Wilson’s disease in Lebanon and regional countries: Homozygosity and hepatic phenotype predominance

Abstract

AIMTo determine the phenotypes and predominant disease-causing mutations in Lebanese patients with Wilson’s disease, as compared to regional non-European data.METHODSThe 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.RESULTSPatients 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.CONCLUSIONFindings do not support presence of a founder effect. Clinical and genetic screening is recommended for family members with index patients and unexplained hepatic dysfunction.

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants

“…In addition, we failed to detect any disease‐causing mutations in one of our clinically diagnosed patients (P025), with only “benign” SNPs being found in the ATP7B gene. Similar cases have been reported recently, albeit rarely (Barada, El Haddad, Katerji, Jomaa, & Usta, ). One hypothesis regarding this is that there may be a second gene responsible for WD, although evidence on such pathogenic variants in other genes involved in copper decompensation has not been reported for large cohorts (N. Forbes et al, ; Lovicu et al, ).…”

Early Diagnosis of Wilson’s Disease in Children in Southern China by Using Common Parameters

“…Thus, we propose that the combined detection of elevated ALT, decreased ceruloplasmin level, and increased 24-h urinary copper level can be useful for an early diagnosis of WD in about 5-year-old asymptomatic children in southern China. In recent years, some researchers thought that genetic screening following serum CP testing reduced costs and facilitated prioritization of non-invasive methods for definitive diagnosis, as well as in asymptomatic or family history cases ( Barada et al, 2017 ; García-Villarreal et al, 2021 ). Furthermore, other researchers believed that the serum CP level, 24-h urinary copper excretion, and K–F rings could be used to identify patients with WD ( Dong et al, 2021 ).…”

Wilson’s disease clinic at the Assiut Liver Center in Egypt: a real well-established step on the way

“…Most patients from Egypt and Saudi Arabia consistently show a high prevalence of consanguinity and homozygosity. Lebanese and Egyptian patients share missense mutations in exons 8, 10, 18, and 19 [9][10][11][12]. The predominant phenotype of WD in the region was also hepatic, suggesting the benefits of screening for WD in patients with unexplained hepatic dysfunction.…”