Family Members of ALS Patients at Increased Risk of Mental Illness

October 20, 2017

By Lorraine L. Janeczko

NEW YORK—Family members of patients with amyotrophic lateral sclerosis (ALS) are at increased risk for developing neuropsychiatric and neurodegenerative disorders, new research from Ireland suggests.

Alcoholism, autism, obsessive-compulsive disorder, psychotic illness, schizophrenia and suicide occur more frequently in ALS kindreds than in controls, the authors report in JAMA Neurology, online October 16.

"ALS is a heterogeneous condition. Our family-aggregation study clearly shows the presence of 'neuropsychiatric endophenotypes' within kindreds of those with ALS. The endophenotypes are not uniformly distributed across the entire ALS population, but rather within approximately 30% of ALS kindreds," Dr. Orla Hardiman of Trinity College Dublin told Reuters Health by email.

"What we consider to be 'familial ALS' (a proxy for a genetic form of the condition) may also encompass other neurological and neuropsychiatric conditions,” she added. “We propose that these conditions all represent disorders of neural networking. The concept of ALS as a 'network disorder' is novel and opens up entirely new perspective in terms of the types of drugs that we might consider using, and also the outcomes that we might use to measure drug efficacy."

Dr. Hardiman and her colleagues invited all 202 patients listed in the Irish ALS Register over a two-year period as having definite, probable, or possible ALS to take part in the study. The 127 patients (mean age at diagnosis, 64; 54% male) who agreed to participate were genotyped for the C9orf72 repeat expansion. The researchers also included 132 age- and sex-matched controls, regardless of neuropsychiatric disease status.

Data were available from 2,116 relatives of patients with ALS, including 924 first-degree relatives, 1,128 second-degree relatives, and 64 third-degree relatives; among controls, the team obtained data from 829 first-degree and 1,310 second-degree relatives. All participants completed questionnaires about neurologic and neuropsychiatric conditions in themselves and their families and were interviewed if possible.

Overall, 61.4% patients with ALS and 38.6% of controls reported at least one first-degree or second-degree relative with a history of alcoholism, autism, depression, psychosis, schizophrenia, or suicide (relative risk, 1.50; P=0.02).

Cluster analysis identified two subgroups based on how many family members had a neuropsychiatric condition: “expected” (between none and two affected family members) and “high” (three or more).

A significantly higher percentage of ALS family members than control family members were present in the “high” group.

Strong and statistically significant family histories of alcoholism, autism, schizophrenia, and suicide were reported in ALS family members.

Among the 29 probands with a strong family history of neuropsychiatric conditions (three or more first- or second-degree relatives), five (17.2%) carried the C9orf72 repeat expansion.

Outside experts welcomed the new research.

"The elegant study is not completely surprising because an association between ALS and schizophrenia had already been reported in Irish kindreds,” said Dr. Sabrina Paganoni of Massachusetts General Hospital in Boston, whose research focuses on developing ALS therapy.

“However, the study is novel in that it expands the spectrum of neuropsychiatric diseases that appear to be more common in families of people with ALS and clarifies that this increased risk is not completely accounted for by the C9orf72 repeat expansion," Dr. Paganoni told Reuters Health by email.

Dr. James Wymer of the University of Florida in Gainesville, who coauthored an editorial about the study, told Reuters Health by email, "ALS is a more complex disease than we had thought. The involvement of psychiatric disease is not entirely unexpected, but the range of diseases found is unexpected. This finding, if corroborated, will help expand our understanding of the pathophysiology of ALS and gives us new potential treatment options."

"This study, however, only identified a correlation between the two," he added. "We need more research on this topic before we can say there is a direct association between ALS and psychiatric diseases."

Dr. Douglas Williamson, an instructor in the department of psychiatry and behavioral sciences at Duke University in Durham, North Carolina, said the study “represents a first step toward discovering the underlying mechanisms of ALS and, as a result, facilitates the development of preventive therapies for this debilitating condition.”

“The important takeaway from this fascinating study is that it points us toward the need to identify the specific shared genetic mechanisms between ALS and neuropsychiatric conditions,” Dr. Williamson told Reuters Health by email. “Discovery of these genes and related molecular pathways could lead to new treatments for both ALS and neuropsychiatric disease."

To Dr. Raymond P. Roos, a professor of neurology at the University of Chicago, one of the most surprising findings was the higher incidence of autism “since this is a disease of childhood whereas ALS is an adult disease."

"The study’s results bring up the possibility that C9orf72-negative kindreds with ALS and neuropsychiatric diseases may have other mutated genes responsible for the clinical abnormalities," he told Reuters Health by email.

Dr. Hardiman cautioned that the work was based on family interviews and that her team had not directly examined relatives. Her group is performing whole-genome sequencing on kindreds and planning to develop new markers of disease progress.


JAMA Neurol 2017.

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