A. Epidemiology

1. Rare Autosomal Recessive Disease
2. Disease affects 1 in ~30 thousand
3. Heterozygote carriers 1:90
4. Most patients present ages 10-30

B. Pathogenesis

1. WD is caused by mutations in ATP7B gene on chromosome 13q14.3
   1. More than 190 distinct mutations have been discovered
   2. However, about 60% have most common His1069Gln
   3. No clear relationship between specific mutations and clinical phenotype
2. Copper accumulates in WD
   1. Result is Hepatolenticular (Liver/Brain) Degeneration
   2. Patients may present with either or both organ systems involved
3. ATP7B is involved in copper excretion
   1. This is a 159K ATP-dependent P-type copper-transporting ATPase
   2. Related to P-glycoprotein transporter MDR1
   3. Localized to the trans-golgi network; may also be targetted to mitochondria
   4. Copper is bound to serum protein ceruloplasmin, and complex is excreted
   5. ATP7B is involved in transport of the copper-ceruloplasmin complex
4. Oxidative Phosphorylation in WD
   1. Oxidative phosphorylation (mitochondrial) defects are also found in WD [2]
   2. Thus, ATP7B may also be involved in copper transport in mitochondria
   3. Cytochrome Oxidase (Complex IV) is a copper-containing enzyme
   4. Copper and substitute for iron in redux reactions with generation of free radicals

C. Symptoms / Signs [3]

1. Hepatic (increased ALT) 42%
   1. Usually in patients who present in teens;
   2. May progress from chronic hepatitis to cirrhosis
2. Neurological 34%
   1. Usually in patients who present at age >20 years
   2. Severe motor dysfunction with extrapyramidal signs
   3. Severe dementia may ensue
3. Corneal deposits in nearly all patients: "Kayser-Fleischer Rings" [4]
4. Psychiatric 10%
5. Hematologic / Endocrine 12%
6. Renal 1%
7. Fatal disease usually due to liver failure unless treated [3]

D. Neurological Symptoms [1]

1. Extrapyramidal involuntary movements
2. Dysarthria, Dysphagia, Drooling
3. Rigidity, Dystonia, Chorea
4. Gait disorder - balance and coordination
5. "Rhesus Sardonicus" - vacuous smile
6. Eyes: Kayser-Fleischer Rings
   1. Brown ring (discoloration) of copper deposition in Cornea
   2. Occurs in Decemet's Membrane of the cornea
   3. These K-F rings are pathomnemonic for Wilson's Disease
   4. The rings may occassionally be seen with naked eye, but usually require special exam
7. Some resolution of these symptoms with treatment

H. Psychiatric Symptoms

1. Personality and Behavioral Changes
2. Depression, Mania
3. Dementia, Paranoid Delusions

I. Other Characteristics

1. Hepatic Changes: hepatitis, cirrhosis
2. Hematologic Changes: Hemolytic anemia (low MCV), hypersplenism
3. Renal: Renal Tubular Acidosis (RTA), renal stones
4. Skeletal: Rickets, blue nails

J. Diagnosis

1. Serum Testing
   1. Hepatitis - mild with mild alkaline phosphatase and bilirubin elevations
   2. Low or low normal ceruloplasmin level
   3. Highly elevated copper level
2. Presence of Kayser-Fleischer Rings on slit lamp exam
3. Gene Analysis [5]
   1. Polymerase Chain Reaction (PCR) based detection
   2. More than 50 different mutations have been detected
   3. Most common mutation is His1069Gln, and PCR method has been developed [5]
   4. Now possible to screen all relatives of affected individuals
   5. Also may use genetic test to confirm diagnosis
4. Elevated urinary copper excretion (not required for diagnosis)

K. Treatment

1. Chelation of copper allows it to be excreted
   1. Penicillamine is treatment of choice (will increase urinary copper excretion)
   2. Trientene® may also be used for chelation
   3. Zinc salts are also beneficial
2. Advanced disease may require liver transplantation (may be lifesaving)

References

1. Ala A, Walker AP, Ashkan K, et al. 2007. Lancet. 369(9559):397
2. Gu M, Cooper JM, Butler P, Walker AP, et al. 2000. Lancet. 356(9228):469
3. Zucker SD and Flieder A. 1997. NEJM. 336(2):118 (Case Report)
4. Miller NR and Newman NJ. 2004. Lancet. 364(9450):2045
5. Maier-Dobersberger T, Ferenci P, Polli C, et al. 1997. Ann Intern Med. 127(1):21