WILSON’S DISEASE Ben Winrow
How to use this SDL This SDL is designed to be informative and interactive Every time you see words that are  underlined  ...
Learning objectives <ul><li>To understand what Wilson’s disease is </li></ul><ul><li>To be aware of its prevalence </li></...
An inborn error of copper metabolism – characterised by an increase in copper accumulation in tissues of the liver (1), br...
<ul><li>The cause of Wilson’s has only recently been deduced but the exact mechanism is always changing. The ATP7B gene pr...
Epidemiology The prevalence of Wilson’s in Northern European Caucasian population is 1/30,000 Even though this makes the d...
Genetics Chromosome 13 carries the gene which causes Wilson’s There are around 300 known mutations the most common being H...
Presentation [1] Hepatic presentation The presentation of hepatic disease due to Wilson’s is diverse.  Most patients that ...
Hepatic presentation Fulminant hepatic failure is the ultimate progression, giving rise to characteristic features– renal ...
Neurological presentation The patient that presents with neurological pathologies tends to be older (>35 years) and sympto...
Neurological presentation Presentation[4] 20% of patients present with a psychiatric disorder, usually in adolescence, and...
Presentation[5] An overview of the possible presentations of Wilson’s is given below.  As can be seen, these are very dive...
Diagnosis [1] <ul><li>Copper and caeruloplasmin measurements </li></ul><ul><ul><ul><li>The normal range for serum   copper...
Diagnosis [2] Urinary copper 24-hour excretion of copper via the urine is an indicator of the amount of ‘free’ copper (unb...
<ul><li>Slit lamp examination of the eye </li></ul><ul><li>Absence of K-F rings does not exclude disease. </li></ul><ul><l...
Advances in genetic diagnosis [1] Over 300 mutations exist on chromosome 13, the chromosome which carries the ATP7B gene, ...
Advances in genetic diagnosis [2] When presented with cryptogenic liver disease in the child or isolated neurological prob...
Treatment [1] Measure urinary copper excretion Induction of intestinal metallothionein Gastritis 200mg tds Zinc Have to me...
Treatment [2] Diet:  For obvious reasons a low copper diet is needed- no vitamin supplements containing copper should be t...
Advances in treatment Tetrathiomolybdate  –  A novel drug currently undergoing phase III trials and not yet commercially a...
Summary <ul><li>Wilson’s disease is a rare autosomal recessive condition </li></ul><ul><li>It’s effects are due to the ina...
Questions <ul><li>What is autosomal recessive inheritance? </li></ul><ul><ul><ul><ul><ul><li>Inheritance which is sex link...
Questions cont. <ul><li>What is the function of the ATP7B gene product? </li></ul><ul><ul><ul><ul><ul><li>It is caerulopla...
Questions cont. <ul><li>What tests should be carried out on a 12 year old that has shown deterioration in school work and ...
References <ul><li>Bingham M. Ong T-J. Physiologic function of the Wilson disease gene product, ATP7B.  AM J Clin Nutr.  1...
Autosomal recessive inheritance:  Inheritance which is not sex linked i.e. the mutation is carried on any chromosome other...
Homozygous:  describing an individual in whom the member of a pair of genes determining a particular characteristic are id...
Missense:  types of point mutations where a nucleotide is changed which results in a different amino acid. This can render...
Dystonia:  muscle dysfunction characterised by spasms or abnormal muscle contraction. Often associated with basal ganglia ...
Caeruloplasmin:  A copper containing protein present in blood plasma and hepatic tissue. In Wilson’s disease it is in an  ...
WRONG:  This is X-linked recessive inheritance, due to the overlap of the X chromosome over the Y chromosome (in males) th...
Haplotype:  a complete set of HLA antigens (inherited from either parent), for the sake of mutation analysis however they ...
WRONG:  This is autosomal dominant inheritance, where only 1 copy of the mutated gene is needed to show symptoms as the al...
CORRECT:  Autosomal recessive inheritance is where 2 mutations of the same gene are needed to show symptoms, it is not sex...
WRONG:  This is a nonsense mutation, the premature stop codon usually results in a non-functional protein product Back to ...
CORRECT:  This is a missense mutation and is the most common mutation seen in Wilson’s disease. It results in a reduced or...
WRONG:  This is a frameshift mutation. This alters the reading frame and causes a completely different protein product aft...
WRONG:  This is an apoprotein (apocaeruloplasmin) and when it binds to copper it becomes caeruloplasmin and makes copper n...
CORRECT:  It is a transporter and transports copper out of the liver. It is the dysfunction of this protein that causes th...
WRONG:  A G-protein linked second messenger cascade can be associated with production of ATP and interaction with many dif...
CORRECT:  Some papers have shown that neurological damage can be seen in as many as 50% of patients 15% of which don’t eve...
WRONG:  There is no evidence that the doses are unpalatable. The doses are given in slide 7. Back to presentation
WRONG:  Efficacy measurement are more difficult to do when using penicillamine but are possible, the equation is seen belo...
Steatosis:  The infiltration of hepatocytes with fat. This can occur in pregnancy, alcoholism, obesity, hepatitis C infect...
Kayser-Fleischer (K-F) rings:  A brownish-yellow ring in the outer rim of the cornea of the eye. It is caused by the depos...
Pro-thrombin time (PTT):  The time taken for blood clotting to occur in a sample of blood to which calcium and thromboplas...
Teratogenic:  The adjective of teratogen, any substance, agent or process that induces the formation of developmental abno...
Maintenance therapy:  Used in patients that are asymptomatic but have a mutation on the Wilson’s gene, or for patients tha...
Tri-partite complex:  A complex that has three (tri) parts (partite) Tetrathiomolybdate Copper Protein Back to presentation
Leukopaenia:  A reduction in the number of white blood cells (leucocytes) in the blood Back to presentation
WRONG:  Although this is an important examination it cannot be done in isolation as at presentation only 40% of patients w...
WRONG:  Although this is a very sensitive test, copper levels may be normal or near normal and therefore it cannot be done...
WRONG:  This is a very important test but the accumulation of copper is not always diffuse through the liver and therefore...
CORRECT:  All of these tests should be carried out, along with liver function tests. The diagnosis of Wilson’s disease can...
CORRECT:  Stopping treatment is dangerous to the mother as this will cause copper to accumulate in her tissues causing the...
WRONG:  Only penicillamine is known to be teratogenic and as most patients are diagnosed by a child-bearing age, they shou...
WRONG:  There is no evidence that this is the case. Side effects of treatment are given on slide 18 Back to presentation
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  1. 1. WILSON’S DISEASE Ben Winrow
  2. 2. How to use this SDL This SDL is designed to be informative and interactive 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
  3. 3. Learning objectives <ul><li>To understand what Wilson’s disease is </li></ul><ul><li>To be aware of its prevalence </li></ul><ul><li>To understand the genetic factors leading to Wilson’s disease </li></ul><ul><li>To understand the molecular processes that lead to the symptoms of Wilson’s disease </li></ul><ul><li>To have an appreciation of the presentation of Wilson’s in the young patient and in the older patient </li></ul><ul><li>To have an awareness of the ways in which Wilson’s disease is diagnosed </li></ul><ul><li>To understand the role of genetic analysis in the diagnosis of first degree relatives of a Wilson’s patient </li></ul><ul><li>To be aware of current treatment of Wilson’s disease </li></ul><ul><li>To understand the shift in treatment options </li></ul><ul><li>To know the recent advances in treatment </li></ul>
  4. 4. 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 . Definition 1 2 3 5 6 4
  5. 5. <ul><li>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. </li></ul><ul><li>The ATP7B gene itself is around 80kb long and has 21 introns. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>The lack of transportation of copper into the bile leads to accumulation of copper in the hepatocytes </li></ul><ul><li>When hepatocyte storage capacity is reached, free copper is slowly released into the blood stream causing an accumulation of copper in extra-hepatic tissue. </li></ul><ul><li>Rarely, a massive release of copper can lead to haemolysis and fulminant hepatic failure </li></ul><ul><li>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. </li></ul>Aetiology
  6. 6. Epidemiology The prevalence of Wilson’s in Northern European Caucasian population is 1/30,000 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 Sicily China Northern India South Korea
  7. 7. Genetics Chromosome 13 carries the gene which causes Wilson’s There are around 300 known mutations the most common being His1069Gln The pattern of inheritance is Autosomal recessive With 2 carrying parents the child has a ¼ chance of having the disease Patients are usually homozygous or compound heterozygous , this can make it difficult to obtain a diagnosis by mutation analysis Mutations are either nonsense, missense or frameshift , the most common mutation found on the gene being missense. The site of the mutation determines the severity of the disease
  8. 8. Presentation [1] Hepatic presentation The presentation of hepatic disease due to Wilson’s is diverse. 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 A majority of patients however present with chronic liver disease having been undiagnosed and therefore have small, scarred livers, ascites and splenomegaly.
  9. 9. Hepatic presentation 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 Presentation [2]
  10. 10. Neurological presentation The patient that presents with neurological pathologies tends to be older (>35 years) and symptoms can often mimic other disorders 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: Presentation [3] Dystonia Dysarthria Dysphagia
  11. 11. Neurological presentation Presentation[4] 20% of patients present with a psychiatric disorder, usually in adolescence, and this can be misdiagnosed as many other mood or affective disorders. 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
  12. 12. 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.
  13. 13. Diagnosis [1] <ul><li>Copper and caeruloplasmin measurements </li></ul><ul><ul><ul><li>The normal range for serum copper is 10-22μmol/L </li></ul></ul></ul><ul><ul><ul><li>Wilson’s patients have a characteristically high level of copper in the liver (>250 µg/g dry weight) found on biopsy </li></ul></ul></ul><ul><ul><ul><li>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. </li></ul></ul></ul><ul><ul><ul><li>Liver function tests </li></ul></ul></ul><ul><ul><ul><li>Depends on type of presentation – if there is an associated haemolytic anaemia then a rise in AST is seen. </li></ul></ul></ul><ul><ul><ul><li>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). </li></ul></ul></ul><ul><ul><ul><li>  </li></ul></ul></ul><ul><ul><ul><li>        </li></ul></ul></ul>
  14. 14. 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 In affected individuals it is always >0.6 µmols/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.
  15. 15. <ul><li>Slit lamp examination of the eye </li></ul><ul><li>Absence of K-F rings does not exclude disease. </li></ul><ul><li>The K-F rings are nearly always associated with neurological presentation of the disease but in total are present only 40% of the time </li></ul>Diagnosis [3] Liver biopsy 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 250 µg/g dry weight is diagnostic.
  16. 16. Advances in genetic diagnosis [1] Over 300 mutations exist on chromosome 13, the chromosome which carries the ATP7B gene, responsible for Wilson’s 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. 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
  17. 17. 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. Mutation analysis involves the following steps; <ul><li>Obtain haplotypes based on polymorphisms surrounding the Wilson’s gene </li></ul><ul><li>Obtain DNA and run PCR to amplify </li></ul><ul><li>Test exons known to carry the most mutations, with haplotypes (di/tri single stranded repeats) </li></ul><ul><li>This highlights where the mutations are on the gene </li></ul><ul><li>Then test 1 st degree relatives DNA for the same mutations </li></ul><ul><li>Most common type of mutation is a missense mutation </li></ul>
  18. 18. Treatment [1] Measure urinary copper excretion Induction of intestinal metallothionein Gastritis 200mg tds Zinc Have to measure the free serum caeruloplasmin level as measuring urinary copper is misleading Reductive copper chelator (less potent then penicillamine) Proteinuria; 20% chance of neural toxicity at commencement of Rx 1.2 - 2.4g/day in 2-4 divided doses before food Trientine Have to measure the free serum caeruloplasmin level as measuring urinary copper is misleading Reductive copper chelator 50% chance of acute neural toxicity at commencement of treatment 500mg bd or 250mg qd + 25mg/day pyridoxine Penicillamine Measure of efficacy Mechanism of action Side effects Dose Drug
  19. 19. 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. 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 The only successful treatment when the patient presents with this condition is liver transplant
  20. 20. 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 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
  21. 21. Summary <ul><li>Wilson’s disease is a rare autosomal recessive condition </li></ul><ul><li>It’s effects are due to the inability to excrete copper in the bile </li></ul><ul><li>Over 300 mutations on the Wilson’s gene are known </li></ul><ul><li>The young patient usually presents hepatically </li></ul><ul><li>The older patient usually presents neurologically </li></ul><ul><li>Due to the amount of mutations that diagnosis by mutation analysis is difficult but techniques are improving </li></ul><ul><li>Treatment is improving with phase III trials continuing </li></ul><ul><li>If presented with cryptogenic liver disease or unexplained neurological deficit always consider Wilson’s disease </li></ul>
  22. 22. Questions <ul><li>What is autosomal recessive inheritance? </li></ul><ul><ul><ul><ul><ul><li>Inheritance which is sex linked and needs 1 copy of the mutated gene to show symptoms </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Inheritance which is not sex linked and needs 1 copy of the mutated gene to show symptoms </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Inheritance which is not sex linked and needs 2 copies of the mutated gene to show symptoms </li></ul></ul></ul></ul></ul><ul><li>2. What is a missense mutation? </li></ul><ul><ul><ul><ul><ul><li>A point mutation in a sequence of DNA that results in a premature stop codon </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>types of point mutations where a nucleotide is changed which results in a different amino acid. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>a genetic mutation that inserts or deletes a number of nucleotides that is not evenly divisible by three from a DNA sequence </li></ul></ul></ul></ul></ul>
  23. 23. Questions cont. <ul><li>What is the function of the ATP7B gene product? </li></ul><ul><ul><ul><ul><ul><li>It is caeruloplasmin, a copper containing apoprotein, which binds copper to make it non-toxic </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>It is a transporter protein, part of the trans Golgi network, transporting copper out of the hepatocytes into bile </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>It is a G-protein linked second messenger cascade, causing copper to be taken up by the liver </li></ul></ul></ul></ul></ul><ul><li>Why is penicillamine no longer the 1 st choice of drug in the treatment of Wilson’s </li></ul><ul><ul><ul><ul><ul><li>It carries a high risk of neurological damage at the onset of treatment </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>The doses needed for it to be effective are unpalatable to the patient </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>To measure efficacy is too difficult </li></ul></ul></ul></ul></ul>
  24. 24. Questions cont. <ul><li>What tests should be carried out on a 12 year old that has shown deterioration in school work and has raised aminotranferases? </li></ul><ul><ul><ul><ul><ul><li>Slit lamp examination of the eye </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>24 hour urine collection </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Liver biopsy </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>All of the above </li></ul></ul></ul></ul></ul><ul><li>What are the dangers of therapy for a Wilson’s patient who is pregnant? </li></ul><ul><ul><ul><ul><ul><li>Copper levels that are too high are dangerous to the mother and levels that are too low are known to be teratogenic </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>The drugs used in the maintenance of a Wilson’s patient are known to be teratogenic </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Side effects of treatment in the mother include syncope and fitting putting both the mother and the unborn child at risk </li></ul></ul></ul></ul></ul>
  25. 25. References <ul><li>Bingham M. Ong T-J. Physiologic function of the Wilson disease gene product, ATP7B. AM J Clin Nutr. 1998;67:982-7 </li></ul><ul><li>Brewer G. Askari F. Wilson’s disease: clinical management and therapy. Journal of hepatology . 2005;42:13-21 </li></ul><ul><li>Caprai S. Loudianos G. et al. Direct diagnosis of Wilson’s disease by molecular genetics. J paediar. 2006;148:138-40 </li></ul><ul><li>Hoogenraad T. Paradigm shift in treatment of Wilson’s disease: Zinc therapy now the treatment of choice. Brain and development. 2006;28:141-46 </li></ul><ul><li>Lin J. J. Lin K-L. Isolated psychological presentation without hepatic involvement. Paediatr neurol. 2006;35:284-6 </li></ul><ul><li>Roberts E. A. Wilson’s disease. Medicine. 2006;11:1-3 </li></ul><ul><li>Roberts E. A. Schilsky M. L. A practice guideline on Wilson’s disease. Hepatology . 2003;37:1475-92 </li></ul><ul><li>Wilson S. A. K. Progressive lenticular degeneration: A familial nervous disease associated with cirrhosis of the liver. Brain. 1912;34:295-509 </li></ul><ul><li>Some useful websites </li></ul><ul><li>www.wilsonsdisease.org/ </li></ul><ul><li>www.wilsons-disease.org.uk/ </li></ul>
  26. 26. Autosomal recessive inheritance: Inheritance which is not sex linked i.e. the mutation is carried on any chromosome other then the sex chromosomes. The effect is only seen when both alleles are the same (both mutated) Back to presentation
  27. 27. Homozygous: describing an individual in whom the member of a pair of genes determining a particular characteristic are identical Compound heterozygous: describing an individual in whom the members of a pair of genes determining a particular characteristic are dissimilar i.e. there is more then one mutation affecting the genes but there is still the presence of the disease (this make mutation analysis very difficult) Back to presentation
  28. 28. Missense: types of point mutations where a nucleotide is changed which results in a different amino acid. This can render the resulting protein non-functional Nonsense: a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated and non-functional protein product Frameshift: a genetic mutation that inserts or deletes a number of nucleotides that is not evenly divisible by three from a DNA sequence, this disrupts the reading frame and results in a completely different translation from the original, producing a non-functional protein product Back to presentation
  29. 29. Dystonia: muscle dysfunction characterised by spasms or abnormal muscle contraction. Often associated with basal ganglia damage Dysarthria: a speech disorder in which the pronunciation is unclear although the language content and meaning are normal Dysphagia: a condition in which the action of swallowing is either difficult to perform, painful. In Wilson’s disease it is caused by neurological co-ordination abnormalities Back to presentation
  30. 30. Caeruloplasmin: A copper containing protein present in blood plasma and hepatic tissue. In Wilson’s disease it is in an apo- form due to the fact that copper has not bound to it (copper stimulates its formation) When copper does bind it forms a non-toxic complex When unbound, as in Wilson’s, the copper becomes toxic Back to presentation
  31. 31. WRONG: This is X-linked recessive inheritance, due to the overlap of the X chromosome over the Y chromosome (in males) the diseases caused by this form of inheritance usually present in men as only 1 copy of the faulty gene is needed to show symptoms of the disease. An example would be haemophilia. Back to presentation
  32. 32. Haplotype: a complete set of HLA antigens (inherited from either parent), for the sake of mutation analysis however they are di/tri single stranded repeats – used to ‘fish’ for mutations. Back to presentation
  33. 33. WRONG: This is autosomal dominant inheritance, where only 1 copy of the mutated gene is needed to show symptoms as the allele is dominant Back to presentation
  34. 34. CORRECT: Autosomal recessive inheritance is where 2 mutations of the same gene are needed to show symptoms, it is not sex-linked and with parents that both carry the mutation each child has a ¼ chance of getting the disease Back to presentation
  35. 35. WRONG: This is a nonsense mutation, the premature stop codon usually results in a non-functional protein product Back to presentation
  36. 36. CORRECT: This is a missense mutation and is the most common mutation seen in Wilson’s disease. It results in a reduced or non-functional protein product Back to presentation
  37. 37. WRONG: This is a frameshift mutation. This alters the reading frame and causes a completely different protein product after the mutation Back to presentation
  38. 38. WRONG: This is an apoprotein (apocaeruloplasmin) and when it binds to copper it becomes caeruloplasmin and makes copper non-toxic to the body HOWEVER it is not the product of the ATP7B gene Back to presentation
  39. 39. CORRECT: It is a transporter and transports copper out of the liver. It is the dysfunction of this protein that causes the build up of copper and the symptoms of Wilson’s Back to presentation
  40. 40. WRONG: A G-protein linked second messenger cascade can be associated with production of ATP and interaction with many different drugs e.g. canabinoid receptors Back to presentation
  41. 41. CORRECT: Some papers have shown that neurological damage can be seen in as many as 50% of patients 15% of which don’t ever recover to baseline neurological activity before the onset of treatment. This is due to the mobilisation of copper from its stores in the body and as it can cross the blood brain barrier, it causes severe deterioration. Back to presentation
  42. 42. WRONG: There is no evidence that the doses are unpalatable. The doses are given in slide 7. Back to presentation
  43. 43. WRONG: Efficacy measurement are more difficult to do when using penicillamine but are possible, the equation is seen below: Non-Cp-Cu (umol/l) = total serum Cu (umol/l) – 0.047 x serum Cp (mg/l) Back to presentation
  44. 44. Steatosis: The infiltration of hepatocytes with fat. This can occur in pregnancy, alcoholism, obesity, hepatitis C infection, some drugs and with Wilson’s disease. A liver showing steatosis (black arrow pointing to fat deposit) Back to presentation
  45. 45. Kayser-Fleischer (K-F) rings: A brownish-yellow ring in the outer rim of the cornea of the eye. It is caused by the deposition of copper granules in decemets membrane. When well developed they can be seen unaided but faint K-F rings need specialist ophthalmological examination (Slit-lamp examination) Back to presentation K-F ring
  46. 46. Pro-thrombin time (PTT): The time taken for blood clotting to occur in a sample of blood to which calcium and thromboplastin have been added. A prolonged PTT indicates a deficiency of coagulation factors, which are required to convert pro-thrombin to thrombin in the final stages of the coagulation cascade. Back to presentation
  47. 47. Teratogenic: The adjective of teratogen, any substance, agent or process that induces the formation of developmental abnormalities in a foetus. Back to presentation
  48. 48. Maintenance therapy: Used in patients that are asymptomatic but have a mutation on the Wilson’s gene, or for patients that have undergone initial therapy and are maintaining their copper levels. Zinc 200mg/tds is used. Back to presentation
  49. 49. Tri-partite complex: A complex that has three (tri) parts (partite) Tetrathiomolybdate Copper Protein Back to presentation
  50. 50. Leukopaenia: A reduction in the number of white blood cells (leucocytes) in the blood Back to presentation
  51. 51. WRONG: Although this is an important examination it cannot be done in isolation as at presentation only 40% of patients will have Kayser-Fleischer rings, the majority of these will be neurologically presenting. Back to presentation
  52. 52. WRONG: Although this is a very sensitive test, copper levels may be normal or near normal and therefore it cannot be done in isolation. The appropriate levels are given in slide 14. Back to presentation
  53. 53. WRONG: This is a very important test but the accumulation of copper is not always diffuse through the liver and therefore may be missed. The appropriate levels of copper (dry weight) are given in slide 15. Back to presentation
  54. 54. CORRECT: All of these tests should be carried out, along with liver function tests. The diagnosis of Wilson’s disease can sometimes be difficult to come to when presented with neurological deterioration with no obvious cause and therefore a high index of suspicion is needed. These tests, when done in conjunction with each other should give the diagnosis of Wilson’s disease. Back to presentation
  55. 55. CORRECT: Stopping treatment is dangerous to the mother as this will cause copper to accumulate in her tissues causing the complications of Wilson’s disease. It is also noted that levels of copper that are too low are teratogenic to the unborn child therefore treatment cannot be too vigorous. Zinc or Trientine is used as maintenance therapy. Back to presentation
  56. 56. WRONG: Only penicillamine is known to be teratogenic and as most patients are diagnosed by a child-bearing age, they should already be on maintenance therapy. In addition to this there has been a shift away from using penicillamine as treatment due to its neurotoxic effects. Back to presentation
  57. 57. WRONG: There is no evidence that this is the case. Side effects of treatment are given on slide 18 Back to presentation
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