Screening the family

Some important facts to understand these recommendations:

1- Wilson’s disease is an autosomal recessive disease

a/ We all carry 46 chromosomes: a set of 23 chromosomes inherited from our mother and a set of 23 chromosomes inherited from our father, or 23 pairs

  • Each chromosome contains thousands of different genes
  • Each gene possesses two alleles (one from the father and one from the mother)
  • The Wilson’s disease gene is situated on chromosome 13
  • More than 500 abnormalities affecting this Wilson’s disease gene have been described in patients with the disease

b/ In France, it is estimated that one person in a hundred carries a single abnormal allele. These so-called heterozygous individuals will not develop the disease but can transmit the abnormal allele to their children

c/ To be affected by Wilson’s disease, it is necessary for the two alleles of the Wilson’s disease gene carried by the two chromosomes 13 to be abnormal

d/ In the very great majority of cases, the parents of a Wilson’s disease patient carry a single abnormal allele. They are referred to as being heterozygous, or healthy carriers, because they will not develop the disease (Diagram 1)

Diagram 1 : Parents, brothers and sisters of a patient diagnosed with Wilson’s disease (most common case)

family diagnosis

e/ The risk that the children of a Wilson’s disease patient will have Wilson’s disease is evaluated at 1 in 200

In theory, there are two possibilities:

  1. The partner has no abnormality affecting the Wilson’s disease gene. All the children are heterozygous and healthy carriers: they will not develop the disease (Diagram 2a)
  2. The partner is heterozygous, and a healthy carrier. In this case, one in two children is affected and one in two is heterozygous and a healthy carrier (Diagram 2b)

In practice, apart from marriages between blood relations, the status of the partner is not known. Indeed, it is not currently recommended to look for genetic abnormalities in an unrelated partner; because all the abnormalities affecting the Wilson’s disease gene are not known, the results of a genetic analysis could be falsely reassuring. Thus, the risk that a child of a Wilson’s disease patient will have the disease is 1 in 200 = the risk of the partner being heterozygous and a healthy carrier of 1 in 100 multiplied by the risk of the child carrying two abnormal alleles, or 1 in 2.

Diagrams 2a and 2b: children of a Wilson’s disease patient

a/ Partner with no abnormality of the Wilson’s disease gene (most common case: 99/100)

family diagnosis 2

b/ Partner who is a heterozygous healthy carrier with an abnormality on one allele of the Wilson’s disease gene (1/100)

2- The most important biological (non-genetic) data used to suggest a diagnosis of Wilson’s disease are:

a/ blood count, platelet count, liver function parameters, prothrombin rate (for coagulation)

b/ copper assessment, which comprises:

  • An assay of serum ceruloplasmin levels (which are often low in Wilson’s disease). This assay is only reliable after the age of 3 years
  • An assay of total copper levels in the blood (also lowered in Wilson’s disease)
  • An assay of copper levels in a 24-hour urine specimen (elevated)
  • Following publications by the CNR, determination of the REC (ratio of exchangeable copper/total copper) should also be included in the blood tests. Exchangeable copper is the free copper circulating in the bloodstream that is considered to be toxic. This REC assay is currently performed at Hôpital Lariboisière in Paris and at Lyon University Hospital.

3- Molecular biology can confirm the diagnosis by identifying abnormalities affecting both alleles of the Wilson’s disease gene

This is the case in most people suffering from Wilson’s disease. Although 500 abnormalities of the Wilson’s disease gene have been described, some are still not known. So for around 8% of patients, screening of the two alleles is not able to demonstrate any abnormalities. In these cases, molecular biology studies can contribute little or nothing to the diagnosis.


The recommendations

An appointment with a psychologist is proposed before and after screening. This aims to provide support for those who need it while waiting for the results.

1- When should family screening be proposed?

It is essential to screen the brothers and sisters of a diagnosed patient, as from the age of 3 years. Each sibling has a 25% risk of being affected by the disease (Diagram 1).

The children of a diagnosed patient should be screened, when they are more than 3 years old, even if in the absence of a blood relationship between the parents the risk is small (0.5%) (Diagram 2).

Parents, uncles, aunts and cousins should be screened, because of some exceptional observations recently published by the CNR. In two cases, one of the parents of a Wilson’s disease patient presented with an asymptomatic form of the disease. Also exceptionally, and in the same family, the disease was found to be present in an aunt and nephew. These are very rare cases, but because effective treatment for Wilson’s disease is available, the CNR prefers to offer a broader family screening.

Screening does not concern the partner of a patient with Wilson’s disease if there is no blood relationship.

  • The risk of a partner being heterozygous (or in other words, a healthy carrier) is 1 in 100. The search for an abnormality on the Wilson’s disease gene can be lengthy and produce negative results. Furthermore, not all changes to the gene can be detected or interpreted.
  • If there is a blood relationship between a Wilson’s disease patient and his or her partner, then screening may be offered to the partner.

2- What tests are carried out?

a/ Family screening includes the following investigations:

  • A physical examination
  • Laboratory tests
    • Blood count, platelet count, liver function parameters, prothrombin rate
    • Copper assessment: serum ceruloplasmin levels, blood copper levels, REC, urinary copper in a 24-hour specimen

b/ A molecular biology test that may vary, depending on the results of family screening:

  • for brothers and sisters with Wilson’s disease:
    • the two genetic abnormalities detected in the Wilson’s disease patient are looked for
    • if a single genetic abnormality is found to be associated with an abnormal copper assessment, a complete analysis is made of the Wilson’s disease gene
  • for relatives:
    • presenting with an abnormal copper assessment, a complete analysis is made of the Wilson’s disease gene
    • presenting with a normal copper assessment, molecular biology investigations are limited to searching for the genetic abnormalities identified in the diagnosed patient. This investigation can determine whether the abnormality found in the Wilson’s disease patient has been transmitted, and if so, which one. It is therefore not designed to diagnose Wilson’s disease