Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease
Abstract
:1. Introduction
2. Clinical Picture of Wilson’s Disease
2.1. Clinical Signs
2.1.1. Liver Disease
2.1.2. Neurological and Psychiatric Disease
2.1.3. Additional Clinical Manifestations
2.2. Diagnosis: Just a Matter of the Leipzig Scale?
2.2.1. Ceruloplasmin
2.2.2. Serum Copper
2.2.3. Urinary Copper
2.2.4. Additional Blood Tests
2.2.5. Liver Biopsy
2.2.6. Imaging Evaluations: Liver and Brain Assessment
3. A Mendelian Disease Caused by Mutations in ATP7B
4. Wilson’s Disease Is Not That Rare
5. Genetic Modifiers
6. Wilson-Like: Genetic Diseases That Mimic the Wilson Phenotype
6.1. Congenital Disorders of Glycosylation
6.2. Progressive Familial Intrahepatic Cholestasis
6.3. Aceruloplasminaemia
6.4. Menkes Disease
6.5. MEDNIK Syndrome
6.6. Alagille Syndrome
6.7. Idiopathic Copper Toxicosis
7. The Need for Biomarkers for a Better Diagnosis
7.1. Biomarkers in WD and Related Clinical Phenotypes
7.2. Potential of Circulating Micrornas as Biomarkers in WD
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Test | Parameter | Score |
---|---|---|
Kayser-Fleischer ring | Present | 2 |
Absent | 0 | |
Neurological symptoms | Severe | 2 |
Mild | 1 | |
Absent | 0 | |
Serum ceruloplasmin | Normal (>0.2 g/L) | 0 |
0.1–0.2 g/L | 1 | |
<0.1 g/L | 2 | |
Coombs-negative hemolytic anemia | Present | 1 |
Absent | 0 | |
Liver copper (in the absence of cholestasis) | >250 µg (>4 µmol) g−1 dry weight | 2 |
50–249 µg (0.8–4 µmol) g−1 | 1 | |
Normal: <50 µg (<0.8 µmol) g−1 | −1 | |
Rhodanine-positive granules | 1 | |
Urinary copper (in the absence of acute hepatitis) | Normal | 0 |
1–2 × ULN | 1 | |
>2 × ULN | 2 | |
Normal but >5 × ULN after D-penicillamine | 2 | |
Mutation analysis of ATP7B | Biallelic deleterious variants | 4 |
One deleterious variant | 1 | |
No mutation detected | 0 | |
Total score | Evaluation | |
≥4 | Diagnosis established | |
3 | Diagnosis possible; more tests needed | |
≤2 | Diagnosis very unlikely |
Type of Variant | No. Mutations | Frequency (%) |
---|---|---|
Regulatory sequences | 12 | 1.28 |
Splicing site | 77 | 8.21 |
Missense and nonsense mutations | 572 | 60.98 |
Small deletions | 158 | 16.84 |
Small insertions | 80 | 8.53 |
Indels | 12 | 1.28 |
Gross deletions | 26 | 2.77 |
Deep intronic | 1 | 0.11 |
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Sánchez-Monteagudo, A.; Ripollés, E.; Berenguer, M.; Espinós, C. Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease. Biomedicines 2021, 9, 1100. https://doi.org/10.3390/biomedicines9091100
Sánchez-Monteagudo A, Ripollés E, Berenguer M, Espinós C. Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease. Biomedicines. 2021; 9(9):1100. https://doi.org/10.3390/biomedicines9091100
Chicago/Turabian StyleSánchez-Monteagudo, Ana, Edna Ripollés, Marina Berenguer, and Carmen Espinós. 2021. "Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease" Biomedicines 9, no. 9: 1100. https://doi.org/10.3390/biomedicines9091100