Familial ALS More Common Than Thought—Do We Need a New Definition?

Amyotrophic lateral sclerosis runs in families more often than scientists originally thought. Researchers have claimed that 5 percent of ALS cases are inherited, with the remainder being sporadic, but a paper in the January 7 Neurology raises the familial ALS (fALS) figure to 8.6 percent. This supports other recent studies that came to similar conclusions, including one that found fALS percentages in the teens. Researchers are working to develop a standard definition for fALS, which neurologists depend on to diagnose and counsel affected families.

As described in the Neurology paper, first author Summer Gibson and senior author Stefan Pulst took advantage of an extensive database at the University of Utah in Salt Lake City. The Utah Population Database started with detailed genealogical records kept by Mormon settlers as long ago as the early 1800s, and passed into the university’s hands in the 1970s. The university linked the records to a variety of health-related data such as cancer registries, hospital stays, and death certificates. Though this population started small, and with some inbreeding, the steady influx of newcomers into Utah has resulted in a population of mixed European heritage, with no obvious evidence for persistent consanguineous marriage or a founder effect from those starting settlers, Gibson said.

The database includes records of death certificates from 1904 to 2009, and the study authors focused on those. Gibson began by querying the database for people who died of ALS. Finding 873 cases, she calculated an incidence for ALS of 1 in 800 for the general population. She then asked how many of these people’s first-degree relatives—parents, siblings, and offspring—had also died of ALS. Of 3,531 such relatives, 32 fit the bill, giving a risk of nearly five times that for people in a control cohort, accounting for similar birth year, gender, and birthplace within or outside Utah. When Gibson examined 9,386 second-degree relatives—grandparents, aunts and uncles, and grandchildren—she found 43 more cases, resulting in an almost threefold risk for ALS, compared to control subjects. Other relatives, third-degree and higher, such as great-grandchildren, had no increased risk. When Gibson defined familial ALS as any case with an affected first- or second-degree relative, she calculated 8.6 percent of cases were familial, higher than the oft-cited figure of 5 percent (Byrne et al., 2011).

These numbers may be an underestimate, Gibson said. Coroners filled out death certificates differently in the early 1900s than they do now. During the 1980s, the records began to include more than one cause of death, boosting the chances that ALS would be included. In addition, a specialist ALS referral center opened in the 1990s, probably resulting in more frequent and accurate diagnoses, Gibson said. When she restricted her search to 1990-2009, ALS and fALS rates rose substantially. The overall risk of ALS (familial and sporadic) rose to 1 in 391, comparable to the rate in other studies (Johnston et al., 2006), and the risk to first-degree relatives rose from five to seven times that of controls. However, in this smaller cohort there were too few affected second-degree relatives to make further calculations about overall fALS rates.

Gibson expects her data will provide a baseline for future studies of how ALS relates to other diseases in the Utah database. For example, some evidence indicates that low levels of uric acid enhance the risk for ALS (see Jul 2009 news story on Keizman et al., 2009). Gibson hypothesizes that high levels of uric acid might reduce risk, as it seems to do for Parkinson’s disease (see Weisskopf et al., 2007). She plans to look for people treated for gout, a condition due to high uric acid, to see if their chances of contracting ALS were unusually low. Another condition that might correlate with ALS would be frontotemporal dementia, which often co-presents with ALS or occurs in relatives, particularly in the case of fALS patients who have a nucleotide expansion in the C9ORF72 gene. However, FTD often does not show up on death certificates, so Gibson could not address it in the current work.

The findings came as no surprise to other researchers in the field. “It confirms what we and other groups found, that the rates are higher for familial ALS than previous studies would have suggested,” commented Orla Hardiman of Trinity College Dublin. The Utah fALS rates are in fact lower than some other reports, which found a risk to relatives of eight- to 10-fold higher than in the general population (Fang et al., 2009; Hanby et al., 2011). Hardiman and colleagues combined patient interviews with searches of death certificates to find 16 percent of ALS cases were familial in Ireland (Byrne et al., 2013).

What do these statistics mean for people with ALS, and their families? Both Gibson and Ammar Al-Chalabi of King’s College London, who was not involved in the study, emphasized that patients’ relatives should not worry too much. Because ALS is so rare, even an increased risk would still be quite low. And Gibson’s study suggests that patients’ third-degree relatives, or those more distantly related, are at no higher risk for the disease than the general population. However, identification of a known ALS gene would indicate greatly increased risk to close relatives, noted Carmel Armon of the Assaf Harofeh Medical Center in Tel Aviv, Israel, in an accompanying Neurology commentary.

Researchers and neurologists believe that a better definition of fALS would be useful. Most clinicians agree that familial disease should be strongly suspected when a person with ALS has a first- or second-degree relative with the disease too, Gibson said. However, neurologists often disagree on specific families. Hardiman’s group polled 95 neurologists, presenting them with different case pedigrees, and found that doctors were often split on diagnosing a given kindred with fALS (Byrne et al., 2012).

Neurologists debated a better definition at a World Federation of Neurology conference in Chicago in 2012, said Al-Chalabi, who added that a consensus statement is being prepared. He supports a system proposed by Hardiman’s team that would divide fALS cases into definite, probable, and possible categories. That language is just like the McKahnn et al., 1984, criteria for Alzheimer’s, but it means something else. Rather than describing clinical stages, in this coming fALS definition, sequence confirmation of a known ALS gene would indicate definite fALS; three or more affected relatives would be probable fALS; and two family members with ALS would constitute a possible fALS diagnosis (Byrne et al., 2011).—Amber Dance

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