The Heritability of Amyotrophic Lateral Sclerosis in a Clinically Ascertained United States Research Registry

The genetic basis of amyotrophic lateral sclerosis (ALS) is not entirely clear. While there are families with rare highly penetrant mutations in Cu/Zn superoxide dismutase 1 and several other genes that cause apparent Mendelian inheritance of the disease, most ALS occurs in families without another affected individual. However, twin studies suggest that all ALS has a substantial genetic basis. Herein, we estimate the genetic contribution to ALS in a clinically ascertained case series from the United States.We used the database of the Emory ALS Center to ascertain individuals with ALS along with their family histories to determine the concordance among parents and offspring for the disease. We found that concordance for all parent-offspring pairs was low (<2%). With this concordance we found that ALS heritability, or the proportion of the disease explained by genetic factors, is between 40 and 45% for all likely estimates of ALS lifetime prevalence.We found the lifetime risk of ALS is 1.1% in first-degree relatives of those with ALS. Environmental and genetic factors appear nearly equally important for the development of ALS

Heritability of Amyotrophic Lateral Sclerosis.

<p>A contour plot of the ALS heritability as a function of male and female lifetime ALS prevalence. The bar on the right shows the color code for the corresponding heritability value. The black lines on the graph show the boundaries for heritability values given by the corresponding number above the line.</p

Demographics.

1<p>Racial data collected was collected from 2007 and is present for 47.7% of the cohort. Percentages based on 508 individuals with available data.</p>2<p>9.4% of probands had insufficient data to establish an age of onset.</p>3<p>6.6% of probands had insufficient data to establish where their first symptoms began. Percentages were based on the total of 1015 individuals.</p

Parent-Offspring Concordance for ALS.

1<p>Missing paternal data on one male proband's father; thus the totals for Male Proband–Father and Male Proband–Mother pairs are not equal.</p

Behavior matters--cognitive predictors of survival in amyotrophic lateral sclerosis.

It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren't comparable with assessments in other dementias.The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients.The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival.ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival

Receiver operating characteristics curve for ALS-BCA and MMSE for the diagnosis of ALS-D.

<p>Areas under the curve are 0.946 for ALS-BCA and 0.746 for MMSE.</p

Baseline characteristics of the validation cohort, including healthy control subjects and ALS patients according cognitive status of normal cognition, cognitive impairment but no dementia (ALS-CI), or dementia (ALS-D).

<p>ALS-BCA: ALS Brief Cognitive Assessment; MMSE: Mini-Mental Status Examination score; TMT: Trail making test;</p>*<p>different from ALS subjects with normal cognition;</p>†<p>different from ALS subjects with normal cognition and ALS-CI.</p