Our findings show consistently restrictive practice for genetic testing in cases of amyotrophic lateral sclerosis. Only three patients with the sporadic variant underwent diagnostic genetic testing, and justification for this was provided in all cases in the medical records. With the exception of one patient with the sporadic variant in whom testing was initiated by a specialist in medical genetics based on the desire of relatives for predictive testing, our practice was in line with European recommendations that specifically discourage genetic testing in typical cases of the sporadic form (9–11).
Two out of seven patients with the familial variant were not offered genetic testing or genetic counselling. Since the issue was not discussed in the medical records, we do not know the reasons why genetic testing was not performed. The absence of any explicit justification may reflect limited awareness about the importance of heredity, or uncertainty regarding access to genetic testing and counselling. This assumption is supported by a study from 20 countries showing that neurologists with extensive experience of amyotrophic lateral sclerosis offer genetic testing more frequently than their less experienced colleagues (14). Another explanation may be a conscious or unconscious desire not to contribute to increased concern that relatives will also develop the disease. The fact that family history was not recorded in the medical records of almost 40 % of patients is consistent with both of these explanations.
The limited use of genetic testing may also reflect the limited provision of such testing in Norway. A number of other ALS-related genes, including C9orf72, which is by far the most common genetic cause of amyotrophic lateral sclerosis, were discovered during the study period. However, Oslo University Hospital tested SOD1 alone throughout the study period, and indeed other ALS-related genes are still not tested today. Mutations in SOD1 account for only a small proportion of familial amyotrophic lateral sclerosis cases (approximately 20 %), and testing of this gene alone is seen as insufficient both in cases of the familial variant and in cases of the sporadic type with atypical disease course (14, 15). The genetic epidemiology has not been mapped in Norway, but by testing C9orf72, FUS and TARDBP in addition to SOD1, the genetic basis of about two-thirds of cases of familial amyotrophic lateral sclerosis and 10 % of cases of the sporadic type could probably be identified (14, 16).
The discovery of new ALS-related genes may lead patients, relatives and doctors to view genetic testing as more worthwhile, as it will mean that testing is more likely to be able to identify or rule out genetic causes of the disease (17). Telemark Hospital now analyses 17 other ALS-related genes besides SOD1, as well as a number of genes associated with other motor neuron diseases, but does not currently test for C9orf72 (Helle Høyer, personal communication).
The main argument for not offering genetic testing in cases of the sporadic variant is that doing so poses a threat to the patients' right not to know, as well as consideration for the relatives' wish to remain ignorant of their disease risk (15). The discovery of an ALS mutation in an ALS patient has far-reaching consequences for healthy relatives. They must deal with the fact that they may be at significantly increased risk of developing the disease and must decide whether they would like predictive testing, which under Norwegian law requires genetic counselling. The uncertainty over the significance of both positive and negative results makes it difficult for healthy relatives to decide whether to undergo testing, as testing will not provide them with an unambiguous answer regarding their own risk (18). This differs from Huntington's disease, where a negative genetic test rules out the disease while a positive finding also provides important information about anticipated prognosis (19).
The relatively restrictive practice of reserving genetic testing for patients with the familial type or an atypical disease course has been challenged in recent years (20), in part because it deprives the patient of the possibility of identifying the cause of their disease (15). In addition, the frequent discovery of ALS mutations in patients with an apparently sporadic form of the disease renders the distinction between familial and sporadic forms more arbitrary than previously assumed (20, 21). The relatively high likelihood of detecting an ALS-related mutation is thus used as an argument for both restrictive and liberal genetic testing practices in sporadic amyotrophic lateral sclerosis (11, 17, 20). Increased insight into the genetic causes of disease is important for understanding disease mechanisms, and many future treatment studies will probably require molecular testing (22). In our experience, many patients wish to participate in clinical trials, and it is therefore likely that the number of patients who request genetic testing will increase. Given that it will be possible to test for a greater number of genes, the chances of detecting gene variants with uncertain disease association and thus uncertain significance in terms of disease risk in relatives will also increase. There will thus be a markedly greater need for genetic counselling.
Many patients wish to know the cause of their own disease and the risk of it being passed on in the family (18). In a survey of 5 591 patients with ALS in the USA, 83 % of respondents stated that genetic testing should be offered to all patients with the disease, with 73 % believing that the benefits outweigh the drawbacks (23). Those who had undergone genetic testing reported mostly positive experiences, irrespective of the type of disease (sporadic or familial) and whether they had received genetic counselling (24). The response rate in this survey was low (8 %), and its generalisability is therefore uncertain. The discrepancy between the positive feedback and the restrictive practice reflected in our findings and in the European recommendations nevertheless raises the question of whether neurologists are adopting a paternalistic and overprotective approach, which perhaps reflects their own discomfort in engaging with these issues.