Abstract
The finding that new variant Creutzfeldt-Jakob disease, the recently discovered prion disease thought to be associated with ingestion of bovine offal1, has a prolonged course and can present with psychiatric symptoms2 raised the possibility that hereditary forms of prion disease may also be associated with serious psychiatric disorders. We have sequenced the open reading frame of the prion protein (PrP) gene isolated from 10 patients with a strong family history of psychiatric illness. In one patient we discovered a previously undescribed sequence alteration, N171S, which raises the possibility of a significant extension in the pathologies associated with inherited prion diseases.
Main
We studied 10 individuals from families with a high incidence of schizophrenic or schizoaffective (DSM-IV) disorders. We sequenced the prion protein gene (PRNP) directly from polymerase chain reaction products amplified from peripheral blood leukocytes from each of these patients. In nine families where the disease was confined to schizophrenia we found no mutations, but one other patient exhibited a previously undescribed adenine to guanine substitution, resulting in an asparagine to serine alteration at codon 171 of the PRNP gene. The individual was a heterozygote for codon 129, a site of a common polymorphism3, and by subsequent cloning and sequencing we found that the mutated allele encoded valine at codon 129. We also found this genotype in five of eleven living relatives of the patient (Fig. 1).
The patient suffered persecutory delusions, auditory hallucinations, severe depression and had a history of suicide attempts and violent behaviour over a 10-year period. Neurological symptoms such as ataxia or dementia, typical of known prion diseases4, were absent. Of the other members of the patient's family identified as mutation carriers, the patient's mother has dementia and urinary incontinence and a 35-year history of similar psychiatric symptoms. The patient's uncle presented seven years ago with abnormal behaviour including apathy, social withdrawal, mutism and occasional violence, and subsequently developed urinary and faecal incontinence, walking difficulty and dementia. Two affected siblings have a psychiatric history of alternating severe depression and aggressiveness and one of them also has persecutory delusions and auditory hallucinations whereas the third was symptom-free.
This pedigree exhibits incomplete penetrance and variable expression of the disease, typical of inherited prion diseases. None of these patients can be easily classified within well-defined clinical categories and all responded poorly to conventional therapies. Of the five siblings with normal PRNP genotype, four have had no psychiatric or neurological illness whereas the fifth has bipolar disorder, characterized by sequences of euphoric, depressive and normal periods. This patient lacks the complex disease progression seen in the family members with N171S.
Our findings indicate that inherited prion diseases might include serious atypical psychiatric disorders, in addition to the well-defined strictly neurological pathologies4 and personality changes5. An analysis of a large number of affected families and individuals known to be free of any mental disorders will establish the frequency of the new PRNP genotype and the strength of its association with mental disease.
References
Collinge, J. Hum. Mol. Genet. 6, 1699–1705 (1997).
Will, R. G. et al. Lancet 347, 921–925 (1996).
Goldfarb, L. G. et al. Science 258, 806–808 (1992).
Prusiner, S. B. Arch. Neurol. 50, 1129–1152 (1993).
Nitrini, R. et al. Ann. Neurol. 42, 138–146 (1997).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Samaia, H., de Jesus Mari, J., Vallada, H. et al. A prion-linked psychiatric disorder. Nature 390, 241 (1997). https://doi.org/10.1038/36757
Issue Date:
DOI: https://doi.org/10.1038/36757
This article is cited by
-
Hereditary Human Prion Diseases: an Update
Molecular Neurobiology (2017)
-
The M129V polymorphism of codon 129 in the prion gene (PRNP) in the Danish population
European Journal of Epidemiology (2008)
-
Genetic prion disease: the EUROCJD experience
Human Genetics (2005)
-
Lack of evidence to support the association of the human prion gene with schizophrenia
Molecular Psychiatry (2001)
-
Creutzfeldt-Jakob disease and the eye. I. Background and patient management
Eye (2000)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.