Aberrant copper metabolism and hepatic inflammation cause neurological manifestations in a mouse model of Wilson's disease.

Pathogenic germline mutations in the P-type copper-transporting ATPase (ATP7B) gene cause Wilson's disease (WD), a hereditary disorder characterized by disrupted copper metabolism. The Arg778Leu (R778L) mutation in exon 8 is prevalent among individuals with WD in East Asia and is associated with more severe phenotypes. In this study, we generated a WD mouse model harboring R778L mutation (R778L mice) using CRISPR/Cas9. R778L mice exhibit a range of pathological characteristics resembling those of patients with WD and the same point mutations, including aberrant copper metabolism, pathological cellular injury, inflammation, and severe hepatic fibrosis. At 3-5 months of age, these mice started to display neurological deficits in motor coordination and cognitive dysfunction, accompanied by increased expression of inflammatory cytokines in the central nervous system. Microglia in the striatum and cortex exhibit significant activation, shorter processes, and decreased branch points. However, the Cu2+ levels in the brain tissue of R778L mice did not differ significantly from those of wild-type mice. Notably, inhibition of hepatic inflammation with PJ34 or siNfkb markedly alleviated the deficiencies in cognitive performance and improved locomotor activity in R778L mice. Thus, this study establishes a novel murine model to investigate the pathophysiology of WD, highlights the liver-brain crosstalk responsible for neurological manifestations in individuals with WD caused by the R778L point mutation, and demonstrates the potential of modulating liver inflammation as a therapeutic strategy for alleviating the neurological manifestations of WD.

[Genotype-phenotype relationship and genetics study of 115 cases with Wilson's disease].

Objective: To explore the genotype-phenotype relationship of Wilson's disease (WD) and further study the mutation spectrum in the ATP7B gene. Methods: The clinical data and genetic test results of 115 cases with WD diagnosed in the First Affiliated Hospital of Zhengzhou University from 2015 to 2022 were retrospectively analyzed. The rank sum test was used for quantitative data comparison, and χ(2) test was used for count data comparison. Multivariate logistic regression was used to analyze the relationship between patients' genotype and phenotype. Results: The onset of liver manifestations (hepatic type) accounted for 60.9%, neurological symptoms (cerebral type) for 13.0%, and mixed hepato-cerebral symptoms for 26.1%. Presymptomatic individuals (hepatic types) accounted for 62.9%. Next-generation sequencing- diagnosed WD cases accounted for 87.8%. Combined multiplex ligation-dependent probe amplification assay-diagnosed WD cases accounted for 89.6%. A single case with a detected pathogenic locus accounted for 10.4%. The diagnostic rate of WD by genetic testing combined with clinical data was 100%. A total of 76 ATP7B mutations were detected, and the top three mutation frequencies were c.2333G>T (p.Arg778Leu) (30.7%), c.2975C>T (p.Pro992Leu) (7.3%), and c.2621C>T (p.Ala874Val) (6.4%). The mutations were mainly distributed in exons 8, 11-13, and 15-18, accounting for more than 90% of the total mutations. Eight new mutations were found, including c.3724G>A (p.Glu1242Lys), c.3703G>C (p.Gly1235Arg), c.3593T>C (p.Val1198Ala), c.2494A>C (p.Lys832Gln), c.1517T>A (p.Ile506Lys), c.484G>T (p.Glu162Ter), c.1870-49A>G, and the missing of exons 10-21. Liver histopathology showed cellular edema, degeneration, inflammation, and necrosis, as well as a 42.8% copper staining positive rate. Genotype-phenotype analysis showed that the p.Arg778Leu mutation had higher alanine aminotransferase (ALT) levels than those carrying other mutations (P=0.024), while the homozygous mutation of p.Arg778Leu was associated with cerebral-type patients (P=0.027). Conclusion: Genetic testing plays an important role in the diagnosis of WD. p.Arg778Leu is the first high-frequency mutation in the Chinese population, and patients carrying it have higher ALT levels. The p.Arg778Leu homozygous mutation is prone to causing cerebral-type WD. This study expands the ATP7B gene mutation spectrum.

Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease.

AIM: To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. METHODS: One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group. RESULTS: In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype-genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. CONCLUSION: In this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

Genotype-phenotype variable correlation in Wilson disease: clinical history of two sisters with the similar genotype.

BACKGROUND: Wilson disease (WD) is an Autosomal-Recessive disorder due to mutations of ATP7B gene on chromosome 13q14.3. Inadequate protein function leads to low ceruloplasmin blood levels and copper accumulation in liver, basal ganglia and chornea. Main clinical manifestations are hypertransaminasemia, tremors, dysarthria, dystonia and psychiatric symptoms. The phenotypic variability in WD is considerable and its onset can be heterogeneous: the most common type in childhood is the hepatic involvement, followed by the neurological one or others. The presence of a genotype-phenotype correlation has not yet been fully demonstrated. The phenotypic variability may be explained by the intervention of other modifier genes regulating copper metabolism in the presence of mutations ATP7B. CASE PRESENTATION: A streaking phenotypic variability was observed in two Sicilian sisters carrying the same genotype for ATB7B gene [c.3207C > A / c.3904-2A > G]. Although both started to present signs at age 10 years, onset was characterized by neurological signs in the first (tremors, motor incoordination, language and cognitive impairment), while liver involvement has been the only sign in the other. They started the same chelation therapy. After a 20-year follow-up the former is severely affected (MRI evidence of basal ganglia copper deposits and hyperchogenic liver, thrombocytopenia), while the latter presents only a moderate liver enlargement. In literature, the splice mutation c.3904-2A > G is also reported in Egypt population, associated with acute liver failure or chronic hepatic disease, and it could be typical of Mediterranean area, not being reported in other geographical zones. CONCLUSION: Based on our clinical experience in Eastern Sicily, there is a considerable phenotypic variability in WD, even in the presence of an identical genotype. The mutation c.3904-2A > G could be associated with this phenotypic variability in Mediterranean population, but further studies should be conducted. This condition could be explained by the intervention of modifier genes regulating copper metabolism in the presence of defective ATP7B protein function. Further investigations on their role by Next Generation Sequencing or Whole Exome Analysis might have a profound impact on patients' management and in particular on therapy.

Genetics of Wilson disease and Wilson-like phenotype in a clinical series from eastern Spain.

Wilson's disease (WD) is an autosomal recessive disorder caused by ATP7B mutations. Subjects with only one mutation may show clinical signs and individuals with biallelic changes may remain asymptomatic. We aimed to achieve a conclusive genetic diagnosis for 34 patients clinically diagnosed of WD. Genetic analysis comprised from analysis of exons to WES (whole exome sequencing), including promoter, introns, UTRs (untranslated regions), besides of study of large deletions/duplications by MLPA (multiplex ligation-dependent probe amplification). Biallelic ATP7B mutations were identified in 30 patients, so that four patients were analyzed using WES. Two affected siblings resulted to be compound heterozygous for mutations in CCDC115, which is involved in a form of congenital disorder of glycosylation. In sum, the majority of patients with a WD phenotype carry ATP7B mutations. However, if genetic diagnosis is not achieved, additional genes should be considered because other disorders may mimic WD.

[Mutational analysis of ATP7B gene of hepatolenticular degeneration in Xinjiang region].

Objective: To understand the mutational characteristics of ATP7B gene of hepatolenticular degeneration in Xinjiang region. Methods: 24 cases were diagnosed as hepatolenticular degeneration and the exon of ATP7B gene was detected in some of their siblings and parents. Results: A total of 45 ATP7B gene mutations (93.75%) were detected in 24 cases, of which 14 cases were homozygous mutations or compound heterozygous mutations, six cases were heterozygous mutations and four cases were no mutations. A total of 24 gene mutations and 14 SNPS were detected, including 8 new mutations: c.251C > A, c.121A > c, c.2945C > A, c.2194C > T, c.2947T > c, c.3626T > A, c.3662_3664del, c.3557G > T. The most common mutations were c.2621C > T (p.A874V) [16.7% (4/24)] and c.2333G > T (p.R778L) [12.5% ​​(3/24)]. A total of 4 cases were diagnosed as pre-symptomatic. Conclusion: In this study, the most common mutation in the ATP7B gene is A874V. The most common genetic mutations in Han and Uyghur patients were different. The most common mutation in Han and Uyghur patients is R778L and A874V. Exon 11 is the gene mutations hot spot for patients with hepatolenticular degeneration in Xinjiang region, and is one of the priority exons to be detected when screening patients with suspected hepatolenticular degeneration.

Clinical features and mutational analysis in 114 young children with Wilson disease from South China.

Wilson disease (WD) is a rare autosomal recessive disorder caused by mutations in the ATP7B gene. Clinical features and mutational analysis of Chinese children with WD at early age were rarely described. Herein, we retrospectively examined 114 children with WD at the mean of 5.9 years old age at diagnosis. Eight patients developed acute liver failure at mean age of 9.7 years old, 4 of whom died. Among the 114 patients, 86.0% were presymptomatic with isolated elevation of transaminases at diagnosis, 99.1% had decreased ceruloplasmin, and 68.4% had urinary copper excretion over 100 µg/24 hr. Bi-allele pathogenic ATP7B mutations were identified in all patients. Among the 60 mutations detected, 10 were novel, including 7 missense mutations (p.I566N, p.T704I, p.C980F, p.G1030 V, p.A1096Q, p.L1327P, and p.L1373F), 1 nonsense mutation (p.K866X), 1 small insertion (p.Y44LfsX2), and 1 small deletion (p.R1118PfsX10). The most frequent mutations were p.R778L, p.P992L, and p.I1148T, which affected 27.2, 25.4, and 20.2% of the 114 WD children, respectively. The patients carrying p.R778L presented a higher rate of acute liver failure than the patients without p.R778L (9.7% vs. 4.8%). These results will be helpful in establishing early diagnosis of WD at the gene level, offering beneficial information for genetic counseling and providing clues to genotype/phenotype correlation of ATP7B mutations.

Mutation Analysis of the ATP7B Gene in Seven Chinese Families with Wilson's Disease.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive disease, which is characterized by an excessive copper accumulation in the liver and brain, leading to subsequent hepatic and/or neurological disorders. The causative gene for WD has been identified as the ATPase Cu2+ transporting beta polypeptide gene (ATP7B), which encodes a protein called copper-transporting ATPase 2. ATP7B mutations may lead to reduced biliary excretion of excess copper and disrupted copper homeostasis, resulting in various clinical symptoms of WD. METHODS: Direct sequencing of the ATP7B gene was performed in 7 Han Chinese families with WD, and haplotype analysis was conducted in families having the same mutation. RESULTS: Nine ATP7B gene mutations were identified, including 7 missense mutations (p.Asp765Gly, p.Arg778Leu, p.Thr888Pro, p.Pro992Leu, p.Asp1047Val, p.Ile1148Thr and p.Ala1295Val), 1 duplication mutation (c.525dupA), and 1 nonsense mutation (p.Gly837*). Combined with our previous data, haplotype analysis revealed that the founder effect accounted for 48% of alleles in Han Chinese, constituted by high allele frequency mutations p.Arg778Leu, p.Pro992Leu and p.Ala1295Val. CONCLUSION: This study revealed genetic defects of 7 Han Chinese families with WD, and has implications for their genetic counseling and clinical management.

Three novel mutations in the ATP7B gene of unrelated Vietnamese patients with Wilson disease.

BACKGROUND: Wilson disease (OMIM # 277900) is a autosomal recessive disorder characterized by accumulation of copper in liver and brain. The accumulation of copper resulting in oxidative stress and eventually cell death. The disease has an onset in a childhood and result in a significant neurological impairment or require lifelong treatment. Another serious consequence of the disease is the development of liver damage and acute liver failure leading to liver transplant. The disorder is caused by mutations in the ATP7B gene, encoding a P-type copper transporting ATPase. CASE PRESENTATION: We performed genetic analysis of three unrelated patients from three different Vietnamese families. These patients had clinical features such as numbness of hands and feet, vomiting, insomnia, palsy, liver failure and Kayser-Fleischer (K-F) rings and were diagnosed with Wilson disease in the Human Genetics Department, Vietnam National Children's Hospital. The entire coding region and adjacent splice sites of ATP7B gene were amplified and sequenced by Sanger method. Sequencing data were analyzed and compared with the ATP7B gene sequence published in Ensembl (ENSG00000123191) by using BioEdit software to detect mutations. CONCLUSIONS: In this study, five mutations in the ATP7B gene were found. Among of these, three mutations were novel: c.750_751insG (p.His251Alafs*19) in exon 2, c.2604delC (p.Pro868Profs*5) in exon 11, and c.3077 T > A (p.Phe1026Tyr) in exon 14. Our results of the mutations associated with Wilson disease might facilitate the development of effective treatment plans.

Presumed missense and synonymous mutations in ATP7B gene cause exon skipping in Wilson disease.

BACKGROUND & AIMS: Wilson disease is an inborn error of metabolism caused by abnormalities of the copper-transporting protein-encoding gene ATP7B. Recently, the phenomenon of exon skipping, in which exonic mutations result in abnormal splicing, has been associated with various diseases. The present study investigated the splicing defects of the ATP7B exonic variants identified in a cohort of 44 patients with Wilson disease. METHOD: All patients were analysed for ATP7B gene by direct sequencing or multiplex ligation-dependent probe amplification analysis. To identify the potential pathogenicity of the candidate mutations that may induce exon skipping, both in vivo RT-PCR analysis using RNA from peripheral leukocytes and in vitro functional splicing by minigene construction were conducted. RESULTS: The patterns of inheritance of the mutations in ATP7B identified in 44 patients exhibited homozygotes (7 patients), compound heterozygotes (32 patients) and heterozygotes (5 patients). In all patients, we detected 25 different ATP7B mutations, including 17 missenses, 1 frameshift, 3 nonsenses, 2 exonic deletions and 2 splicing alteration. In these mutations, 4 mutations have not been previously described in the literature or entered in human genome mutation database. Furthermore, we identified synonymous mutation c.4014T>A and missense mutation R919G caused exon skipping in the ATP7B mRNA transcript. CONCLUSION: Our results suggest that aberrant exon skipping associated to putative splicing enhancer disruption and silencer creation is one previously unrecognized mechanism in Wilson disease. What is more, the multiplex ligation-dependent probe amplification assay for the detection of exon deletions may be valuable in individuals with clinical Wilson disease diagnosis where one or no mutation has been identified by sequencing.

Molecular genetic diagnosis of Wilson disease by ARMS-PCR in a Pakistani family.

Wilson disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene causing hepatic and neurological damage due to copper accumulation. Early diagnosis and treatment could lead to improved survival of patients. Patients are best treated at pre-symptomatic stages but early diagnosis of Wilson disease is challenging owing to complex diagnosis. Evidence based genetic counseling requires characterization of underlying mutations in Wilson disease families. The aim was to characterize the causative mutation(s) in a Pakistani Wilson disease family by custom developed ARMS-PCR assay. A proband (19 years old boy) having Wilson disease with evidence of K-F ring, severe neurological and psychiatric manifestations and clinical findings supported by biochemical abnormalities was followed. Following screening for 12 putative mutations in ATP7B, we identified a homozygous mutation (p.Cys271*, c.813C > A) in proband by T-ARMS-PCR assay and validated by Sanger DNA sequencing. Furthermore, on screening of his family members, a younger sister (aged 9 years) was found to have the same homozygous mutation even though she was clinically asymptomatic except for a light K-F ring. Parents were heterozygous for this mutation and an elder brother was homozygous normal. Molecular diagnosis by PCR based assays (M-ARMS-PCR and T-ARMS-PCR) is cost effective, reliable, and efficient for preliminary screening of mutations in the ATP7B gene in developing countries like Pakistan, which can be successfully applied to Wilson disease families for genetic testing and follow-up evidence based genetic counseling.

A special case of recurrent gross hematuria: Answers.

Wilson's disease (WD) is an autosomal recessive disorder, and has a variety of presentations. We reported a case of 9-year-old girl who presented with a history of recurrent gross hematuria, renal histological changes of IgA nephropathy, and finally had been confirmed to be Wilson's disease-associated IgA nephropathy.

Age-dependent changes of cerebral copper metabolism in Atp7b -/- knockout mouse model of Wilson's disease by [64Cu]CuCl2-PET/CT.

Copper is a nutritional metal required for brain development and function. Wilson's disease (WD), or hepatolenticular degeneration, is an inherited human copper metabolism disorder caused by a mutation of the ATP7B gene. Many WD patients present with variable neurological and psychiatric symptoms, which may be related to neurodegeneration secondary to copper metabolism imbalance. The objective of this study was to explore the feasibility and use of copper-64 chloride ([64C]CuCl2) as a tracer for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD using an Atp7b -/- knockout mouse model of WD and positron emission tomography/computed tomography (PET/CT) imaging. Continuing from our recent study of biodistribution and radiation dosimetry of [64C]CuCl2 in Atp7b -/- knockout mice, PET quantitative analysis revealed low 64Cu radioactivity in the brains of Atp7b -/- knockout mice at 7th weeks of age, compared with 64Cu radioactivity in the brains of age- and gender-matched wild type C57BL/6 mice, at 24 h (h) post intravenous injection of [64C]CuCl2 as a tracer. Furthermore, age-dependent increase of 64Cu radioactivity was detected in the brains of Atp7b -/- knockout mice from the 13th to 21th weeks of age, based on the data derived from a longitudinal [64C]CuCl2-PET/CT study of Atp7b -/- knockout mice with orally administered [64Cu]CuCl2 as a tracer. The findings of this study support clinical use of [64Cu]CuCl2-PET/CT imaging as a tool for noninvasive assessment of age-dependent changes of cerebral copper metabolism in WD patients presenting with variable neurological and psychiatric symptoms.

Screening of Wilson's disease in a psychiatric population: difficulties and pitfalls. A preliminary study.

BACKGROUND: Wilson's disease (WD) is a rare autosomal-recessive, inherited disorder caused by a mutation in the copper-transporting gene ATP7B affecting the liver and nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and diagnosis can be difficult to establish. The objectives of the present preliminary study were [1] to evaluate the relevance of serum copper (Cu) and ceruloplasmin (Cp) measures in hospitalized patients with psychiatric disorders; and [2] to identify possible mutations in the ATP7B gene in patients with abnormal biological copper profile. METHODS: All psychiatric patients who participated in this study were hospitalized in Saint-Jean de Dieu Hospital (Lyon, France). Cp was measured by immunoturbidimetry and serum Cu by inductively coupled plasma-optical emission spectrometry. When Cp and serum Cu levels were inferior to, respectively, 0.18 g/L and 0.88 mg/L in combination with atypical psychiatric presentations, complete clinical examinations were performed by multidisciplinary physicians specialized in WD. In addition, mutation detection in the ATP7B gene was performed. RESULTS: A total of 269 patients completed the study. (1) 51 cases (19%) showed both decreased Cp and Cu concentrations. (2) Molecular genetic tests were performed in 29 patients, and one ATP7B mutation (heterozygous state) was found in four patients. We identified three different missense mutations: p.His1069Gln, c.3207C>A (exon 14), p.Pro1379Ser, c.4135C>T (exon 21) and p.Thr1434Met, c.4301C>T (exon 21). No pathogenic mutation on either ATP7B allele was detected. CONCLUSION: Results of Cp and/or serum Cu concentrations below the normal limits are common in patients with psychiatric disorders and nonrelevant and/or informative for the WD diagnosis. WD diagnosis is based on a combination of clinical and biological arguments. Psychiatric patients with suspicion of WD should be evaluated in a reference center. Trial registration CPP Lyon Sud-Est IVNo 10/044, CNIL No DR-2011-470, Afssaps No B100832-40 and CCTIRS No 10.612 bis, registered 8 June 2010.

[Complexity of the diagnosis of Wilson disease in clinical practice: our experience in 15 patients]. / Dificultades en el diagnóstico de los pacientes con enfermedad de Wilson en la práctica clínica: experiencia de 15 casos.

BACKGROUND: Wilson disease (WD) is an inherited disorder that causes copper (Cu) accumulation, leading to mainly liver, neurological and/or psychiatric manifestations. In the absence of some of the typical features, diagnosis of WD is difficult and is based on the combination of clinical, biochemical and genetic testing. The aim of this study was to illustrate the complexity of the approach to WD in daily clinical practice. METHODS: We retrospectively analyzed the medical records of patients with WD, including the clinical presentation, histological and biochemical findings, and follow up after treatment. We also carried out genetic testing, and the Leipzig diagnostic score was applied. RESULTS: We included 15 patients. Four were symptomatic, with liver (n=1), neurological (n=1), psychiatric (n=1) and mixed clinical manifestations (n=1), and 11 were presymptomatic, with elevated transaminases (n=8) and family study (n=3). We observed Kayser-Fleischer ring in 2 patients, both without neurologic symptoms. Ceruloplasmin ≤ 5 mg/dL was present in 73%, and 24-hour urinary Cu> 100 µg in 40%. Liver Cu was >250 µg/g.d.t. in 85% of the patients. The final diagnosis of WD was given by genetic testing (ATP7B gene mutations) in 5 patients with minimal disease features, including one symptomatic patient (psychiatric symptoms). We identified 5 previously reported mutations (p.M645R, p.R827W, p.H1069Q, p.P768L and p.G869R) and 3 unpublished mutations (p.L1313R, p.I1311T and p.A1179D); the most frequent mutation was p.M645R. After treatment, biochemical parameters (transaminases, urinary cooper) and symptoms improved, except in patients with neurological and psychiatric manifestations. CONCLUSIONS: Our series illustrates the important role of genetic testing in the diagnosis of WD. The identification of the p.M645R mutation in most of our patients should be kept in mind in the molecular analysis of the ATP7B gene in our region.

Late-onset Wilson Disease in a Patient Followed-up for Nonalcoholic Fatty Liver Disease.

A 73-year-old woman was referred to our hospital for persistent liver dysfunction. When the patient was 45 years old, her youngest sister had been diagnosed with Wilson disease (WD). The patient therefore underwent several family screening tests, all of which were unremarkable. She had an annual medical checkup and was diagnosed with liver dysfunction and fatty liver at 68 years old. A liver biopsy and genetic testing were performed, and she was diagnosed with WD; chelation therapy was then initiated. In patients with hepatic disorders and a family history of WD, multiple medical examinations should be conducted, as the development of WD is possible regardless of age.

A Case of Wilson's Disease Suspected to Involve a Novel Genetic Mutation of ATP7B Gene, Requiring a Differential Diagnosis with Non-alcoholic Steatohepatitis.

A 19-year-old Japanese man was referred for a further evaluation of liver dysfunction. Despite the absence of symptoms or obesity, the liver biopsy results were consistent with non-alcoholic steatohepatitis. Subsequent investigations revealed low serum ceruloplasmin, increased urinary copper excretion, and a known mutation c.3809A>G (p.Asn1270Ser) in the copper-transporting enzyme P-type ATPase (ATP7B) gene, leading to a diagnosis of Wilson's disease. A previously unreported variant, i.e., c.3866A>T (p.Asp1289Val) was detected on the patient's other allele and was considered a novel mutation, classified as 'likely pathogenic' according to the American College of Medical Genetics guidelines.

Phenotype and molecular characterization of Wilson's disease in Morocco.

BACKGROUND AND STUDY AIMS: In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients. PATIENTS AND METHODS: We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing. RESULTS: The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 µg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation. CONCLUSION: In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.

Copper Conundrum: Navigating Atypical Wilson's Disease Through Radiological Insights.

Wilson's disease is a rare genetic disorder characterized by abnormal copper metabolism due to mutations in the ATP-7B gene. This case report details the presentation of a 14-year-old male child exhibiting severe generalized dystonia, rigidity, myoclonic jerks, dysarthria, and excessive salivary drooling. During ophthalmic examination, Kayser-Fleischer rings were identified. Symmetrical hyperintensities in cortical and subcortical areas, including the basal ganglia and brainstem, were noted on brain magnetic resonance imaging (MRI). Additionally, diffusion restriction in the bilateral fronto-parietal region was observed. The diagnosis of Wilson's disease was confirmed through further diagnostic assessments, such as serum ceruloplasmin levels and urine copper excretion. Treatment was initiated with penicillamine, anticonvulsants, and supportive measures, resulting in partial recovery after a three-month follow-up period. This case emphasizes the significance of identifying atypical MRI brain findings in Wilson's disease, which aids in early diagnosis and appropriate management to prevent irreversible neurological damage.