Familial ALS: less common than we think?
- 1Centre of Excellence in Neuroscience of Université de Montréal, CHUM Research Center, Montreal, Quebec, Canada
- 2Université de Montreal, Faculty of Medicine, Department of Medicine, Montreal, Quebec, Canada
- 3Research Center, CHU Sainte-Justine, Université de Montreal, Montreal, Quebec, Canada
- Correspondence to Dr Guy Rouleau, CHUM Research Centre, Notre-Dame Hospital, 1560 Sherbrooke E., Y-3633, Montreal, Quebec H2L 4M1, Canada;
Contributors VVB and GAR both drafted the manuscript.
- Received 9 June 2012
- Accepted 13 June 2012
- Published Online First 11 July 2012
Amyotrophic lateral sclerosis (ALS) is an adult onset motor neuron disease that affects both upper and lower motor neurons. The disease progresses rapidly, with 70%–80% of individuals dying within 5 years, typically from respiratory failure.1 Familial cases of ALS (FALS), where there is co-occurrence of ALS in first-, second- or third-degree relatives, have been reported to represent about 10% of all cases.2 However, because familial and sporadic ALS cases are clinically undistinguishable with the exception of the presence of some kind of family history of the disease in relatives,3 some seemingly sporadic cases could be of familial origin. Examples of situations where absence of family history may lead one to falsely conclude that the case is sporadic, includes very small families, instances where the patient is not aware of the health status of their relatives, or if some family members are misdiagnosed or may have a disease not obviously linked to ALS, as was the case for frontotemporal dementia for many years. In addition, considering that the age of onset varies significantly, it is possible that some factors trigger the onset of ALS earlier in certain patients, while their mutation-carrying relatives are still unaffected, or they died before developing the disease. Adoption or illegitimacy can definitely shuffle the cards. Another reason for lack of family history is situations where certain genetic mechanisms occur, such as recessive forms of the disease or alleles with low penetrance. Finally, some cases may result from de novo mutations, where an ALS-predisposing mutation appears in the sperm, oocyte or early in embryogenesis. This latter mechanism, as well as variable penetrance, are common in repeat diseases, and may be relevant for the newly described C9ORF72 mutation. All these examples might result in calling some cases as sporadic, while they actually have ALS caused by a FALS gene.
Considering these issues, some investigators estimated that the prevalence of FALS may be up to 17%–23%,3–6 while others evaluated that 5% represents the true population-based rate of familial ALS after performing a systematic review and meta-analysis of all studies.7 One way to address this issue is to define and study FALS based on different family structures, such as affected siblings, parent-child transmission, affected uncle/nephew pairs, and so on. This is exactly what was done by Conte et al,8 who proposed a set of criteria for FALS, breaking down families as definite, probable and possible FALS. They first classified their 53 kindred as definite, probable and possible FALS based on the degree of relationship with the proband. They then evaluated the frequency of mutations in known ALS causative genes for each of these categories. They found mutations in 62%, 42% and 11% of definite, probable and possible cases of FALS, respectively. These data, showing a lower frequency of mutations in families with increasingly distant relationships between affected individuals, suggest that in such FALS kindred, there is either the occurrence of sporadic cases in relatives, or undiscovered genes with reduced penetrance, or co-inheritance of many low-penetrance alleles. Therefore, one may conclude from this data that FALS resulting from penetrant mutations likely represents no more than 10% of ALS cases.
What does this mean with respect to the existence of undiscovered FALS genes? In this study, FALS gene mutations were found in most of the larger FALS kindred, suggesting that a significant fraction of families with several affected first- or second-degree relatives can be now explained genetically. In addition, few mutations were found in the kindred with possible FALS, suggesting that many of these are probably not FALS families. Based on these findings, it is likely that FALS causative genes remain undiscovered for only a small proportion of ALS families. At this point, it is impossible to know if the remaining FALS genes will be highly penetrant, like for SOD1 and C9ORF72, or will have reduced penetrance.
Lastly, how does this study impact the way we counsel families? While more data is needed, this study suggests that in families with distantly related cases, the risks of recurrence are likely to be low. In addition, screening of possible FALS kindred will likely not identify a causative gene.
In conclusion, FALS is probably not as common as suggested by the higher estimates. Indeed, some of the possible FALS kindred may simply represent the occurrence of ALS in distant relatives by chance.
Linked article 302897.R2
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.