Neuropsychiatric Disorders and Amyotrophic Lateral Sclerosis

Epidemiological data suggest that ALS is linked to a wide spectrum of neuropsychiatric disorders in families. Expansion of C9orf72 accounts for up to 10% of ALS cases and up to 30% of frontotemporal dementia in Europeans. C9orf72 also linked to other neuropsychiatric conditions, such as Huntington disease, obsessive-compulsive disorder, and bipolar disorder. But rates of psychosis and suicidal behavior are also higher in relatives of ALS patients without this gene variant. What neuropsychiatric conditions are relatives of people with ALS at risk for? Are other genes involved besides C9orf72?

The study comprised 127 patients from the Irish ALS Register between January 2012 to January 2014. There were 58 women and 69 men with a mean age of 64.2 years. Study subjects were matched by age and sex to 132 controls. Researchers looked at family data from 2116 ALS relatives, and 139 control relatives. Participants were genotyped for C9orf72 repeat expansion.

Compared with controls, increased risk of neuropsychiatric disorders were seen in first and second-degree relatives of ALS patients. Findings indicate over 3 times increased risk of schizophrenia or psychotic illness (RR 3.40, 95% CI, 1.27-9.30; P = .02); over 3 times increased risk of death by suicide (RR 3.30, 95% CI, 1.07-10.05; P = .04); over 10 times increased risk of autism (RR 10.10; 95% CI, 1.30-78.80; P = .03); 48% increased risk of alcoholism (RR, 1.48; 95% CI, 1.01-2.17; P = .045); and over 5 times increased risk of OCD and rigid personality disorder (RR 5.60; 95% CI, 1.23-25.05; P = .02).

The C9orf72 repeat expansion was carried by 17.2% of ALS patients with a strong family history of neuropsychiatric conditions. Depression and alcoholism were the most common neuropsychiatric conditions linked to C9orf72. The majority (79.3%) of ALS patients carried no known pathogenic variants of C9orf72.

“The presence of the C9orf72 repeat expansion does not fully account for [these] finding[s], suggesting the presence of additional pleiotropic genes associated with both ALS and neuropsychiatric disease in the Irish population,” wrote first author Margaret O’Brien, PhD, Trinity College Dublin, Dublin, Ireland, and colleagues.

This study confirms findings from previous epidemiological studies that link ALS and schizophrenia. Moreover, this study extends findings to other neuropsychiatric conditions involved with impulse control, addiction, alcoholism, personality rigidity, and autism spectrum disorder.

Reference
O'Brien M, Burke T, Heverin M, et al. Clustering of neuropsychiatric disease in first-degree and second-degree relatives of patients with amyotrophic lateral sclerosis. JAMA Neurol. 2017;74:1425-1430.