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Yu CE, Marchani E, Nikisch G, Müller U, Nolte D, Hertel A, Wijsman EM, Bird TD. The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010 May;67(5):631-3. PubMed.
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In The Thousand Mile Stare, I describe a frightening scene in which my sister threatened to kill my brother-in-law because she thought he was a stranger who broke into the house. This is only one of a number of incidents in which paranoid behavior has been exhibited by members of my family while in the throes of living with Alzheimer's. I also described how one of my uncles, who was institutionalized as was Frau D., lay curled up in the fetal position, incontinent and unresponsive in the final stage of his disease. This also happened to more than one of my family members. These descriptions are quite similar to Dr. Alzheimer's observations of his patient, who did not trust, and was at times, afraid of her family, and reacted in a paranoid fashion to her caregivers. And, she was described in the final stage of her disease as lying in her bed, curled in the fetal position, incontinent and unresponsive. I find the similarity of the descriptions of Frau D.'s suffering uncannily similar to the suffering of my family, and the age of onset of her symptoms and death are precisely that of my father and of many other members of my family.
And one more personal observation, even more subjective. The first time I saw a picture of Frau D., I thought I was looking at the picture of a relative. The cheekbones and eyes appear very similar to the facial construction of my father's generation that was 100 percent ethnic German.
View all comments by Gary ReiswigAC Immune SA
The discussion of founder effects of the different FAD mutations is an interesting topic and can increase our knowledge about familial Alzheimer disease, maybe even AD overall.
This mutation is certainly very old. It is possible that it traveled from Germany to the Volga region and then the U.S. One question one could ask next is whether the phenotype of the disease caused by a given mutation expressed in different environments is different. To do this, it would be necessary to compare phenotypes in larger pedigrees living in separated, well-defined areas.
Having a family described in Fulda is clear proof that this particular presenilin-2 mutation is still “alive” in Germany. More generally, there are surprisingly few FAD cases with demonstrated mutations in Germany, as compared to Sweden, England, Spain, and Belgium, for example. Whether this is due to relatively little ongoing human AD genetics research, few carriers, or few large pedigrees in Germany remains an open question. An argument toward the second possibility is that for other neurodegenerative diseases (e.g., PD or CADASIL), research groups in Germany have successfully identified pedigrees, meaning the methods and interest seem to be in place. My previous group's search for FAD mutations in German and Swiss families found a presenilin-1 mutation in a family of whom one carrier agreed to participate in neuroimaging research (Mondadori et al., 2006).
References:
Mondadori CR, Buchmann A, Mustovic H, Schmidt CF, Boesiger P, Nitsch RM, Hock C, Streffer J, Henke K. Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years. Brain. 2006 Nov;129(Pt 11):2908-22. PubMed.
StatSoft, Inc
This is certainly the evidence we all have been waiting for: a "Founder" effect originating in Germany, rather than the Volga River region of Russia where this mutation had been traced to previously. This discovery by Dr. Tom Bird and colleagues at the University of Washington-Seattle may unfold to show that the number of people affected by this mutated gene is larger than previously thought, e.g., that the families from Fulda, Germany, and the American Volga German families with eFAD share the same N141I PSEN2 mutation on an identical haplotypic background. [Editor's note: Gary Miner is prominently featured in Gary Reiswig's book, The Thousand Mile Stare; see ARF related news story.]
References:
Familial Alzheimer's Disease: Molecular Genetics & Clinical Perspectives, Edited by Miner, Richter, Blass, Valentine, and Winters-Miner, 1989. Dekker, NY: ISBN 0-8247-8068-X (alk.paper)
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