Familial ALS accounts for 8% of all cases, analysis suggests
However, various factors affect the estimates, researchers advise
The proportion of people diagnosed with familial amyotrophic lateral sclerosis (ALS) among all cases is 8%, according to a pooled analysis of studies published worldwide.
Still, data show there was a wide variation of estimates across the studies based partly on geographical differences, study design, the definition of familial ALS, and the decade when assessed.
The researchers noted there were few studies outside of European populations, therefore, more population-based studies in non-European populations are needed.
In addition, the researchers suggested that increased genetic testing may address some of the limitations in estimating the proportion of familial ALS.
The pooled analysis was published in the journal Neurology Genetics, in the study, “Estimated Familial Amyotrophic Lateral Sclerosis Proportion.”
Muscle weakness and atrophy (wasting) are hallmark features in all individuals with ALS, a neurological disorder caused by the progressive death of nerve cells that control voluntary movements called motor neurons.
Estimates suggest about 5%-10% of ALS cases have a known family history, referred to as familial ALS (fALS). The remaining 90% are considered sporadic (sALS) due to a lack of family connections.
However, it has been a challenge to clearly determine the proportion of familial versus sporadic ALS cases due to variations in the design of studies examining their prevalence.
Suggested reasons for such variation include different definitions of familial ALS, geographical discrepancies, changes over time, misdiagnosis, or the early death of family members who would have developed ALS. A lack of family history also can result from low gene penetrance, meaning not all family members who inherit an ALS-linked gene develop ALS, an assessment further complicated by family size.
“These situations may result in erroneous labeling of patients as sporadic, when family inheritance occurred,” according to a team led by researchers at Emory University, in Georgia, in collaboration with Biogen.
Estimating the proportion of cases
Thus, the team conducted a pooled (meta) analysis, funded by Biogen, of published studies to estimate the proportion of familial ALS by geographic region and examine study characteristics that may have influenced these estimates.
Database searches yielded a final sample of 165 study estimates, of which 58 (35%) identified ALS cases using large population methods and 107 (65%) were based on case series with smaller groups of patients.
A clear definition of familial ALS was reported in 56 studies. Among them, 13 (23%) restricted the definition to first-degree relatives only (parent or offspring), 14 (25%) restricted to first or second-degree relatives (grandparent and grandchild, half-siblings, aunt/uncle or niece/nephew), and 8 eight (14%) allowed for more distant generations.
In addition, eight (14%) studies considered those with confirmed genetic mutations to be classified as familial ALS, one (2%) required an ALS family history in multiple relatives, while 12 (21%) allowed a family history that included other neurological diseases.
Across all 165 studies, the pooled proportion of familial ALS was 8%. Europe had the highest proportion of familial ALS at 9%, followed by the Middle East and North Africa at 9% and Australasia at 8%. The lowest proportion was found in Asia at 4% and Sub-Saharan Africa at 5%. “Few studies outside of European ancestral populations were available,” the team noted.
When divided by study design, the proportion of familial ALS was higher among case series compared with population-based studies (9% vs. 5%). The researchers noted this result was likely due to referral bias, a type of selection bias that occurs when individuals included in a study are not representative of the overall population.
Defining the disease matters
As expected, population-based studies with a broader definition of familial ALS (first- or second-degree or more distant family history) had a higher proportion at 11%. In comparison, in studies that restricted the definition to first- or second-degree, the proportion of familial ALS was 7%, and 5% among those including first-degree relatives only.
Population-based studies from the 2000s or earlier reported a lower proportion of familial ALS than those published in the 2010s or later (3% vs. 9%). According to researchers, these findings likely were due to changes in ALS case identification, diagnostic criteria, an understanding of the disease, familial ALS classification, environmental risk factors, and the average family size.
When cases considered sporadic due to missing/unknown family history were included, as well as studies that allowed for alternative motor neuron diseases, the results remained consistent.
Still, excluding the eight studies that classified familial ALS based on confirmed genetic mutations, the proportion of familial ALS was slightly lower in all studies (7% vs. 8%) and in case series (8% vs. 9%). European studies drove these changes. Population-based studies and other regional data remained unchanged.
“This study contributes to an improved understanding of factors that affect variability in reports of the proportion of ALS cases that are of familial vs sporadic origin in the epidemiologic literature,” the researchers wrote.
“Future identification of ALS cases, especially fALS cases, with an underlying genetic etiology may benefit from increased genetic testing to address limitations in estimating proportion fALS,” they added.
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