Methylene Tetrahydrofolate Reductase Gene Polymorphism is Associated with Severity of Liver Steatosis in Chronically Infected Patients with HCV Genotype 4.

BACKGROUND: Methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism was reported as a genetic variant in liver steatosis and fibrosis. This is a study of the association between MTHFR C677T polymorphism and HCV core with severity of steatosis in HCV GT4 patients. METHODS: 111 HCV patients and 112 control subjects were recruited. Polymorphism was detected by RFLP analysis, core Ag was detected by ELISA. RESULTS: Combined HCV infection and MTHFR C677T polymorphism increases the risk to develop steatosis by 3.63- and 5.21-fold in subjects with single (CT) and double (TT) substitutions, respectively. Patients with chronic HCV infection had a 2.88- and 8.57-fold higher risk to develop steatosis in CT and TT genotypes, respectively, than patients with the (CC) genotype. No significant difference in core Ag titers were observed. CONCLUSIONS: MTHFR C677T polymorphism is a valuable genetic marker for steatosis, while HCV core Ag titer had no association with grades of steatosis in GT4 infections.

Mutations in Recombination Activating Gene 1 and 2 in patients with severe combined immunodeficiency disorders in Egypt.

The Recombination Activating Genes (RAG) 1/2 are important for the development and function of T and B cells. Loss of RAG1/2 function results in severe combined immunodeficiency (SCID), which could lead to early death. We studied the prevalence of RAG1/2 mutations in ten SCID patients in Egypt. We identified two novel homozygous nonsense mutations in RAG1, a novel homozygous deletion, and a previously reported homozygous missense mutation from four patients, as well as two homozygous mutations in RAG2 from the same patient. Prenatal diagnosis performed in the mother of a patient with RAG1 deficiency determined that the fetus was heterozygous for the same mutation. This represents the first report on RAG1/2 mutations in SCID patients in Egypt. The early diagnosis dramatically affects the outcome of the disease by allowing bone marrow transplantation at an early age, and providing prenatal diagnosis and genetic counseling for families with a history of SCID.

Value of Egy-Score in diagnosis of significant, advanced hepatic fibrosis and cirrhosis compared to aspartate aminotransferase-to-platelet ratio index, FIB-4 and Forns' index in chronic hepatitis C virus.

AIM: Serum markers and developed scores are of rising importance in non-invasive diagnosis of hepatic fibrosis. Aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4 and Forns' index are validated scores used for diagnosis of liver fibrosis. The Egy-Score is a newly developed score for detection of hepatic fibrosis with promising results. We aimed to assess the accuracy of the Egy-Score in the diagnosis of significant fibrosis, advanced fibrosis and cirrhosis compared to APRI, FIB-4 and Forns' in chronic hepatitis C virus (HCV) patients. METHODS: A retrospective study including 100 chronic hepatitis C naïve Egyptian patients was performed. Patients were classified according to stages of fibrosis into three groups: significant fibrosis (≥ F2), advanced fibrosis (≥ F3) and cirrhosis (F4). Egy-Score, APRI, FIB-4 and Forns' index were calculated. Regression analysis and receiver-operator curves were plotted to assess the sensitivity, specificity and predictive values for the significant scores with the best cut-off for diagnosis. RESULTS: An Egy-Score of 3.28 or more was superior to APRI, FIB-4 and Forns' index for detecting advanced fibrosis with a sensitivity of 91% and specificity of 78%. An Egy-Score of 3.67 or more was superior to APRI, FIB-4 and Forns' index for detecting cirrhosis with a sensitivity of 82% and specificity of 87%. Forns' index was superior to Egy-Score, FIB-4 and APRI for detecting significant fibrosis. CONCLUSION: The Egy-Score is a promising, accurate, easily calculated, cost-effective score in the prediction of hepatic fibrosis in chronic HCV patients with superiority over APRI, FIB-4 and Forns' index in advanced hepatic fibrosis and cirrhosis.

Evaluation of GALAD Score in Diagnosis and Follow-up of Hepatocellular Carcinoma after Local Ablative Therapy.

Background and Aims: Strategies for detection of early hepatocellular carcinoma (HCC) are still limited. The GALAD score is a serum biomarker-based model designed to predict the probability of having HCC. We aimed to assess the ability of GALAD score to diagnose early HCC and its validity to follow patients after local ablation therapy. Methods: This multicenter prospective study included 108 patients in two groups, 58 HCC patients (67 focal lesions) with local ablative therapy (study group), and a control group of 50 patients with liver cirrhosis. The GALAD scores of the study and control groups, and of the HCC patients before and after ablative therapy were compared. Results: Most patients were men (74.1% in study group and 76% in controls) with hepatitis C virus infection (98.30% in the study group, and 94% in controls). GALAD scores were significantly higher in HCC patients than in those with benign cirrhosis (2.65 vs. -0.37, p=0.001). Ablative therapy was successful in 94.4% of focal lesions <2 cm, and in 86.10% of 2-5 cm lesions. The GALAD score was also significantly lower at 1 month after ablation in patients with well-ablated tumors (2.19 vs. 0.98, p=0.001). The best cutoff values of GALAD score for diagnosis of early HCC, and for prediction of well ablation of HCC were 0.74 and ≤3.31 (areas under the curve of 0.92 and 0.75, sensitivities of 84.48% and 76.19%, specificities of 89.13% and 83.33%, positive predictive values of 90.74% and 94.1%, and negative predictive values of 82% and 35.7% respectively). Conclusion: The GALAD score was effective for the diagnosis of early HCC and for follow-up after ablative therapy.

Highly Sensitive Serum miRNA Panel for the Diagnosis of Hepatocellular Carcinoma in Egyptian Patients with HCV-Related HCC.

OBJECTIVE: This study aimed at exploring the potential role of a panel of serum micro-RNA (miRNA) markers in liver fibrosis and hepatocellular carcinoma (HCC) diagnosis in patients with chronic hepatitis C virus (HCV) infection. METHODS: The study included 157 chronic HCV patients and 62 HCC patients who presented to the Cairo University Center for Hepatic Fibrosis, Endemic Medicine Department, from 2015 to 2017. Relevant clinical and laboratory data were collected and sera were subjected to miRNA expression profiling. Eleven miRNA markers were studied and receiver operating characteristic curves were constructed to investigate the best cutoff values of the miRNAs that showed altered expression in HCC compared to HCV-associated advanced fibrosis. RESULTS: miRNA expression profiling revealed 5 miRNAs (miR-124, miR-141, miR-205, miR-208a, miR-499a) were significantly upregulated and 2 miRNAs were significantly downregulated (miR-103a, miR-15a) in HCC compared to advanced fibrosis patients. No significant difference was observed in miRNA expression between advanced fibrosis and early hepatic fibrosis apart from a significant downregulation of miR-155-5p in advanced fibrosis. CONCLUSION: Serum miRNAs could serve as potential diagnostic tools for the diagnosis of HCC.

Copy Number Variations in Genetic Diagnosis of Congenital Adrenal Hyperplasia Children.

Background: Congenital adrenal hyperplasia (CAH) is a monogenic disorder caused by genetic diversity in the CYP21A2 gene, with 21-hydroxylase deficiency (21-OHD) as the most common type. Early sex assignment and early diagnosis of different genetic variations with a proper technique are important to reduce mortality and morbidity. Proper early sex identification reduces emotional, social, and psychological stress. Aim: Detection of a spectrum of aberrations in the CYP21A2 gene, including copy number variations, gene conversion, chimeric genes, and point variations. Methods: The CYP21A2 gene was screened using MLPA assay in 112 unrelated Egyptian children with 21-OHD CAH (33 males and 79 females). Results: In the studied group, 79.5% were diagnosed within the first month of life. 46.8% of the genetic females were misdiagnosed as males. Among the copy number variation results, large deletions in 15.4% and three types of chimeric genes in 9% (CH-1, CH-7, and CAH-X CH-1) were detected. Regarding gene dosage, one copy of CYP21A2 was found in 5 cases (4.5%), three copies were detected in 7 cases (6.3%), and one case (0.9%) showed four copies. Eight common genetic variants were identified, I2G, large deletions, large gene conversion (LGC), I172N, F306 + T, -113 SNP, 8bp Del, and exon 6 cluster (V237E and M239K) with an allelic frequency of 32.62%, 15.45%, 7.30%, 3.00%, 2.58%, 2.15%, 0.86%, and 0.86%, respectively. Conclusion: High prevalence of copy number variations highlights the added value of using MLPA in routine laboratory diagnosis of CAH patients.

Evaluation of red cell distribution width to platelet ratio as a novel non-invasive index for predicting hepatic fibrosis in patients with chronic hepatitis C.

BACKGROUND AND STUDY AIMS: Assessing the extent of fibrosis is an essential part of therapeutic decisions in patients with chronic hepatitis C (CHC). Liver biopsies are the "gold standard" for evaluating liver fibrosis but have many limitations. Thus, noninvasive predictors of fibrosis have been developed. This study aimed to determine the effectiveness of red cell distribution width (RDW) to platelet ratio as a simple noninvasive method for predicting the hepatic fibrosis stage in patients with CHC. PATIENTS AND METHODS: This cross-sectional study included 197 Egyptian patients with CHC. A routine pretreatment reference needle liver biopsy was performed. Fib-4, transient elastography (TE) by Fibroscan, AST to Platelet Ratio Index (APRI), and RDW to platelet ratio (RPR) were measured. Predictors of significant fibrosis (Metavir score ≥ F2) and advanced fibrosis (Metavir score ≥ F3) were identified. RESULTS: Fib-4, TE, APRI, and RPR values differed significantly when comparing different stages of fibrosis (p < 0.01). Fib-4, TE, APRI, and RPR were reliable diagnostic tools at cutoff values of 1.17, 7.75, 0.18, and 0.07, respectively, for predicting significant fibrosis and cutoff values of 1.99, 8, 1.77, and 0.08, respectively, for predicting advanced fibrosis. Using logistic regression analysis, TE was identified as an independent predictor associated with significant and advanced fibrosis. Fib-4 was significantly associated with advanced fibrosis only. CONCLUSION: The use of Fib-4, TE, APRI, and RPR measurements may decrease the need for liver biopsies for predicting significant and advanced fibrosis. RPR showed fair sensitivity, specificity, positive and negative predictive values, and overall accuracy for predicting significant fibrosis in patients with CHC.

Monogenic leptin deficiency in early childhood obesity.

BACKGROUND: Early childhood obesity is a public health problem worldwide. It affects different aspects of physical and mental child's health. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Analysis of serum leptin levels and leptin gene mutations is a rapid and easy step toward the diagnosis of congenital leptin deficiency that is considered an important cause in early childhood obesity. OBJECTIVES: The aim of this study was to diagnose monogenic leptin deficiency in Egyptian children presenting with early onset obesity (EOO). METHODS: The current cross-sectional study included 80 children who developed obesity during the first year of life with BMI > 2 SD (for age and sex). The studied population was subjected to history taking, auxological assessment, serum leptin assay, and leptin gene sequencing. RESULTS: Ten cases had leptin deficiency (12.5%), while 18 cases showed elevated leptin levels (22.5%). Leptin gene variants in the coding region were identified in 30% of the leptin-deficient group: two novel homozygous disease-causing variants (c.104 T > G and c.34 delC) and another previously reported homozygous pathogenic variant (c.313C > T). CONCLUSION: Leptin deficiency is considered a significant cause of monogenic obesity in Egyptian children with early-onset obesity as the diagnosis of these patients would be a perfect target for recombinant leptin therapy.

CYP21A2 genetic profile in 14 Egyptian children with suspected congenital adrenal hyperplasia: a diagnostic challenge.

CYP21A2 genotyping remains an important element in the diagnosis and management of congenital adrenal hyperplasia, and establishing accurate genotype-phenotype correlations has facillitated adequate genetic counseling and prenatal management for at-risk families. Despite extensive efforts to establish a clear genotype-phenotype correlation, some discordance remains. Establishing a diagnosis of congenital adrenal hyperplasia on the basis of biochemical and clinical data is occasionally challenging, and the identification of CYP21A2 mutations may help confirm the diagnosis. We review the diagnostic challenges despite an extensive genetic evaluation for 14 patients with a suspected clinical and biochemical diagnosis of congenital adrenal hyperplasia. Other diagnostic entities should be considered in the absence of convincing genetic data.

Role of Serum Soluble CD163 in the Diagnosis, Risk of Bleeding, and Prognosis of Gastro-Esophageal Varices in Cirrhotic Patients.

Research is continuous for noninvasive tools for the prediction of portal hypertension than upper gastrointestinal endoscopy. Serum sCD163 correlates with hepatic venous pressure gradient, aiding in the prediction of portal hypertension. We aimed at investigating the role of sCD163 in the prediction of the presence and size of varices as well as a stratification tool for surveillance or prophylaxis by assessment of prognosis and risk of bleeding. Two hundred forty-three cirrhotic patients were divided into 3 groups: group I: no varices, group II: small-sized varices, and group III: medium-sized and large-sized varices. Serum sCD163 levels were assessed and correlated with abdominal ultrasound and laboratory investigations. Follow-up for 1 year was conducted to assess the risk of bleeding, and band ligation was performed for significant varices with follow-up of obliteration. sCD163 levels were significantly higher in patients with varices requiring prophylactic interventions (P = 0.03) and in large varices (P = 0.012), patients at risk of bleeding (P = 0.04), and the bleeder patients (P = 0.001). No relationship between the sCD163 levels and the rate of variceal obliteration was reported. sCD163 levels were positively correlated with the Child score (P = 0.05), the portal vein diameter (P = 0.02), and the splenic size (P = 0.04). Although sCD163 level cannot predict the development of varices, it serves as a good predictor for the detection of size of varices (large varices), the need of prophylactic interventions, and risk of variceal bleeding. sCD163 level is a helpful indicator with the progression of cirrhosis and portal hypertension.

Validation of Hepa-index as a non-invasive biomarkers panel for assessment of hepatic fibrosis in Egyptians with chronic hepatitis C.

OBJECTIVES: To validate the diagnostic performance of Hepa-Index in predicting different stages of hepatic fibrosis in Egyptian patients with chronic hepatitis C (CHC). Methods: Hundred treatment naïve chronic hepatitis C Egyptian patients were prospectively enrolled between June 2014 and January 2015. They were subjected to: platelet count, alpha-2-macroglobulin (α2-MG), total bilirubin, gamma glutamyl transpeptidase (GGT), total cholesterol, liver biopsy and histopathological staging of hepatic fibrosis according to METAVIR scoring system. Hepa-Index was calculated according to the formula: Hepa-Index=exp (-0.021 x platelet +1.65 x α2-MG+0.2 x total bilirubin + 0.026 x GGT -1.215 x total cholesterol) / (1+exp (-0.021 x platelet + 1.65 x α2-MG + 0.2 x total bilirubin +0.026 x GGT -1.215 x total cholesterol).  Results: Hepa-Index correlates positively with the stage of hepatic fibrosis. Cut off values of Hepa-Index were: 0.2 for predicting significant hepatic fibrosis (≥F2 METAVIR), 0.3 for severe hepatic fibrosis (≥F3 METAVIR) and 0.4 for cirrhosis (F4 METAVIR). Hepa-Index was able to detect significant fibrosis with sensitivity of 69.4%, specificity of 76.3% and AUROC of 0.803. Hepa-Index was also able to detect severe hepatic fibrosis with sensitivity of 79.2%, specificity of 64.5% and AUROC of 0.783 and cirrhosis with sensitivity of 81.8%, specificity of 68.5% and AUROC of 0.744. Conclusion: Hepa-Index is a good non-invasive biomarkers panel that can be used for non-invasive assessment of hepatic fibrosis in chronic hepatitis C patients.

Impact of old Schistosomiasis infection on the use of transient elastography (Fibroscan) for staging of fibrosis in chronic HCV patients.

BACKGROUND AND AIM: In tropical regions, Hepatitis C virus (HCV) - Schistosomiasis coinfection remains one of the health problems. With the new era of HCV treatment and the variety of methods of assessment of liver fibrosis so we aimed to evaluate the effectiveness of FibroScan for staging hepatic fibrosis in HCV-Schistosomiasis coinfected patients. METHODOLOGY: Three groups of patients were enrolled. Group 1: chronic HCV with out antischistosomal antibody (122 patients), Group 2: chronic HCV with positive antischistosomal antibodies and without periportal tract thickening (122 patients), Group 3: chronic HCV with positive antischistosomal antibodies and ultrasonographic picture of periportal tract thickening (108 patients). Routine laboratory workup, serum Antischistosomal antibody, and Schistosomal antigen in serum were performed. Ultrasound guided liver biopsy with histopathological examination; abdominal ultrasound and fibroscan examination were done for all patients. RESULTS: The agreement between results of liver biopsy and results of fibroscan in the staging of fibrosis was the best in group 1 (55.7%), Although the agreement was higher among those with no periportal tract thickening (70.7%) and the disagreement was higher among those with positive schistosomal serology (66.5%), yet this relation was not statistically significant. Multivariate logistic regression analysis showed that disagreement is significantly associated with older age, higher BMI (≥30), and increase in anti Schistosomal antibody titer. CONCLUSION: Fibroscan is a reliable, non-invasive tool for staging hepatic fibrosis among HCV-schistosomiasis co-infected patients with no effect of the induced periportal tract thickening on the readings. Only higher antischistosomal antibody titres may cause disagreement between liver biopsy and fibroscan.

Identification of insulin gene variants in neonatal diabetes.

OBJECTIVES: Permanent neonatal diabetes (PNDM) is caused by mutations in the genes responsible for the synthesis of different proteins that are important for the normal behavior of beta cells in the pancreas. Mutations in the insulin gene (INS) are considered as one of the causes of diabetes in neonates. This study aimed to investigate the genetic variations in the INS gene in a group of Egyptian infants diagnosed with PNDM. METHODS: We screened exons 2 and 3 with intronic boundaries of the INS gene by direct gene sequencing in 30 PNDM patients and 20 healthy controls. A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found to carry an INS variant. RESULTS: We identified five variants (four SNPs and one synonymous variant), c(0).187 + 11T > C, c.-17-6T > A, c.*22A > C, c.*9C > T, and c.36G > A (p.A12A), with allelic frequencies of 96.7%, 80%, 75%, 5%, and 1.7%, respectively. All showed no statistically significance difference compared with the controls, with the exception of c.*22A > C. CONCLUSION: Genetic screening for the INS gene did not reveal an evident role in the diagnosis of PNDM.

Genetic Counseling in Primary Immunodeficiency Disorders: An Emerging Experience in Egypt.

BACKGROUND: Primary immunodeficiency disorders (PIDs) are a heterogeneous group of diseases of the immune system leading to life-threatening infections, and, unless urgently treated with immune reconstitution, patients do not usually survive. With the continuing progress in molecular diagnosis, many mutations have been described in more than 300 genes. Genetic counseling has recently been considered an essential part of the management of PIDs. This study presents the experience of genetic counseling services in the largest PID center in Egypt, and reports on our management plan and the impact of prenatal diagnosis (PND) on families. METHODS: Based on the biochemical and molecular diagnosis of index cases, PND was offered for 10 families in 12 subsequent pregnancies. Five different genes were sequenced by Sanger sequencing in fetal samples. RESULTS: Seven fetuses were either normal or were carriers, while five fetuses were affected and human leukocyte antigen typing was performed, seeking a suitably related donor for stem cell transplantation. CONCLUSION: In spite of the genetic heterogeneity behind PIDs, genetic counseling should play a critical role in the management and future decisions of affected families.

Interleukin 10 (- 1082 G/A) and (- 819 C/T) gene polymorphisms in Egyptian women with polycystic ovary syndrome (PCOS).

Cytokines play critical roles in the pathogenesis of Polycystic Ovarian Syndrome (PCOS). This work was designed to study the implication of IL10 gene polymorphisms (- 1082 G/A and - 819 C/T) on the susceptibility of Egyptian women to have PCOS. Rotterdam consensus criteria were used to diagnose PCOS patients. Genotyping was performed by single-stranded polymorphism-polymerase chain reaction (SSP-PCR) in 61 PCOS patients and 80 healthy controls, and IL-10 serum levels were measured using Enzyme linked immunosorbent assay (ELISA). The frequency of IL10 - 1082 G/G (46%) genotype was significantly increased (p < 0.001) while the frequency of - 1082 A/A (16%) genotype was significantly decreased (p < 0.05) in PCOS patients compared to controls (14% and 35% for G/G and A/A genotypes; respectively). G allele (65%) is significantly increased (p < 0.01( in PCOS patients while A allele (61%) is significantly increased (p < 0.001( in control subjects. The distribution of IL10 -819 T/T genotype was significantly increased (p < 0.05) in PCOS group. G/G genotype (odd ratio (OR = 5.322) with confidence interval (CI = 2.364-11.982) and the G allele (OR = 2.828 with CI = 1.73-4.61) of - 1082 G/A and T/T genotype of - 819 C/T (OR = 4.18 with CI = 1.26-13.86) could be considered as risk factors for PCOS. IL-10 levels were significantly lower among PCOS patients (313.42 ± 30.10) compared to normal controls (4914.36 ± 303.72). Depending on our preliminary work, IL10 - 1082 G/G might be considered as a host genetic factor for PCOS susceptibility in Egyptian women. Studies concerning other cytokine gene polymorphisms are required to get a better understanding of the pathogenesis of PCOS disease.

Egy-score as a noninvasive score for the assessment of hepatic fibrosis in chronic hepatitis C: a preliminary approach.

BACKGROUND AND AIMS: Egy-Score is a new noninvasive score for prediction of severe hepatic fibrosis in patients with chronic liver diseases. The aim of this study was to validate Egy-Score as a noninvasive score for predicting stage of hepatic fibrosis in a group of Egyptian chronic hepatitis C patients. PATIENTS AND METHODS: One hundred Egyptian patients with chronic hepatitis C were enrolled. Mean age was 40.25 ± 9.39 years. They were subjected to CA19-9, alpha-2-macroglobulin, total bilirubin, platelet count and albumin, liver biopsy, and histopathological staging of hepatic fibrosis according to METAVIR scoring system as part of their assessment for treatment. Egy-Score was calculated according to the following formula: Egy-Score = 3.52 + 0.0063 × CA19-9 + 0.0203 × age + 0.4485 × alpha-2-macroglobulin + 0.0303 × bilirubin - 0.0048 × platelet - 0.0462 × albumin. Egy-Score results were correlated to the stage of hepatic fibrosis. RESULTS: Egy-Score correlates positively with the stage of hepatic fibrosis (F0-F4). Egy-Score was able to differentiate significant hepatic fibrosis, severe hepatic fibrosis, and cirrhosis accurately. Cutoff values of Egy-Score were 2.91850 (for significant fibrosis), 3.28624 (for severe fibrosis), and 3.67570 (for cirrhosis). Sensitivity, specificity, and areas-under-ROC curve (AUROCs) were 75.8%, 68.42%, and 0.776 (for significant fibrosis "≥F2"), 91.67%, 77.63%, and 0.875 (for severe fibrosis "≥F3"), and 81.82%, 86.52%, and 0.874 (for cirrhosis "F4"), respectively. CONCLUSION: Egy-Score is a useful noninvasive panel of surrogate biomarkers that could accurately predict different stages of hepatic fibrosis in patients with chronic hepatitis C.

Gene mutations in Wilson disease in Egyptian children: report on two novel mutations.

BACKGROUND AND STUDY AIMS: Wilson disease (WD) is an autosomal recessive disorder, caused by defects in copper-transporting P-type adenosine triphosphatase (ATPase) encoded by the ATP7B gene, resulting in the deposition of copper in the liver and brain with significant disability or death if left untreated. An available regimen of treatment gives hope to those predisposed to the disease if diagnosed early. The objective of this study was to determine the frequency of the most common European mutation (p.H1069Q) in Egyptian children with WD, in addition to screening for previously reported mutations in the Egyptian patients in our selected group. PATIENTS AND METHODS: Direct DNA sequencing was applied to exons (13, 14, 18, and 19) of the ATP7B gene for 19 patients previously diagnosed with WD. Then DNA sequencing and pedigree analysis were performed in the families of the patients showing variations in their results for the purpose of family screening and carrier detection. Six out of 19 patients were studied with their families (three families). RESULTS: We identified five variants of which two were novel among the studied patients. One of the novel variants was synonymous substitution (p.A1074A) in 16% of patients and the other was predicted to be missense disease-causing mutations (p.T1076I) in 16% of patients, and three previously published mutations p.H1069Q were detected in 5% of patients, p.P1273Q in 10% of patients, and a silent variant p.A1003A in 26% of patients. CONCLUSION: Screening for the two exons 14 and 18 of the ATP7B gene is important in Egyptian patients especially in suspected patients without hepatic manifestations.