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Clustering of neuropsychiatric disease in first-degree and second-degree relatives of patients with amyotrophic lateral sclerosis

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posted on 2023-06-09, 08:27 authored by Margaret O'Brien, Tom Burke, Mark Heverin, Alice Vajda, Russell McLaughlin, John Gibbons, Susan Byrne, Marta Pinto-Grau, Marwa Elamin, Niall Pender, Orla Hardiman
Importance Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative condition primarily involving the motor system. There is increasing epidemiologic evidence of an association between ALS and a wider spectrum of neurodegenerative and neuropsychiatric disorders among family members, including schizophrenia and psychotic illness and suicidal behavior. Objective To examine the frequency and range of neuropsychiatric conditions that occur within individual first-degree and second-degree relatives of patients with ALS. Design, Setting, and Participants In this population-based, case-control family aggregation study, all 202 patients included in the Irish ALS Register between January 1, 2012, and January 31, 2014, with definite, probable, or possible ALS as defined by El Escorial criteria were invited to participate. A total of 75 patients were unable or refused to participate and were excluded; the remaining 127 patients with incident ALS were genotyped for the C9orf72 repeat expansion and 132 age- and sex-matched controls were included in the study. Main Outcome and Measures The prevalence of defined neuropsychiatric disease in first-degree and second-degree relatives of patients with ALS and matched controls was determined. Results Mean (SD) age at diagnosis of the 127 patients in the study (58 women and 69 men) was 64.2 (10.7) years. Data from 2116 relatives of patients with ALS were reported, including 924 first-degree relatives, 1128 second-degree relatives, and 64 third-degree relatives. Data from controls were reported from 829 first-degree and 1310 second-degree relatives. A total of 77 patients with ALS (61.4%) and 51 control participants (38.6%) reported at least 1 first-degree or second-degree relative with a history of schizophrenia, psychosis, suicide, depression, alcoholism, or autism (relative risk [RR], 1.50; 95% CI, 1.08-2.17; P?=?.02). Cluster analysis suggested the following 2 subgroups based on the number of family members with a neuropsychiatric condition: expected (0-2) and high (=3). Within the high subgroup, ALS kindreds presented a significantly higher rate of psychiatric illness than did controls (28 of 39 [71.8%]; mean [SD] number of siblings, 4.29 [1.41]; P?=?.001). A strong family history of schizophrenia (RR, 3.40; 95% CI, 1.27-9.30; P?=?.02), suicide (RR, 3.30; 95% CI, 1.07-10.05; P?=?.04), autism (RR, 10.10; 95% CI, 1.30-78.80; P?=?.03), and alcoholism (RR, 1.48; 95% CI, 1.01-2.17; P?=?.045) was reported in ALS kindreds. A total of 5 of 29 probands (17.2%) with a strong family history of neuropsychiatric conditions (=3 first-degree or second-degree relatives) carried the C9orf72 repeat expansion. Conclusions and Relevance Neuropsychiatric symptoms in addition to schizophrenia, including obsessive-compulsive disorder, autism, and alcoholism, occur more frequently in ALS kindreds than in controls. The presence of the C9orf72 repeat expansion does not fully account for this finding, suggesting the presence of additional pleiotropic genes associated with both ALS and neuropsychiatric disease in the Irish population.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

JAMA Neurology

ISSN

2168-6149

Publisher

American Medical Association

Issue

12

Volume

74

Page range

1425-1430

Department affiliated with

  • BSMS Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2017-10-26

First Open Access (FOA) Date

2018-10-16

First Compliant Deposit (FCD) Date

2017-10-26

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