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The Potential for Genetic Etiology

Jill S. Goldman, MS, MPhil, CGC; Bruce L. Miller, MD; Jiri Safar, MD; Sunita de Tourreil, MSc; Jennifer L. Martindale, BS, BA; Stanley B. Prusiner, MD; Michael D. Geschwind, MD, PhD

Arch Neurol. 2004;61:213-216.

Background  Approximately 2% of Alzheimer disease cases and 10% to 15% of prion disease cases are due to mutations in autosomal dominant genes. Mutations have been found in patients without family histories of neurological disease.

Objectives  To emphasize the need for consideration of a genetic etiology of prion disease and early-onset Alzheimer disease, regardless of the absence of a significant family history, as well as the need for pretest genetic counseling of all patients or their families.

Design  Three case reports.

Patients and Results  Patient 1, a 53-year-old man with possible Creutzfeldt-Jakob disease, was enrolled in a research study that included sequencing of the prion protein gene. Although there was no family history of neurological disease, an E200K mutation was found. This unexpected result caused the family significant distress. Patient 2, a 55-year-old woman with biopsy-proven Creutzfeldt-Jakob disease, participated in a prion disease research study. Her family was counseled about the possibility of hereditary Creutzfeldt-Jakob disease, despite the lack of family history. After assessing the ramifications, the family decided not to learn about the patient's genetic test results. Patient 3 was a 54-year-old man with a 6-year history of memory loss. A diagnosis of probable Alzheimer disease was given, and the patient and his family were counseled on the availability of presenilin 1 testing, although there was no known family history of dementia. The family agreed to testing, and a presenilin 1 mutation was identified.

Conclusions  Certain neurodegenerative diseases may have a genetic etiology, despite the lack of a positive family history. Revealing a newly discovered hereditary cause of Creutzfeldt-Jakob disease or Alzheimer disease can have a profound effect on families. Pretest counseling on genetic issues is essential to better prepare families and to allow them to make an informed choice about learning genetic test results.

From the University of California, San Francisco, Memory and Aging Center (Mss Goldman and Martindale and Drs Miller and Geschwind); Institute for Neurodegenerative Diseases (Drs Safar and Prusiner and Ms de Tourreil); and Departments of Neurology (Drs Safar and Prusiner) and Biochemistry and Biophysics (Dr Prusiner), University of California, San Francisco, San Francisco, Calif.

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