Genetic Epidemiology of Amyotrophic Lateral Sclerosis
Genetische epidemiologie van amyotrofische lateraal sclerose
This thesis aims to use epidemiologic methods to investigate genetic and environmental factors playing a role in ALS. We conducted a case control study between 1989-1991 at the Neurological Institute Columbia University Medical Center in New York. The study population consisted of 151 newly diagnosed ALS patients and 140 neurologic controls, matched for age (+ 5 years), gender (83 pairs of men and 57 pairs of women) and insurance status. In chapter 2 the current insights in the relation of ALS, dementia and parkinsonism is summarized. As described in the review (chapter 3) until the 1960s, ALS was considered to be a non-hereditary neurologic disease. In a land-mark report in 1955, Kurland and Mulder described 18 families with hereditary ALS from a 100-year review of the world literature. Only in the past decade, genetic analysis of familial forms of ALS led to the identi.cation of several mendelian inherited forms of ALS. These familial forms comprise 5-10% of all cases. Thus far six autosomal dominant and three autosomal recessive forms were found to be associated with familial ALS. In addition, a growing number of genetic defects are being associated with syndromes featuring familial recurrence of ALS, frontotemporal dementia and parkinsonism. In the 90% of cases were ALS is sporadic, changes in various genes have been linked to an increased risk for ALS, so called susceptibility genes. Susceptibility genes are thought to interact with other low penetrant genes and/or with environmental risk factors. In chapter 4 of this thesis we used epidemiologic methods to .nd evidence for a shared genetic susceptibility for ALS, dementia and parkinsonism. To do so, we investigated familial aggregation of these three disorders in families of ALS patients. In the casecontrol study we compared the family histories of ALS patients and controls. A semistructured questionnaire was used to ascertain valid information on neurologic conditions for each sibling, parent and grandparent, individually. The data showed familial recurrence of ALS in .ve percent of the patients and not in controls. We found that the risk (cumulative incidence) of dementia was twofold increased for relatives of ALS patients.
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