Clinical and molecular neurogenetics and neuromics have achieved considerable success recently in providing a clearer understanding of gene interactions responsible for neurologic disorders such as Alzheimer’s disease, multiple sclerosis (MS), and cortical brain malformations. “Clearly, the field of neurogenetics/neuromics is alive and well, prospering with an avalanche of new concepts and innovative data,” said Roger N. Rosenberg, MD, Editor of Archives of Neurology, in an editorial highlighting the wide range of original scientific reports in the March and April issues of the journal. Dr. Rosenberg is a Professor of Neurology at the University of Texas Southwestern Medical Center at Dallas.
Genetics and Risk for Alzheimer’s Disease
If both parents have a clinical diagnosis of Alzheimer’s disease, are their children at increased risk? That was the question Suman Jayadev, MD, and colleagues attempted to answer in a retrospective study of 111 conjugal couples who had 297 children surviving to adulthood. Of the 297 offspring, 22.6% had developed Alzheimer’s disease, with the risk increasing as they aged. Among those older than 60, 31% (58 of 137) had Alzheimer’s disease; among those older than 70, 41.8% (41 of 98) had the disease. Dr. Jayadev, Assistant Professor of Neurology, University of Washington, Seattle, pointed out that because 79% of the offspring are younger than 70, the risk of occurrence will only increase. This work confirmed results of a small pilot study involving the offspring of 31 of the couples, which found a higher rate of Alzheimer’s disease than would be expected in the general population.
“A family history of Alzheimer’s disease beyond the parents did not change the risk of Alzheimer’s disease in the children but did reduce the median age at onset in affected children,” Dr. Jayadev and colleagues said. In addition, although the apolipoprotein E ε4 allele has an important role, it “did not account for all Alzheimer’s disease cases in offspring, supporting the hypothesis that this is a complex polygenic phenomenon” and calling for a better definition of the role of family history and specific genes involved, they concluded.
Genome-wide association studies are being used as a tool for identifying genetic contributions to complex diseases and have shown success, for example, in helping to identify risk for age-related macular generation and diabetes mellitus. “Whether this will hold true for a genetically complex and heterogeneous disease such as Alzheimer’s disease is not known, although early reports are encouraging,” noted Dr. Rosenberg and Stephen C. Waring, DVM, PhD, Assistant Professor in the Department of Epidemiology at the University of Texas School of Public Health at Houston and a researcher with the Texas Alzheimer’s Research Consortium. Drs. Rosenberg and Waring reported on results of genome-wide association studies to date that combine high-throughput arrays, bioinformatics, and advances in software to investigate significant markers associated with the risk of Alzheimer’s disease.
Examining Single-Gene Neurogenetic Disorders
In another study, Thomas D. Bird, MD, and colleagues conducted a retrospective review to describe the occurrence of single-gene neurogenetic disorders in eight elderly patients. Seven patients were men—two had Huntington’s disease (ages 85 and 87), three had spinocerebellar ataxia types 5, 6, and 14 (ages 86, 78, 78, respectively), one had presenilin 1 familial Alzheimer’s disease mutation (age 85), and one had autosomal dominant hereditary neuropathy (age 87). An 84-year-old woman had limb-girdle muscular dystrophy type 2A.
“Three patients had no family history of neurologic disease,” said Dr. Bird, a Professor of Neurology at the University of Washington, Seattle, and colleagues. “Their median age of 83 years is remarkable because genetic diseases are generally assumed to be relegated to much younger populations.” Five patients had late symptom onset; the other three “had onset of symptoms at much younger ages but survived many decades and did not receive specific genetic diagnoses until relevant genetics tests became available in their senior years.”
The researchers noted that recognition of single-gene diseases in elderly patients can be explained by the aging of the population, increased awareness of symptom onset, and DNA-based genetic testing. “The specific diagnosis of genetic diseases is readily available to a degree completely unknown a few years ago,” they said. “Patients in this study would have been considered to have senile chorea, senile dementia, and unexplained myopathy before the advent of such testing.”
Parent-of-Origin Effect
Ilse A. Hoppenbrouwers, MD, from the Department of Neurology, MS Centre Erasmus, Rotterdam, the Netherlands, and colleagues investigated parental relationships among patients with MS using extensive genealogic information from the Genetic Research in Isolated Populations program. Fewer than 400 individuals comprised the mid-18th-century founding population of a region located in the southwest Netherlands. To date, approximately 20,000 descendants live in eight adjacent communities and are generally related. More than 90,000 people spanning 23 generations are included in a genealogic database. Of these, 24 patients (19 women) with MS “could be linked to the most recent common ancestor in 14 generations.”