The Exploitation Of The Gene Mutation And Clinical Characteristics Of A Family With Fulminant Wilson's Disease

Hepatolenticular Degeneration (Wilson's Disease) is an autosomalrecessive disease. The genetic defect causes disorder of coppermetabolism,then excessive copper accumulated in the body and coulddamage the organs. Despite the extreme rarity in everyday clinicalpractice, WD is important because it is fatal if not recognized andtreated.The copper deposits in the liver, brain, kidneys, and the eyes. Thedeposits of copper cause tissue damage, death of the tissues, andscarring, which causes the affected organs to stop functioning properly.Since the clinical manifestations of WD is varied dramatically, falsediscovery rate of initial diagnosis was highly about 50%～90%.Thecondition may mainly manifest as acute hepatitis firstly. Fulminantwilson's disease is a rare and severe type of WD, which is extremelypoorly prognostic. Moreover, FWD mortality rate is almost 100 percentif not undertaken liver transplantation. Therefore, FWD often poses agreat diagnostic and therapeutic challenge. However, up to date, there isno any foreign or domestic report that WD's patient could betreated successfully by internal medical methods, and there is no studyeither about pathological examination of the liver specimen in WDpatients or long-term follow up of patients. Somehow, there is only one study about WD gene mutation.Objective1 Systematically observe and sum up the clinical characteristics,Abnormalities of copper metabolism, pathological changes andTreatment plus Clinical Outcome of a FWD patient, in order to rendersome scientific and powerful evidence for the diagonosis and treatmentof FWD2 Systematically analysing gene mutation of this FWD patient andhis direct relatives, find mutation, make clear the law of geneticmutation and, its molecular mechanisms of pathogenesis, explored thecorrelation between mutation type and clinical manifestationsMethods:1 Combined with penicillamine, plasma placement and corticoid,to save the life of this patient. Laboratory tests used to monitor patientsinclude blood and urine routine, liver function tests, serumceruloplasmin levels, and serum copper levels at due timePathological Examining of liver biopsy specimens when the conditionallowed. Follow up one year2 Using PCR and sequencing methods, detecting all exons,jointregions of exons and introns, partial introns of WD genome of thispatient and his direct relatives, if not found any mutation,continuedetecting 5'-residue modulating sequence. Main steps as following: using self-designed primers, all exons and promoter were amplifiedseparately by PCR. Following PCR products retrieved and purified thendirectly sequenced and analysized.Results1 Given combined internal medical methods, the patientrecoveried. Having followed up one year, the condition of patient keptstable, liver function tests was in a normal range. This suggested thatthe combined treatment is effective to some of WD patient, probablywith a relatively good long-term prognosis, which posing a vital role indetermining strategy of treating WD.2 The hepatic histologic pattern after 4 months progressed into oneof a macronodular or mixed micro-macronodular cirrhosis, with fibroussepta (containing predominantly typesⅠandⅢcollagen), bile ductuleproliferation, and variable septal round cell infiltration. Hepatocytes atthe periphery of the nodules frequently contain Mallory hyalin. In fact,FWD is pathological characterized by expensive hepatic injuries on thelong-termed cirrhosis3 Cer level is higher in acute period than in recovery period,indicating that we cannot exclude the WD only because of Cer in thenormal range. That Urine copper rise up dramatically play a verysignificant role in the diagnosis of WD 4 Using self-designed primers and self-modulated experimentalconditions,we successfully amplified all exons,joint regions of exonsof WD genome.The longation of PCR products was justexpected,direct sequencing results was as same as consensussequence,suggesting that primers designed correctly, experimentalconditions appropriate,and therefore the experimental results wereliable5 A novel missense mutation Ala1295Val in exon18,located in theregions of ATP hinge domain was found in the patient and his father,brother.It is suggested that this mutation originated from his father, maybe a pathogenesis-related gene. Maybe it could influence the ATPcombination and then result in ATP7B functional disorder6. A novel deletion 3700-23delg was found near 3' in intron 17 inthe patient and his mother: 3700-23delg. This mutation originated fromhis mother, whether it is pathogenesis-related or polymorphism is stillkept unclear, need advanced research.7. 1-17 and 19,20,21 exons were not found any mutations.Conclusions:1. After taken internal medical methods,we successfully saved aWD patient,Moreover,followed up one year,the conditions of patientskept stable,suggesting that the treatment is effective to part of WDpatient,high value for the strategy of treating WD 2 After outbreak of the disease,hepatic pathology manifested thatextensive injuries based on cirrhosis.Cer is higher in acute period thanin recovery period, indicating that we cannot exclude the WD justbecause Cer was in the normal range. That urine copper rise updramatically play a very significance role in the diagnosis of WD3 Having found A novel, unreported missense mutation Ala1295Valin exon18, located in the regions of ATP hinge domain was found in thepatient and his father, brother.It is suggested that this mutationoriginated from his father, may be a pathogenesis-related gene. A noveldeletion 3700-23delg was found near 3' in intron 17 in the patient andhis mother. Whether This mutation is polymorphic or pathogenitic to beexplored in the future.1-17 and 19,20,21 exons were not found anymutations.