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Rheumatology 2001; 40: 606-609
© 2001 British Society for Rheumatology
Editorials |
Genetic counselling in familial Mediterranean fever: has the time come?
Departments of Medicine and
1 Human Genetics, Hadassah Hebrew University Hospital, Jerusalem 91120, Israel
Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever and peritonitis, pleuritis, arthritis or an erysipelas-like skin disorder [1, 2]. The disease affects mainly non-Ashkenazi Jews, Armenians, Turks and Arabs. The disease may present at any age, more than 80% of patients being symptomatic by the age of 20 yr. One of the major complications of FMF is amyloidosis of the kidneys, which causes a nephrotic syndrome leading to end-stage renal disease. Some of the patients who survive dialysis or renal transplantation may develop heart failure and fatal arrhythmias due to cardiac amyloidosis [3].
Colchicine is the drug of choice for FMF. It prevents the acute attacks as well as the development of amyloidosis [2]. More than 90% of FMF patients will respond to this medication, which either abolishes the attacks completely or significantly decreases their frequency.
Until recently, the diagnosis of FMF was based upon clinical manifestations, family history and response to colchicine. However, in cases where the above components of diagnosis are missing or negative, the diagnosis of FMF becomes very difficult. Furthermore, the presence of other periodic diseases, such as Hibernian fever and hyper-IgD syndrome, widens the differential diagnosis, leading to greater difficulty in FMF diagnosis [4].
Three years ago, a gene associated with the disease (MEFV) was cloned and some of the mutations causing FMF were identified [5, 6]. Genes associated with the other two periodic diseases mentioned above were also cloned [7–9]. Cloning the MEFV gene and identification of the mutations causing FMF raised the issues of possible genetic counselling for families with this disorder and of carrier screening in high-risk populations. We wish to discuss these subjects by trying to evaluate the contribution of gene cloning and the available data regarding the genotype–phenotype correlation in this disease.
Most physicians treating FMF patients may regard genetic counselling in this disease as unjustified. The rationale behind this attitude is that FMF is a treatable disease with a high rate of response. Therefore, issues discussed in genetic counselling concerning reproductive decisions may appear irrelevant.
The questions we would like to raise are whether FMF should always be regarded as a non-severe disease and whether the cloning of the MEFV gene might change the expectations from genetic counselling in FMF?
Familial Mediterranean fever can be an unpleasant disease. However, most of the patients who are treated with colchicine experience only a few attacks every year, have a very low risk of developing amyloidosis, and conduct a nearly normal life with normal survival. Nevertheless, there are still FMF patients who develop amyloidosis, and their disease is much more severe. Amyloidosis can appear in two modes. In type I, FMF patients develop this complication following years of attacks of the disease, usually because they do not receive colchicine or are non-compliant. In type II, the first presentation of FMF is proteinuria or nephrotic syndrome due to renal amyloidosis. In these cases the patients develop renal failure in their childhood or adolescence and need dialysis or renal transplantation, which exposes them to the complications of these therapies. Thus, extreme differences in the perception of the severity of FMF can be expected in families with and without amyloidosis. In families with a severe presentation of FMF the possibility of prenatal diagnosis may be raised. This is a concept that is rarely discussed in this disorder. One reason is that, in most families where amyloidosis develops late in life, the younger siblings have already been born, so that the question of prenatal diagnosis is not relevant. However, where an elder sibling has developed amyloidosis and the parents plan to have more children, genetic counselling should be considered. It will be important for the genetic counsellor to know why the patient has amyloidosis. Has he (or she) started colchicine treatment too late? Was he/she non-compliant? If the answer to these questions is positive, the counsellor should emphasize that amyloidosis can be prevented in the next sibling by colchicine treatment. As a result of the counselling, most parents will probably see no reason for prenatal diagnosis. On the other hand, in families where at least one member has phenotype II FMF the approach may be different.
Possible assistance in giving appropriate genetic counselling could derive from studies that have tried to define the genotype–phenotype correlation in FMF. This issue has been studied extensively during the last 2 yr, and substantial reports indicate that a specific mutation (M694V) in its homozygous form is highly associated with amyloidosis [10–12]. On the other hand, other investigators claim that this mutation is not associated with amyloidosis any more than other sequence alterations [13]. Moreover, it is well known that not all patients who are homozygous for this mutation (M694V) do develop amyloidosis. Thus, current knowledge indicates that the mere finding of homozygosity for the M694V mutation does not necessarily predict a severe form of the disease. All these limitations should be discussed with the parents in order to help them arrive at informed reproductive decisions. Furthermore, we suggest that if, after extensive genetic counselling, they ask for prenatal diagnosis, this request should not be denied. It is important to note that the issue of prenatal diagnosis should be approached very cautiously because the mere raising of the option of prenatal diagnosis may lead to the impression that termination of a pregnancy with a fetus with FMF is normal.
Prenatal diagnosis of a genetic disorder aims to allow parents to decide about termination of the gestation of a fetus with a serious disease. But how can we define which diseases are severe enough to justify termination of pregnancy? Disease severity is a subjective concept, and different people may perceive the same disorder differently [14]. A wide range of perceptions regarding the severity of genetic disorders is found even among geneticists [15]. Therefore, one can expect a large gap between family members and their physicians in the severity attributed to FMF. This assumption is supported by a study on another congenital disorder, cleft lip and palate. Doctors usually regard this malformation as an ‘aesthetic lesion’, whereas most parents of children with cleft lip and/or palate consider it as a serious defect [16]. Therefore, we are left with the question of who should decide about the justification of pregnancy termination. This problem was addressed in the study of Wertz [15], which was carried out among geneticists from the USA, Europe and Latin America. In the USA and Europe most of the responders thought that the individual patient should decide, whereas in Latin America the majority of participants favoured the option that a national ethics committee should decide but some suggested that the doctors should decide.
We would like to emphasize that genetic counselling is an educational process that seeks to assist affected and at-risk individuals to understand the nature of the genetic disorder, its transmission and the options open to them in the management of the disease and family planning [17]. FMF is a hereditary disease and the families in which it occurs deserve to receive a full explanation concerning the disorder and its transmission. Such knowledge can improve their understanding and eliminate wrong beliefs and conceptions about this disorder. Frequently, people have attributed their disease to the wrong cause, leading to unjustified guilt feelings [18]. Since genetic counselling is a mutual communication interaction, these misconceptions can be revealed and corrected by the counsellor. In addition, during the process of genetic counselling, families with FMF can learn about the risk of recurrence of the disease among their children. It is well documented that in the absence of this information people tend to overestimate the risk [19]. For example, a patient may fear that all his children will have the disease, but with thoughtful explanation he may realize that if he were to marry a person from a particular ethnic group the chance of the disease may decrease significantly.
Another possible goal of genetic counselling for FMF is in presenting the possibility of presymptomatic diagnosis. As already mentioned, amyloidosis is the most serious complication of FMF, and may be prevented by vigorous treatment with colchicine. Therefore, it seems reasonable to make an effort to detect individuals at risk of developing this complication, and genetic testing can serve this purpose. Siblings of an individual with FMF can be tested and preventive treatment with colchicine be considered in the homozygotes. Nevertheless, since we do not have a definite means of predicting the risk of amyloidosis, the question remains whether to treat every asymptomatic member with a genetic diagnosis of FMF. The answer should take into account (i) the fact that amyloidosis does not develop in all FMF patients, even without colchicine treatment, and (ii) the risk of side-effects of the drug.
Colchicine is a relatively safe medication [20] and generally a patient with normal liver and kidney function should not have any complication on regular treatment. However, if liver or renal function is disturbed, colchicine intoxication may be fatal [20]. In weighing the risk of amyloidosis against the risk of adverse effects of colchicine in an asymptomatic patient who is homozygous for a mutation strongly associated with amyloidosis, we suggest that the odds are in favour of treatment. However, because no data to support this approach are available, an alternative recommendation would be, at least for the time being, to follow homozygotes by checking their urine and start treating them only if proteinuria appears or if they become symptomatic.
The last dilemma we wish to discuss is the justification of population screening for FMF mutation carriers and the screening of newborn infants for homozygosity for such mutations. This possibility may be raised in countries where the disease is common. Population carrier screening aims to identify couples who are at risk of giving birth to children affected with a genetic disease because the parents are carriers. The World Health Organization has defined the preconditions for such community carrier screening as follows [21]: (i) the disease should be a major health problem; (ii) the course of the disease should be defined as severe; (iii) there must be a simple, cheap and accurate carrier test which provides information that can be understood by the carrier and the clinician; (iv) there should be a solution to the problem; (v) there should be educational and counselling backup in the community. If we apply these preconditions to FMF, it seems that some of them are not fulfilled. The disease is indeed common (at least in Mediterranean countries), but we still do not have enough data to interpret the various results in different situations. The controversy around the issue of genotype–phenotype correlation is a crucial problem in this setting. Detecting carriers in the general population will cause a great deal of confusion without offering a real solution to the problem. An even stronger argument against carrier screening is that such screening should be done only for those diseases that are considered by the medical establishment to be severe enough to justify prenatal diagnosis and pregnancy termination. This certainly would not apply to FMF; therefore, in our opinion population carrier screening for FMF should not be carried out.
The other type of population screening, newborn screening, is open to discussion. This screening aims to identify babies who are homozygous for MEFV mutations in order to offer early surveillance or even presymptomatic treatment for homozygotes for certain mutations, as discussed previously. This screening is therefore adequate only if there are strong indications that presymptomatic diagnosis is beneficial. These indications are impossible to achieve for the time being because long-term clinical trials are needed.
In conclusion, cloning the MEFV gene has raised the possibility of genetic counselling for families with FMF patients. We suggest that a thorough study should be conducted in order to evaluate the attitude of FMF families to knowing more about the genetic aspects of the disease, their perception of the severity of the disease, their attitudes towards prenatal diagnosis of FMF, and whether they would consider the termination of pregnancy. We have to remember that medical professionals present only one side of the picture; patients and their families are the other important side. We should also widen our knowledge about the genetics of the disease and the correlation between clinical manifestations and the genetic profile, so that we can have the appropriate tools for genetic counselling. Genetic counselling should be given by counsellors who have, besides their training in genetics, substantial experience in an FMF clinic. It seems that close collaboration between the treating physician and the genetic counsellor would be of great benefit and value to FMF patients and their families.
This work was supported by a grant for FMF research from Hadassah Medical Relief, UK.
Notes
References
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