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By Alexander Shtilbans, MD, PhD
Assistant Professor of Neurology, Weill Cornell Medical College, Hospital for Special Surgery
Dr. Shtilbans reports no financial relationships relevant to this field of study.
SYNOPSIS: In this prospective, population-based study, mean lifetime heritability of amyotrophic lateral sclerosis was 52% in the entire cohort and 37% in patients devoid of any known pathogenic mutations. The highest heritability was seen in mother-daughter parings in both groups.
SOURCE: Ryan M, Heverin M, McLaughlin RL, et al. Lifetime risk and heritability of amyotrophic lateral sclerosis. JAMA Neurol 2019;76:1367-1374.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder causing progressive weakness leading to respiratory paralysis and death. Recently, several genetic mutations have been discovered and linked to familial forms of ALS, which in the past predominately was considered a sporadic disease. In epidemiological studies that evaluated lifetime risk of development of ALS in various cohorts, heritability and the proportion of genetic factors contributing to the risk of developing this disease were unclear. There are conflicting reports of ALS heritability from twin, pedigree, and population genome-wide single-polymorphism studies. For clarity, heritability refers to the proportion of variance in the risk of developing a disease that is explained by genetic factors.
Ryan et al conducted a prospective, population-based study using a pedigree approach to estimate heritability and determine if it is modulated by sex, based on parent-offspring concordance. They used the Irish ALS registry to evaluate 1,117 cases recorded from 2008 to 2017 to estimate heritability. The authors first calculated the annual incidence of ALS, followed by lifetime risk of developing ALS. There were 69 C9orf72 mutation-positive cases among 674 patients for whom gene status was available. Five patients with sporadic ALS carried other known pathogenic mutations and were excluded from the study. The data analysis showed that patients with a parental history of ALS had a younger mean age of onset, 57.9 years, compared to patients without a parental history, with mean onset of 65.1 years. The overall mean incidence was estimated to be 3.1 per 100,000 people. The adjusted lifetime risk of developing ALS was one in 347 men and one in 436 women. Concordance was highest in mother-daughter pairs (2.6%). Of those patients with parental history of ALS who had C9orf72 testing performed, 61% were positive. The mean lifetime heritability of ALS in the entire C9orf72 cohort was 52.3% overall and was highest in mother-daughter pairings (66.2%). In C9orf72-negative patients, the mean lifetime heritability of ALS was 36.9%, while female-female heritability was 48.5%. The lifetime risk of first-degree relatives of patients with ALS who tested negative for all known gene mutations was still increased at 0.7%, compared to general population (0.3%).
The authors concluded that inherited and non-inherited factors contribute about equally to the risk of ALS, even in people without known pathogenic gene mutations.
The investigators evaluated heritability of ALS in one of the largest population-based pedigree studies using the Irish ALS registry. The results were similar to previously published data on U.S. clinic-based populations.1 However, in this study, heritability also was assessed in a cohort without known genetic mutations and was found to be significant. Indeed, this suggests there might be many other genetic contributions accounting, at least partially, for the development of ALS. Another striking finding was the high mother-to-daughter heritability rates in both C9orf72-positive and -negative pairings, suggesting complex interaction between sex and disease phenotype. Heritability estimates between other pairings: son-mother, son-father, and daughter-father pairings were lower. Therefore, further studies of potential involvement of the X chromosome in the heritability of ALS should be initiated. The study also showed that affected offspring with a parental history of ALS developed their symptoms much earlier than their parents, suggesting an anticipation phenomenon similar to what is observed in some Huntington disease patients.
There are limitations in this study, which the authors acknowledged. It was not known if the incidence of ALS changed during the lifespan of the patients and their parents. Association of environmental factors with risk of the disease was not evaluated directly in this study. Importantly, only 674 patients were tested for C9orf72 repeats out of 1,117 in the cohort. Thus, it is possible the presented heritability data pertaining to C9orf72 status might be skewed because of the unknown status of the large remaining part of the cohort.
Overall, however, this complex epidemiological study was well designed and executed. The findings clearly warrant further studies in larger and more diverse groups of patients to evaluate heritability in ALS. Furthermore, additional studies aimed to discover new genetic loci contributing to the heritability and pathogenesis of ALS are needed as well.
Financial Disclosure: Neurology Alert’s Editor in Chief Matthew Fink, MD; Peer Reviewer M. Flint Beal, MD; Editorial Group Manager Leslie Coplin; Editor Jason Schneider; Executive Editor Shelly Morrow Mark; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.