease
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Presentation[5]
An overview of the possible presentations of Wilson’s is given below. As can be
seen, these are very diverse and it is important to have a high index of suspicion
when presented with the symptoms below with no obvious cause.
1.
Title page
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How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
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Diagnosis [1]
Copper and caeruloplasmin measurements
The normal range for serum copper is 10-22μmol/L
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Title page
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How to use this SDL
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Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
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Genetic diagnosis
11.
Treatment
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Summary
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Questions
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References
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Wilson’s patients have a characteristically high level of copper
in the liver (>250µg/g dry weight) found on biopsy
Serum caeruloplasmin should be between 200-600mg/L - the
combination of caeruloplasmin below this level and K-F rings in
the eyes is diagnostic of Wilson’s. These results have to be taken
in light of the clinical picture as copper-levels can be near
normal in many Wilson’s patients.
Liver function tests
Depends on type of presentation – if there is an associated
haemolytic anaemia then a rise in AST is seen.
If the liver is cirrhotic, ALP and bilirubin will be increased but
serum albumin will be decreased. If there is progression to liver
failure, pro-thrombin time is also increased).
Diagnosis [2]
Urinary copper
24-hour excretion of copper via the urine is an indicator of the
amount of ‘free’ copper (unbound to caeruloplasmin) in the blood
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Title page
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How to use this SDL
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Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
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Diagnosis
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Genetic diagnosis
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Treatment
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Summary
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Questions
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References
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In affected individuals it is always >0.6µmols/24hrs.
Challenge with Penicillamine
Penicillamine increases the amount of copper excreted via the
urine. Another collection of 24hr urine is collected and analysed
An increase to >25 µmols/24hrs is indicative of Wilson’s disease.
Diagnosis [3]
Slit lamp examination of the eye
Absence of K-F rings does not exclude disease.
1.
Title page
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How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
The K-F rings are nearly always associated with neurological
presentation of the disease but in total are present only 40% of the time
Liver biopsy
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This is a definitive test. A wide section of the liver needs to be
taken for biopsy as accumulation of copper is not always diffuse
in the liver. Liver parenchymal levels of copper greater than
250µg/g dry weight is diagnostic.
Advances in genetic diagnosis [1]
Over 300 mutations exist on chromosome 13, the chromosome
which carries the ATP7B gene, responsible for Wilson’s
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
8.
Presentation of disease
9.
Diagnosis
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Genetic diagnosis
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Treatment
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Summary
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Questions
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References
ATP7B codes for an ATPase transporter protein, which is part of the
trans-golgi network (protein shown below)
The mutations cause a variably defective protein, hence the range of ages
that present with differing symptoms.
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The most common mutation is His1069Gln, which is shown on the above
structure, this mutation seems to affect ATP binding and therefore the
protein cannot carry out it’s function
Advances in genetic diagnosis [2]
When presented with cryptogenic liver disease in the child or isolated
neurological problems in the adult, mutation analysis of the DNA
(specifically chromosome 13 and the ATP7B gene) should be carried out.
1.
Title page
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How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
• Obtain haplotypes based on polymorphisms surrounding the Wilson’s
9.
Diagnosis
gene
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Genetic diagnosis
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Treatment
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Summary
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Questions
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References
Mutation analysis involves the following steps;
• Obtain DNA and run PCR to amplify
• Test exons known to carry the most mutations, with haplotypes (di/tri
single stranded repeats)
• This highlights where the mutations are on the gene
• Then test 1st degree relatives DNA for the same mutations
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• Most common type of mutation is a missense mutation
Treatment [1]
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Title page
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How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
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Treatment
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Summary
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Questions
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References
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Drug
Dose
Side effects
Mechanism
of action
Measure of
efficacy
Penicillamine
500mg bd or
250mg qd
+ 25mg/day
pyridoxine
50% chance of
acute neural toxicity
at commencement
of treatment
Reductive copper
chelator
Have to measure the
free serum
caeruloplasmin level
as measuring urinary
copper is misleading
Trientine
1.2 - 2.4g/day in 2-4
divided doses before
food
Proteinuria;
20% chance of
neural toxicity at
commencement of
Rx
Reductive copper
chelator (less
potent then
penicillamine)
Have to measure the
free serum
caeruloplasmin level
as measuring urinary
copper is misleading
Zinc
200mg tds
Gastritis
Induction of
intestinal
metallothionein
Measure urinary
copper excretion
Treatment [2]
Diet: For obvious reasons a low copper diet is needed- no vitamin
supplements containing copper should be taken and analysis of the
drinking water in the home is needed. The level of copper in the water
should not exceed 0.1ppm.
1.
Title page
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How to use this SDL
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Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
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Treatment
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Summary
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Questions
14.
References
Avoid mushrooms, nuts, shell fish and dried fruit especially
Pregnancy: Should stay on anti-copper therapy for the protection of
the mothers health, however penicillamine is known to be teratogenic,
therefore the patient should be put on trientine or zinc. Therapy should
be monitored and the lowest effective dose used as copper deficiency is
also teratogenic.
Prophylactic treatment of the asymptomatic patient:
Asymptomatic patients are usually siblings of an affected patient that
have been diagnosed using mutation analysis. These patients should be
treated as if they are on maintenance therapy, usually with zinc.
Fulminant liver failure
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The only successful treatment when the patient presents with this
condition is liver transplant
Advances in treatment
Tetrathiomolybdate – A novel drug currently undergoing phase
III trials and not yet commercially available. To be used on the
neurologically presenting patient
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
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Epidemiology
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Genetics
8.
Presentation of disease
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Diagnosis
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Genetic diagnosis
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Treatment
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Summary
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Dose: 20mg tds + 60mg at bedtime (away from food)
Acts by forming a tri-partite complex between itself, copper and
protein
If taken away from food it enters the bloodstream and binds with
copper and albumin – rapidly reducing the toxicity of the high
levels of copper
Take with a chelating agent (e.g. Trientine) to increase the amount
of free copper to form a tri-partite complex with
If on Tetrathiomolybdate, only 5% of patients experience
neurological worsening compared to 20% and 50% of patients on
Trientine and Penicillamine, respectively
Test efficacy by carrying out neurological tests once a week (as this
drug is used for the neurologically presenting patient
Test for toxicity – FBC and LFT’s once every 2 weeks – any
toxicity (anaemia, leukopaenia) is responsive to lowering the dose
Summary
• Wilson’s disease is a rare autosomal recessive condition
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Title page
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How to use this SDL
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Learning outcomes
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Definition
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Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
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Genetic diagnosis
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Treatment
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Summary
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Questions
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References
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• It’s effects are due to the inability to excrete copper in the bile
• Over 300 mutations on the Wilson’s gene are known
• The young patient usually presents hepatically
• The older patient usually presents neurologically
• Due to the amount of mutations that diagnosis by mutation
analysis is difficult but techniques are improving
• Treatment is improving with phase III trials continuing
• If presented with cryptogenic liver disease or unexplained
neurological deficit always consider Wilson’s disease
Questions
1.
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
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2.
What is autosomal recessive inheritance?
a)
Inheritance which is sex linked and needs 1 copy of
the mutated gene to show symptoms
b)
Inheritance which is not sex linked and needs 1
copy of the mutated gene to show symptoms
c)
Inheritance which is not sex linked and needs 2
copies of the mutated gene to show symptoms
What is a missense mutation?
a)
A point mutation in a sequence of DNA that results
in a premature stop codon
b)
types of point mutations where a nucleotide is
changed which results in a different amino acid.
c)
a genetic mutation that inserts or deletes a number
of nucleotides that is not evenly divisible by three
from a DNA sequence
Questions cont.
3.
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
4.
What is the function of the ATP7B gene product?
a)
It is caeruloplasmin, a copper containing
apoprotein, which binds copper to make it non-toxic
b)
It is a transporter protein, part of the trans Golgi
network, transporting copper out of the hepatocytes
into bile
c)
It is a G-protein linked second messenger cascade,
causing copper to be taken up by the liver
Why is penicillamine no longer the 1st choice of drug in the treatment of
Wilson’s
a)
It carries a high risk of neurological damage at the
onset of treatment
b)
The doses needed for it to be effective are
unpalatable to the patient
c)
To measure efficacy is too difficult
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Questions cont.
5.
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
6.
What tests should be carried out on a 12 year old that has shown
deterioration in school work and has raised aminotranferases?
a)
Slit lamp examination of the eye
b)
24 hour urine collection
c)
Liver biopsy
d)
All of the above
What are the dangers of therapy for a Wilson’s patient who is
pregnant?
a)
Copper levels that are too high are dangerous to
the mother and levels that are too low are known
to be teratogenic
b)
The drugs used in the maintenance of a Wilson’s
patient are known to be teratogenic
c)
Side effects of treatment in the mother include
syncope and fitting putting both the mother and
the unborn child at risk
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References
• Bingham M. Ong T-J. Physiologic function of the Wilson disease gene
product, ATP7B. AM J Clin Nutr. 1998;67:982-7
• Brewer G. Askari F. Wilson’s disease: clinical management and therapy.
Journal of hepatology. 2005;42:13-21
1.
Title page
2.
How to use this SDL
3.
Learning outcomes
4.
Definition
5.
Aetiology
6.
Epidemiology
7.
Genetics
8.
Presentation of disease
9.
Diagnosis
10.
Genetic diagnosis
11.
Treatment
12.
Summary
13.
Questions
14.
References
• Caprai S. Loudianos G. et al. Direct diagnosis of Wilson’s disease by
molecular genetics. J paediar. 2006;148:138-40
• Hoogenraad T. Paradigm shift in treatment of Wilson’s disease: Zinc
therapy now the treatment of choice. Brain and development. 2006;28:141-46
• Lin J. J. Lin K-L. Isolated psychological presentation without hepatic
involvement. Paediatr neurol. 2006;35:284-6
• Roberts E. A. Wilson’s disease. Medicine. 2006;11:1-3
• Roberts E. A. Schilsky M. L. A practice guideline on Wilson’s disease.
Hepatology. 2003;37:1475-92
• Wilson S. A. K. Progressive lenticular degeneration: A familial nervous
disease associated with cirrhosis of the liver. Brain. 1912;34:295-509
Some useful websites
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• www.wilsonsdisease.org/
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• www.wilsons-disease.org.uk/