Dataset Information

Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients.

ABSTRACT:

Background

Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the ATP7B gene. WD is characterized by heterogeneous clinical presentations expressed by hepatic and neuropsychiatric phenotypes. The disease is difficult to diagnose, and misdiagnosed cases are commonly seen.

Methods

In this study, the presented symptoms of WD, the biochemical parameters as well as its natural history are described based on cases collected in Mohammed VI Hospital University of Marrakech (Morocco). We screened and sequenced 21 exons of ATP7B gene from 12 WD patients that confirmed through biochemical diagnosis.

Results

Mutational assessment of the ATP7B gene showed six homozygous mutations in 12 individuals however, 2 patients had no evidence of any mutation in promoter and exonic regions. All mutations are pathogenic and most were missense mutations. c.2507G > A (p.G836E), c.3694A > C (p.T1232P) and c.3310 T > C (p.C1104R) that were identified in 4 patients. The other mutations were a non-sense mutation (c.865C > T (p.C1104R)) detected in 2 patients, a splice mutation (c.51 + 4A > T) detected in 2 patients and a frameshift mutation (c.1746 dup (p.E583Rfs*25) detected in 2 patients.

Conclusion

Our study is the first molecular analysis in Moroccan patients with Wilson's disease, the ATP7B mutational spectrum in the Moroccan population is diverse and still unexplored.

SUBMITTER: Lafhal K

PROVIDER: S-EPMC10267639 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients.

Lafhal Karima K Sabir Es-Said ES Hakmaoui Abdelmalek A Hammoud Miloud M Aimrane Abdelmohcine A Najeh Samira S Assiri Imane I Berrachid Abdelaati A Imad Najwa N Boujemaa Chaima Ait CA Aziz Faissal F El Hanafi Fatima Zahra FZ Lalaoui Abdessamad A Aamri Hasna H Boyko Iryna I Sánchez-Monteagudo Ana A Espinós Carmen C Sab Imane Ait IA Aboussair Nisrine N Bourrahouat Aicha A Fdil Naima N

Molecular genetics and metabolism reports 20230607

<h4>Background</h4>Wilson Disease (WD) is an autosomal recessive inherited metabolic disease caused by mutations in the <i>ATP7B</i> gene. WD is characterized by heterogeneous clinical presentations expressed by hepatic and neuropsychiatric phenotypes. The disease is difficult to diagnose, and misdiagnosed cases are commonly seen.<h4>Methods</h4>In this study, the presented symptoms of WD, the biochemical parameters as well as its natural history are described based on cases collected in Mohamme ...[more]

PMID: 37323222

Similar Datasets

Project description:BackgroundWilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations.MethodsA total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype-phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms.ResultsWe identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele frequency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 different variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation; high age-at-onset was a factor associated with tremor; and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V genotype displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype.ConclusionsOur work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.

Project description:Background: Wilson's disease (WD) is an autosomal recessive disease that is caused by mutations in the ATP7B (a copper-transporting P-type ATPase) gene. The disease has a low prevalence and is characterized by a copper metabolism disorder. However, various characteristics of the disease are determined by race and geographic region. We aimed to discover novel ATP7B mutations in pediatric patients with WD from Yunnan province, where there is a high proportion of ethnic minorities. We also performed a comprehensive analysis of ATP7B mutations in the different ethnic groups found in Southwest China. Methods: We recruited 45 patients who had been clinically diagnosed with WD, from 44 unrelated families. Routine clinical examinations and laboratory evaluations were performed and details of age, gender, ethnic group and symptoms at onset were collected. Direct sequencing of the ATP7B gene was performed in 39 of the 45 patients and their families. Results: In this study, participants came from seven different ethnic groups in China: Han, Bai, Dai, Zhuang, Yi, Hui and Jingpo. Three out of ten patients from ethnic minorities presented with elevated transaminases, when compared to the majority of the Han patients. Forty distinct mutations (28 missense, six splicing, three non-sense, two frameshift and one mutation of uncertain significance) were identified in the 39 patients with WD. Four of the mutations were novel and the most frequent mutation was c.2333G > T (p.R778L, allelic frequency: 15.38%). Using the phenotype-genotype correlation analysis, patients from ethnic minorities were shown to be more likely to have homozygous mutations (p = 0.035) than Han patients. The patients who carried the c.2310C > G mutation had lower serum ceruloplasmin levels (p = 0.012). In patients with heterozygous mutations, c.3809A > G was significantly associated with ethnic minorities (p = 0.042). The frequency of a protein-truncating variant (PTV) in Han patients was 34.38% (11/32), while we did not find PTV in patients from ethnic minorities. Conclusion: This study revealed genetic defects in 39 pediatric patients with WD from Yunnan province. Four novel mutations were identified and have enriched the WD database. We characterized the genotypes and phenotypes in different minorities, which will enhance the current knowledge on the population genetics of WD in China.

Project description:Glutaric acidemia type 1 (GA1) is an inherited metabolic autosomal recessive disorder that is caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Untreated patients suffer primarily from severe striatal damage. More than 250 variants in the GCDH gene have been reported with a variable frequency among different ethnic groups. In this study, we aimed to characterize 89 Egyptian patients with GA1 and identify the variants in the 41 patients who were available for genotyping. All of our patients demonstrated clinical, neuroradiological, and biochemical characteristics that are consistent with a diagnosis of GA1. All patients presented with variable degrees of developmental delay ranging from mild to severe. Most of the 89 patients presented with acute onset type (71.9%), followed by insidious (19%) and asymptomatic (9%). A delay in diagnosis was inversely associated with macrocephaly. The prevalence rate ratio (PR) for macrocephaly that was associated with each 6-month delay was 0.95 (95%CI 0.91-0.99). However, high body weight was associated with a higher likelihood of having macrocephaly (PR 1.16, 95%CI 1.06-1.26 per 1 SD increment of Z score weight). However, body weight was inversely associated with the morbidity score. Consanguinity level was 64% among our patient's cohort and was positively associated with the C5DC level (β (95%CI) 1.06 (0.12-1.99)). Forty-one patients were available for genotyping and were sequenced for the GCDH gene. We identified a total of 25 variants, of which the following six novel variants were identified: three missense variants, c.320G > T (p.Gly107Val), c.481C > T (p.Arg161Trp) and c.572 T > G (p.Met191Arg); two deletions, c.78delG (p.Ala27Argfs34) and c.1035delG (p.Gly346Alafs*11); and one indel, c.272_331del (p.Val91_Lys111delinsGlu). All of the novel variants were absent in the 300 normal chromosomes. The most common variant, c.*165A > G, was detected in 42 alleles, and the most commonly detected missense variant, c.1204C > T (p.Arg402Trp), was identified in 29 mutated alleles in 15/41 (34.2%) of patients. Our findings suggest that GA1 is not uncommon organic acidemia disease in Egypt; therefore, there is a need for supporting neonatal screening programs in Egypt.

Dataset Information

Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients.

Background

Methods

Results

Conclusion

Publications

Clinical, biochemical and molecular characterization of Wilson's disease in Moroccan patients.

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