SEARCHNARRATIVE_REVIEWneurology, gastroenterology

narrative_review·neurology, gastroenterology, genetics, epidemiology, public health·PMC10889319

Epidemiology of Wilson’s Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions

International Journal of Molecular Sciences · 4 authors, 2 centres

AI SUMMARY

FIDELITY 96%

This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.

AGENT 01 · STRUCTURED SUMMARY

TRACE TO SOURCE

“

TL;DR

This review shows that the prevalence of Wilson’s disease (WD) has increased dramatically worldwide, from 0.4–2.9 per 100,000 in the late 20th century to as high as 36.6 per 100,000 in Sardinia and 14.2 per 100,000 in the UK, largely due to improved molecular diagnostics. Over 900 pathogenic variants in the ATP7B gene have been identified, with the p.His1069Gln variant predominating in Europe and America (e.g., 72% in Poland, 63% in East Germany) but varying by ethnicity and geography. These findings underscore the need for wider, cost-effective genetic screening to improve early diagnosis and reduce disability from this treatable disorder.

Full summary

3,406 CHARS

**Background** Wilson’s disease (WD) is a severe autosomal recessive disorder caused by excessive copper accumulation due to pathogenic variants in the ATP7B gene. It presents with a wide age of onset (3–74 years) and diverse symptoms, primarily hepatic and neuropsychiatric. Historically considered rare, with prevalence estimates of 1–3 per 100,000, recent data suggest much higher rates. This review summarizes current epidemiological findings and the molecular basis of ATP7B dysfunction.

**Methods** This is a narrative review of published epidemiological studies and molecular genetic data on WD. The authors compiled prevalence figures from multiple countries and time periods, and catalogued the frequency of specific ATP7B pathogenic variants across populations. They also reviewed the structure and function of the ATP7B protein and the impact of different mutation types.

**Key Results** - Prevalence has increased markedly: in Scotland from 0.4:100,000 (1989) to 14.2:100,000 in the UK (2013); in Ireland from 0.67:100,000 (1971) to 9.0:100,000 (2011); in Sardinia from 2.9:100,000 (1983) to 36.6:100,000 (2013); in the USA from 2:100,000 (2001) to 6.34:100,000 (2006–2011); in Korea 13:100,000 (2017). - In Russia, official prevalence is 0.4:100,000, but regional studies show 1.5:100,000 (Khabarovsk), 4:100,000 (Udmurt), and 5.6–6.5:100,000 (Primorsky). - Over 900 different ATP7B pathogenic variants have been identified. The most common missense variant, p.His1069Gln (c.3207C>A), shows high frequency in Eastern Europe: Poland 72%, Lithuania 69.2%, Czech Republic 57%, East Germany 63%, Belarus 61%, Latvia 52.2%, Ukraine 100% (50% homozygous). In Russia, its allelic frequency is 35–50%, varying by ethnicity (Russians 55.5%, Tatars 38.9%, Bashkirs 44.4%, Chuvash 83.3%). - Other population-specific variants include p.Met645Arg in Spain, p.Arg778Leu in East Asia (China 31%, Korea 37.9%, Japan 16.7%), c.-441_-427del in Sardinia (92%), and p.Ala1135GlnfsTer13 in Brazil (11.4%) and Venezuela (26.9%). - Carrier frequency of ATP7B pathogenic variants is high: 1:25 in the UK, 1:31 in France, 1:53 in Korea, 1:43 in Russia, and 1:793 in Hong Kong adolescents. This contrasts with much lower clinical prevalence, suggesting underdiagnosis. - The ATP7B protein has six metal-binding domains, eight transmembrane segments, and domains for ATP binding (N), phosphorylation (P), and activation (A). Pathogenic variants can cause complete or partial loss of function by affecting copper binding, ATP hydrolysis, protein folding, or intracellular trafficking. For example, p.His1069Gln prevents proper folding and Golgi localization, leading to moderate neuropsychiatric disease with onset at 20–22 years.

**Clinical Implications** The marked discrepancy between high genetic carrier rates and low clinical diagnosis indicates that WD is significantly underdiagnosed. Improved, cost-effective genetic screening (e.g., NGS panels or PCR-based methods like ARMS) is urgently needed, especially in regions with high prevalence. Early diagnosis is critical because effective chelation therapy (d-penicillamine, trientine, zinc) can prevent disability and death. Understanding the genotype-phenotype correlation may help predict disease course and tailor treatment. The review highlights the need for population-specific mutation databases to facilitate genetic testing and public health planning.

STUDY TYPE

narrative_review

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

96% · A

ORIGINAL PAPER

PMC10889319

Epidemiology of Wilson’s Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions

International Journal of Molecular Sciences

READ THE FULL PAPER

ABSTRACT

Abstract Wilson’s disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient’s condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000–45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed. Keywords: Wilson’s disease (WD), copper transport ATPase, prevalence, genetic diagnosis

CITATION EXPORT

Elena Vasilievna Ovchinnikova, Mikhail Maksimovich Garbuz, Anna Aleksandrovna Ovchinnikova et al.. Epidemiology of Wilson’s Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions. International Journal of Molecular Sciences. (2024). https://doi.org/10.3390/ijms25042402

AUTHORS

4 · 2 CENTRES

Elena Vasilievna Ovchinnikova, Mikhail Maksimovich Garbuz, Anna Aleksandrovna Ovchinnikova, Vadim Vladimirovich Kumeiko

1Institute of Life Sciences and Biomedicine, School of Natural Sciences, Far Eastern Federal University, Vladivostok 690922, [email protected] (M.M.G.);
2A.V. Zhirmunsky National Scientific Center of Marine Biology, Far Eastern Branch of Russian Academy of Sciences, Federal University, Vladivostok 690041, Russia