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Vörös K, Márkus B, Atzél K, Szalay F, Gráf L, Németh D, Masszi T, Torzsa P, Kalabay L. Serum fetuin-A is decreased in cirrhotic patients with Wilson's disease. PLoS One 2023; 18:e0282801. [PMID: 36881584 PMCID: PMC9990947 DOI: 10.1371/journal.pone.0282801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/23/2023] [Indexed: 03/08/2023] Open
Abstract
INTRODUCTION Wilson's disease may lead to cirrhosis, but timely medical treatment could slow down its progression. Clinical markers helping early diagnosis are essential. Decreased fetuin-A concentration has been reported in cirrhosis of different etiologies. The aim of this study was to investigate whether decreased serum fetuin-A concentration could identify patients with Wilson's disease who developed cirrhosis. MATERIALS AND METHODS In this cross-sectional study we determined the serum fetuin-A concentration of 50 patients with Wilson's disease. We analyzed the data of patients with liver involvement, comparing cirrhotic and non-cirrhotic patients. RESULTS Among patients with liver involvement those with cirrhosis had significantly lower fetuin-A and albumin level, white blood cell and platelet count. Fetuin-A negatively correlated with disease duration, bilirubin level, positively with total protein and albumin concentration, but not with copper and ceruloplasmin concentrations or markers of systemic inflammation. In multivariate analysis with fetuin-A and the Nazer score or its parameters only fetuin-A was a significant determinant of having cirrhosis. In receiver operator curve analysis among patients with liver involvement the fetuin-A level of 523 μg/ml was associated with cirrhosis with 82% sensitivity and 87% specificity. The presence of the H1069Q mutation was not associated with alteration in fetuin-A concentration. CONCLUSIONS The serum concentration of fetuin-A is a sensitive marker of liver cirrhosis in Wilson's disease, independently of the H1069Q mutation, ceruloplasmin concentration or systemic inflammation.
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Affiliation(s)
- Krisztián Vörös
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
- * E-mail:
| | - Bernadett Márkus
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
| | - Klára Atzél
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
| | - Ferenc Szalay
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - László Gráf
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
| | - Dániel Németh
- Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Tamás Masszi
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
| | - Péter Torzsa
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
| | - László Kalabay
- Department of Family Medicine, Semmelweis University, Budapest, Hungary
- Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary
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Pop TL, Grama A, Stefanescu AC, Willheim C, Ferenci P. Acute liver failure with hemolytic anemia in children with Wilson's disease: Genotype-phenotype correlations? World J Hepatol 2021; 13:1428-1438. [PMID: 34786177 PMCID: PMC8568583 DOI: 10.4254/wjh.v13.i10.1428] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/23/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Wilson's disease (WD) is a rare autosomal recessive inherited disorder of copper metabolism. Acute liver failure (ALF) and hemolytic anemia represent the most severe presentation of WD in children. No clear genotype-phenotype correlations exist in WD. Protein-truncating nonsense, frame-shift, or splice-site variants may be associated with more severe disease. In contrast, missense variants may be associated with late-onset, less severe disease, and more neurological manifestations. Recently, a gene variant (HSD17B13:TA, rs72613567) with a possible hepatic protective role against toxins was associated with a less severe hepatic phenotype in WD. AIM To analyze the possible genotype-phenotype correlations in children with WD presented with ALF and non-immune hemolytic anemia. METHODS The medical records of children with WD diagnosed and treated in our hospital from January 2006 to December 2020 were retrospectively analyzed. The clinical manifestations (ALF with non-immune hemolytic anemia or other less severe forms), laboratory parameters, copper metabolism, ATP7B variants, and the HSD17B13:TA (rs72613567) variant were reviewed to analyze the possible genotype-phenotype correlations. RESULTS We analyzed the data of 51 patients with WD, 26 females (50.98%), with the mean age at the diagnosis of 12.36 ± 3.74 years. ALF and Coombs-negative hemolytic anemia was present in 8 children (15.67%), all adolescent girls. The Kayser-Fleisher ring was present in 9 children (17.65%). The most frequent variants of the ATP7B gene were p.His1069Gln (c.3207A>G) in 38.24% of all alleles, p.Gly1341Asp (c.4021G>A) in 26.47%, p.Trp939Cys (c.2817G>T) in 9.80%, and p.Lys844Ter (c.2530A>T) in 4.90%. In ALF with hemolytic anemia, p.Trp939Cys (c.2817G>T) and p.Lys844Ter (c.2530A>T) variants were more frequent than in other less severe forms, in which p.His1069Gln (c.3207A>G) was more frequent. p.Gly1341Asp (c.4021G>A) has a similar frequency in all hepatic forms. For 33 of the patients, the HSD17B13 genotype was evaluated. The overall HSD17B13:TA allele frequency was 24.24%. Its frequency was higher in patients with less severe liver disease (26.92%) than those with ALF and hemolytic anemia (14.28%). CONCLUSION It remains challenging to prove a genotype-phenotype correlation in WD patients. In children with ALF and hemolytic anemia, the missense variants other than p.His1069Gln (c.3207A>G) and frame-shift variants were the most frequently present in homozygous status or compound heterozygous status with site splice variants. As genetic analysis is usually time-consuming and the results are late, the importance at the onset of the ALF is questionable. If variants proved to be associated with severe forms are found in the pre-symptomatic phase of the disease, this could be essential to predict a possible severe evolution.
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Affiliation(s)
- Tudor Lucian Pop
- 2 Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania.
| | - Alina Grama
- 2 Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania
| | - Ana Cristina Stefanescu
- 2 Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca 400177, Romania
| | - Claudia Willheim
- Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Wien A-1090, Austria
| | - Peter Ferenci
- Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Wien A-1090, Austria
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Li J, Jiang Y, Xu T, Zhang Y, Xue J, Gao X, Yang X, Wang X, Jia X, Cheng W, Jin S. Wilson Disease With Novel Compound Heterozygote Mutations in the ATP7B Gene Presenting With Severe Diabetes. Diabetes Care 2020; 43:1363-1365. [PMID: 32291276 DOI: 10.2337/dc19-2033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 03/22/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To determine the relationship between ATP7B mutations and diabetes in Wilson disease (WD). RESEARCH DESIGN AND METHODS A total of 21 exons and exon-intron boundaries of ATP7B were identified by Sanger sequencing. RESULTS Two novel compound heterozygous mutations (c.525 dupA/ Val176Serfs*28 and c.2930 C>T/ p.Thr977Met) were detected in ATP7B. After d-penicillamine (D-PCA) therapy, serum aminotransferase and ceruloplasmin levels in this patient were normalized and levels of HbA1c decreased. However, when the patient ceased to use D-PCA due to an itchy skin, serum levels of fasting blood glucose increased. Dimercaptosuccinic acid capsules were prescribed and memory recovered to some extent, which was accompanied by decreased insulin dosage for glucose control by 5 units. CONCLUSIONS This is the first report of diabetes caused by WD.
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Affiliation(s)
- Juyi Li
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Pharmacy, The central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yanli Jiang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Teng Xu
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yao Zhang
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiajia Xue
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiao Gao
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoyan Yang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiufang Wang
- Department of Pain, The central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiong Jia
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wenzhuo Cheng
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Si Jin
- Department of Endocrinology, Institute of Geriatric Medicine, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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Barada K, El Haddad A, Katerji M, Jomaa M, Usta J. Wilson's disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance. World J Gastroenterol 2017; 23:6715-6725. [PMID: 29085216 PMCID: PMC5643292 DOI: 10.3748/wjg.v23.i36.6715] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/16/2017] [Accepted: 07/12/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the phenotypes and predominant disease-causing mutations in Lebanese patients with Wilson's disease, as compared to regional non-European data. METHODS The clinical profile of 36 patients diagnosed in Lebanon was studied and their mutations were determined by molecular testing. All patients underwent full physical exam, including ophthalmologic slit-lamp examination ultrasound imaging of the liver, as well as measurement of serum ceruloplasmin and 24-h urinary-Cu levels. In addition, genetic screening using PCR followed by sequencing to determine disease-causing mutations and polymorphisms in the ATP7B gene was carried on extracted DNA from patients and immediate family members. Our phenotypic-genotypic findings were then compared to reported mutations in Wilson's disease patients from regional Arab and non-European countries. RESULTS Patients belonged to extended consanguineous families. The majority were homozygous for the disease-causing mutation, with no predominant mutation identified. The most common mutation, detected in 4 out of 13 families, involved the ATP hinge region and was present in patients from Lebanon, Egypt, Iran and Turkey. Otherwise, mutations in Lebanese patients and those of the region were scattered over 17 exons of ATP7B. While the homozygous exon 12 mutation Trp939Cys was only detected in patients from Lebanon but none from the regional countries, the worldwide common mutation H1069Q was not present in the Lebanese and was rare in the region. Pure hepatic phenotype was predominant in patients from both Lebanon and the region (25%-65%). Furthermore, the majority of patients, including those who were asymptomatic, had evidence of some hepatic dysfunction. Pure neurologic phenotype was rare. CONCLUSION Findings do not support presence of a founder effect. Clinical and genetic screening is recommended for family members with index patients and unexplained hepatic dysfunction.
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Affiliation(s)
- Kassem Barada
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut 110236, Lebanon
| | - Aline El Haddad
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut 110236, Lebanon
| | - Meghri Katerji
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 110236, Lebanon
| | - Mustapha Jomaa
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 110236, Lebanon
| | - Julnar Usta
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut 110236, Lebanon
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Lv T, Li X, Zhang W, Zhao X, Ou X, Huang J. Recent advance in the molecular genetics of Wilson disease and hereditary hemochromatosis. Eur J Med Genet 2016; 59:532-539. [PMID: 27592149 DOI: 10.1016/j.ejmg.2016.08.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 07/12/2016] [Accepted: 08/31/2016] [Indexed: 02/07/2023]
Abstract
Metabolic liver diseases such as Wilson disease (WD) and hereditary hemochromatosis (HH) possess complicated pathogenesis and typical hereditary characteristics with the hallmarks of a deficiency in metal metabolism. Mutations in genes encoding ATPase, Cu + transporting, beta polypeptide (ATP7B) and hemochromatosis (HFE) or several non-HFE genes are considered to be causative for WD and HH, respectively. Although the identification of novel mutations in ATP7B for WD and HFE or the non-HFE genes for HH has increased, especially with the application of whole genome sequencing technology in recent years, the biological function of the identified mutations, as well as genotype-phenotype correlations remain to be explored. Further analysis of the causative gene mutation would be critical to clarify the mechanisms underlying specific disease phenotypes. In this review, we therefore summarize the recent advances in the molecular genetics of WD and HH including the updated mutation spectrums and the correlation between genotype and phenotype, with an emphasis on biological functional studies of the individual mutations identified in WD and HH. The weakness of the current functional studies and analysis for the clinical association of the individual mutation was also discussed. These works are essential for the understanding of the association between genotypes and phenotypes of these inherited metabolic liver diseases.
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Affiliation(s)
- Tingxia Lv
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Xiaojin Li
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Wei Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Xinyan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
| | - Jian Huang
- Liver Research Center, Experimental Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xuan-wu District, Beijing, 100050, China.
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Wu F, Wang J, Pu C, Qiao L, Jiang C. Wilson's disease: a comprehensive review of the molecular mechanisms. Int J Mol Sci 2015; 16:6419-6431. [PMID: 25803104 PMCID: PMC4394540 DOI: 10.3390/ijms16036419] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Revised: 03/03/2015] [Accepted: 03/03/2015] [Indexed: 02/06/2023] Open
Abstract
Wilson's disease (WD), also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder resulting from abnormal copper metabolism. Reduced copper excretion causes an excessive deposition of the copper in many organs such as the liver, central nervous system (CNS), cornea, kidney, joints, and cardiac muscle where the physiological functions of the affected organs are impaired. The underlying molecular mechanisms for WD have been extensively studied. It is now believed that a defect in P-type adenosine triphosphatase (ATP7B), the gene encoding the copper transporting P-type ATPase, is responsible for hepatic copper accumulation. Deposited copper in the liver produces toxic effects via modulating several molecular pathways. WD can be a lethal disease if left untreated. A better understanding of the molecular mechanisms causing the aberrant copper deposition and organ damage is the key to developing effective management approaches.
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Affiliation(s)
- Fei Wu
- Department of imaging, the Affiliated Zhongshan Hospital of Dalian University, 6 Jiefang Street, Zhongshan District, Dalian 116001, Liaoning, China.
| | - Jing Wang
- Department of Internal Medicine, the Second Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning, China.
| | - Chunwen Pu
- Department of Biobank, the Sixth People's Hospital of Dalian, 269 Luganghuibai Road, Ganjingzi District, Dalian 116031, Liaoning, China.
| | - Liang Qiao
- Storr Liver Centre, Westmead Millennium Institute for Medical Research, Faculty of Medicine, the University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
| | - Chunmeng Jiang
- Department of Internal Medicine, the Second Hospital of Dalian Medical University, 467 Zhongshan Road, Shahekou District, Dalian 116023, Liaoning, China.
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Usta J, Wehbeh A, Rida K, El-Rifai O, Estiphan TA, Majarian T, Barada K. Phenotype-genotype correlation in Wilson disease in a large Lebanese family: association of c.2299insC with hepatic and of p. Ala1003Thr with neurologic phenotype. PLoS One 2014; 9:e109727. [PMID: 25390358 PMCID: PMC4229086 DOI: 10.1371/journal.pone.0109727] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2014] [Accepted: 09/04/2014] [Indexed: 12/15/2022] Open
Abstract
Genotype phenotype correlations in Wilson disease (WD) are best established in homozygous patients or in compound heterozygous patients carrying the same set of mutations. We determined the clinical phenotype of patients with WD carrying the c.2298_2299insC in Exon 8 (c.2299insC) or the p. Ala1003Thr missense substitution in Exon 13 mutations in the homozygous or compound heterozygous state. We investigated 76 members of a single large Lebanese family. Their genotypes were determined, and clinical assessments were carried out for affected subjects. We also performed a literature search retrieving the phenotypes of patients carrying the same mutations of our patients in the homozygous or compound heterozygous state. There were 7 consanguineous marriages in this family and the prevalence of WD was 8.9% and of carriers of ATP7B mutation 44.7%. WD was confirmed in 9 out of 76 subjects. All 9 had the c.2299insC mutation, 5 homozygous and 4-compound heterozygous with p. Ala1003Thr. Six of our patients had hepatic, 2 had neurologic and 1 had asymptomatic phenotype. Based on our data and a literature review, clear phenotypes were reported for 38 patients worldwide carrying the c.2299insC mutation. About 53% of those have hepatic and 29% have neurologic phenotype. Furthermore, there were 10 compound heterozygous patients carrying the p. Ala1003Thr mutation. Among those, 80% having c.2299insC as the second mutation had hepatic phenotype, and all others had neurologic phenotype. We hereby report an association between the c.2299insC mutation and hepatic phenotype and between the p. Ala1003Thr mutation and neurologic phenotype.
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Affiliation(s)
- Julnar Usta
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Antonios Wehbeh
- Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Khaled Rida
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Omar El-Rifai
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | | | - Tamar Majarian
- Department of Biochemistry and Molecular Genetics; Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Kassem Barada
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, Faculty of Medicine, Beirut, Lebanon
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Cocoş R, Şendroiu A, Schipor S, Bohîlţea LC, Şendroiu I, Raicu F. Genotype-phenotype correlations in a mountain population community with high prevalence of Wilson's disease: genetic and clinical homogeneity. PLoS One 2014; 9:e98520. [PMID: 24897373 PMCID: PMC4045667 DOI: 10.1371/journal.pone.0098520] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Accepted: 04/29/2014] [Indexed: 12/12/2022] Open
Abstract
Wilson’s disease is an autosomal recessive disorder caused by more than 500 mutations in ATP7B gene presenting considerably clinical manifestations heterogeneity even in patients with a particular mutation. Previous findings suggested a potential role of additional genetic modifiers and environment factors on phenotypic expression among the affected patients. We conducted clinical and genetic investigations to perform genotype-phenotype correlation in two large families living in a socio-culturally isolated community with the highest prevalence of Wilson’s disease ever reported of 1∶1130. Sequencing of ATP7B gene in seven affected individuals and 43 family members identified a common compound heterozygous genotype, H1069Q/M769H-fs, in five symptomatic and two asymptomatic patients and detected the presence of two out of seven identified single nucleotide polymorphisms in all affected patients. Symptomatic patients had similar clinical phenotype and age at onset (18±1 years) showing dysarthria and dysphagia as common clinical features at the time of diagnosis. Moreover, all symptomatic patients presented Kayser-Fleischer rings and lack of dystonia accompanied by unfavourable clinical outcomes. Our findings add value for understanding of genotype-phenotype correlations in Wilson’s disease based on a multifamily study in an isolated population with high extent of genetic and environmental homogeneity as opposed to majority of reports. We observed an equal influence of presumed other genetic modifiers and environmental factors on clinical presentation and age at onset of Wilson’s disease in patients with a particular genotype. These data provide valuable inferences that could be applied for predicting clinical management in asymptomatic patients in such communities.
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Affiliation(s)
- Relu Cocoş
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Genome Life Research Centre, Bucharest, Romania
| | | | - Sorina Schipor
- National Institute of Endocrinology “C. I. Parhon”, Bucharest, Romania
| | - Laurenţiu Camil Bohîlţea
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Sf. Pantelimon Clinical Emergency Hospital, Bucharest, Romania
| | | | - Florina Raicu
- Chair of Medical Genetics, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
- Francisc I. Rainer Anthropological Research Institute, Romanian Academy, Bucharest, Romania
- * E-mail:
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