Phenotypic and Genetic Characterization of a Cohort of Pediatric Wilson Disease Patients

BMC Pediatrics

Hartmut Schmidt¹  Ezzat S Elsobky³  Ahmed Shadeed²  Suzan Elnaghy⁴  Solaf M Elsayed³  Tawhida Y Abdel Ghaffar² 

[1]Klinische und Experimentelle Transplantationshepatologie, Universitätsklinikum, Münster, Germany

[2]Children's Hospital, Ain Shams University, Cairo, Egypt

[3]Medical Genetics Center, Cairo, Egypt

[4]Yassin Abdel Ghaffar Charity Center for Liver Disease and Research, Cairo, Egypt

关键词: Wilson disease;    pediatric;    neurological;    mutations;    hepatic;   

Others  :  1172153
DOI  :  10.1186/1471-2431-11-56

 received in 2011-01-18, accepted in 2011-06-17,  发布年份 2011

【 摘 要 】

Background

In Egypt, Wilson disease seems to be under diagnosed and clinical data on large cohorts are limited. The aim of this study is to highlight the clinical, laboratory and genetic characteristics of this disease in our pediatric population as well as to report our experience with both treatment options and outcome.

Methods

The study included 77 patients from 50 unrelated families (62 were followed up for a mean period of 58.9 ± 6.4 months and 27 were asymptomatic siblings). Data were collected retrospectively by record analysis and patient interviews. Diagnosis was confirmed by sequencing of the ATP7B gene in 64 patients

Results

Our patients had unique characteristics compared to other populations. They had a younger age of onset (median: 10 years), higher prevalence of Kayser-Fleischer rings (97.6% in the symptomatic patients), low ceruloplasmin (93.5%), high rate of parental consanguinity (78.9%) as well as a more severe course. 71.42% of those on long term D-penicillamine improved or were stable during the follow up with severe side effects occurring in only 11.5%. Preemptive treatment with zinc monotherapy was an effective non-toxic alternative to D-penicillamine. Homozygous mutations were found in 85.7%, yet limited by the large number of mutations detected, it was difficult to find genotype-phenotype correlations. Missense mutations were the most common while protein-truncating mutations resulted in a more severe course with higher incidence of acute liver failure and neurological symptoms.

Conclusions

Egyptian children with Wilson disease present with early Kayser-Fleischer rings and early onset of liver and neurological disease. The mutational spectrum identified differs from that observed in other countries. The high rate of homozygous mutations (reflecting the high rate of consanguinity) may potentially offer further insights on genotype-phenotype correlation

【 授权许可】

   
2011 Abdel Ghaffar et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Loudianos G, Dessi V, Lovicu M, Angius A, Figus A, Lilliu F, Nurchi AM, Deplano A, Moi P, Pirastu M, Cao A: Molecular characterization of Wilson's disease in the Sardinian population-evidence of a founder effect. Hum Mutat 1999, 14:294-303.
• [2]Scheinberg IH: Wilson's disease. J Rheumatol Suppl 1981, 7:90-93.
• [3]Merle U, Schaefer M, Ferenci P, Stremmel W: Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 2007, 56:115-120.
• [4]Satio T: Presenting symptoms and natural history of Wilson disease. Eur J Pediatr 1987, 146:261-265.
• [5]Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW: The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 1993, 5:327-337.
• [6]Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM, Devoto M, Peppercorn J, Bush AI, Sternlieb I, Pirastu M, Gusella JF, Evgrafov O, Penchaszadeh GK, Honig B, Edelman IS, Soares MB, Scheinberg IH, Gilliam TC: The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 1993, 5:344-350.
• [7]Brewer GJ, Dick RD, Johnson VD, Brunberg JA, Kluin KJ, Fink JK: Treatment of Wilson's disease with zinc: XV long-term follow-up studies. J Lab Clin Med 1998, 132:264-278.
• [8]Dhawan A, Taylor RM, Cheeseman P, De Silva P, Katsiyiannakis L, Mieli-Vergani G: Wilson's disease in children: 37-year experience and revised King's score for liver transplantation. Liver Transpl 2005, 11:441-448.
• [9]Abdelghaffar TY, Elsayed SM, Elsobky E, Bochow B, Büttner J, Schmidt H: Mutational analysis of ATP7B gene in Egyptian children with Wilson disease: 12 novel mutations. J Hum Genet 2008, 53:681-687.
• [10]Arnon R, Calderon JF, Schilsky M, Emre S, Shneider BL: Wilson disease in children: serum aminotransferases and urinary copper on triethylene tetramine dihydrochloride (trientine) treatment. J Pediatr Gastroenterol Nutr 2007, 44:596-602.
• [11]Daniel WW: Biostatistics: A foundation for analysis in the health sciences. 6th edition. John Wiley and sons, Inc., New York; 1995.
• [12]Ferenci P, Caca K, Loudianos G, Mieli-Vergani G, Tanner S, Sternlieb I, Schilsky M, Cox D, Berr F: Diagnosis and phenotypic classification of Wilson disease. Liver Int 2003, 23:139-142.
• [13]Giacchino R, Marazzi MG, Barabino A, Fasce L, Ciravegna B, Famularo L, Boni L, Callea F: Syndromic variability of Wilson's disease in children. Clinical study of 44 cases. Ital J Gastroenterol Hepatol 1997, 29:155-161.
• [14]Walshe JM: The liver in Wilson's disease. In Diseases of the liver. 6th edition. Edited by Schiff L, Schiff ER. Philadelphia, PA: J B Lippincott; 1987:1037-1050.
• [15]Amira M, Sano I: Genetic studies of Wilson's disease in Japan. Birth Defects 1968, 4:54-9.
• [16]Asadi Pooya AA, Eslami NS, Haghighat M: Wilson Disease in Southern Iran. Turk J Gastroenterol 2005, 16:71-74.
• [17]Kalra V, Khurana D, Mittal R: Wilson's disease--early onset and lessons from a pediatric cohort in India. Indian Pediatr 2000, 37:595-601.
• [18]Sternlieb I: Perspectives on Wilson's disease. Hepatology 1990, 12:1234-9.
• [19]Ozsoylu S, Kocak N: Wilson disease in Turkish children. Eur J Pediatr 1988, 147:334.
• [20]Sallie R, Chiyende J, Tan KC, Bradley D, Portmann B, Williams R, Mowat AP, Mieli-Vergani G: Fulminant hepatic failure resulting from coexistent Wilson's disease and hepatitis E. Gut 1994, 35:849-853.
• [21]Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD): Diagnosis and treatment of Wilson disease: an update. Hepatology 2008, 47:2089-2111.
• [22]Steindl P, Ferenci P, Dienes HP, Grimm G, Pabinger I, Madl C, Maier-Dobersberger T, Herneth A, Dragosics B, Meryn S, Knoflach P, Granditsch G, Gangl A: Wilson's disease in patients presenting with liver disease: a diagnostic challenge. Gastroentterology 1997, 113:212-218.
• [23]Kasai N, Miyoshi I, Osanai T, Yamashita T, Kamimura E, Yoshida MC: Effects of sex hormones on fulminant hepatitis in LEC rats: a model of Wilson's disease. Lab Anim Sci 1992, 42:363-368.
• [24]Falkmer S, Samuelson G, Sjolin S: Penicillamine-induced normalization of clinical signs, and liver morphology and histochemistry in a case of Wilson's disease. Pediatrics 1970, 45:260-268.
• [25]Walshe JM: Copper chelation in patients with Wilson's disease. A comparison of penicillamine and triethylene tetramine dihydrochloride. Q J Med 1973, 42:441-452.
• [26]Sternlieb I: Copper and the liver. Gastroenterology 1980, 78:1615-1628.
• [27]Czlonkowska A, Gajda J, Rodo M: Effects of long-term treatment in Wilson's disease with D-penicillamine and zinc sulphate. J Neurol 1996, 243:269-273.
• [28]Iorio R, D'Ambrosi M, Marcellini M, Barbera C, Maggiore G, Zancan L, Giacchino R, Vajro P, Marazzi MG, Francavilla R, Michielutti F, Resti M, Frediani T, Pastore M, Mazzarella G, Fusco G, Cirillo F, Vegnente A, Hepatology Committee of Italian Society of Paediatric Gastroenterology Hepatology and Nutrition: Serum transaminases in children with Wilson's disease. J Pediatr Gastroenterol Nutr 2004, 39:331-336.
• [29]Brewer GJ, Dick RD, Yuzbasiyan-Gurkan V, Johnson V, Wang Y: Treatment of Wilson's disease with zinc. XIII: Therapy with zinc in presymptomatic patients from the time of diagnosis. J Lab Clin Med 1994, 123:849-858.
• [30]Cousins RJ: Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin. Physiol Rev 1985, 65:238-309.
• [31]Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani P: Oral zinc therapy for Wilson's disease. Ann Intern Med 1983, 99:314-319.
• [32]Mokhtar MM, Abdel-Fattah MM: Consanguinity and advanced maternal age as risk factors for reproductive losses in Alexandria, Egypt. Eur J Epidemiol 2001, 17:559-565.
• [33]Merle U, Weiss KH, Eisenbach C, Tuma S, Ferenci P, Stremmel W: Truncating mutations in the Wilson disease gene ATP7B are associated with very low serum ceruloplasmin oxidase activity and an early onset of Wilson disease. BMC Gastroenterol 2010, 10:8. BioMed Central Full Text