- 1Department of Neurology, University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
2Department of Gastroenterology, University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Background: Wilson's disease (WD) is an autosomal-recessive disorder of copper deposition caused by pathogenic variants in the copper-transporting ATP7B gene. There is not a clear correlation between genotype and phenotype in WD regarding symptom manifestations. This is supported by the presentation of genetically identical WD twins with phenotypic discordance and different response behavior to WD-specific therapy.
Case presentation: One of the female homozygous twins (age: 26 yrs) developed writing, speaking, swallowing and walking deficits which led to in-patient examination without conclusive results but recommended genetic testing. Both sisters were tested and were heterozygous for the C.2304dupC;p(Met769Hisf*26) and the C.3207C>A;p(His1069Gln) mutation. Self-medication of the affected sibling with 450 mg D-penicillamine (DPA) did not prevent further deterioration. She developed a juvenile parkinsonian syndrome and became wheelchair-bound and anarthric. A percutaneous endoscopic gastrostomy was applied. Her asymptomatic sister helped her with her daily life. Despite the immediate increase of the DPA dose (up to 1800 mg within 3 weeks) in the severely affected patient and the initiation of DPA therapy (up to 600 mg within 2 weeks) in the asymptomatic patient after the first visit in our institution, liver function tests further deteriorated in both patients. After 2 months, the parkinsonian patient started to improve and walk again, but experienced several falls, broke her right shoulder and underwent two necessary surgical interventions. With further consequent copper elimination therapy, liver dysfunction improved in both patients, without need for orthotopic liver transplantation (LTX) in the severely affected patient. Her excellent recovery of liver and brain dysfunction was only transiently interrupted by the development of a nephrotic syndrome which disappeared after switching to Cuprior®. Unfortunately, she died from fulminant pneumonia.
Conclusion: Despite identical genetic disposition, WD symptom presentations may develop differently in monozygotic twins, and they may need to be placed on a very different therapeutical regimen. The underlying gene-environment interaction is unclear so far.