The objective of this literature review and meta-analysis was to estimate the rate of familial amyotrophic lateral sclerosis (FALS) by geography and study type.

ALS is a rare neurodegenerative disorder. Most cases are sporadic, with a smaller proportion, usually reported as 5-10%, occurring in families and likely of genetic etiology. Present understanding of FALS is dependent on reported family history with limited genetic testing in current standard practice. A systematic review and meta-analysis of FALS rate has not been conducted recently. 

A comprehensive literature review was conducted to identify all original studies reporting number of FALS in an ALS cohort. Results were stratified by geographic region and study design (probable case series or population-based). Subgroup analyses were conducted according to family history criteria used to define FALS. We report the weighted average and range, in part because of substantial heterogeneity across studies.

The pooled FALS rate based on 136 total studies was 8% (0%, 71%). Overall FALS rates by geographic region were 4% (1%, 19%; N=17 studies) for Asian countries excluding Japan, 10% (0%, 71%; N=78) for Europe, 11% (0%, 27%; N=6) for Latin America, 10% (1%, 40%; N=7) for Middle East, and 6% (2%, 16%; N=19) for North America. The FALS rate was 9% (0%, 71%) among 81 probable case series and 7% (0%, 27%) among 55 population-based studies. Among population-based studies, criteria used to define FALS were reported by 20 studies (36%) and the FALS rate was 5% (2%, 12%; N=5) for first-degree, 11% (5%, 27%; N=6) for first- or second-degree, and 16% (8%, 24%; N=3) for more distant family history of ALS.

The rate of FALS was marginally higher among probable case series compared to population-based studies, likely due to referral bias. Criteria used to define FALS were largely unreported and are one potential source of heterogeneity.