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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).

Figure 1: Family pedigree.
figure 1

Squares denote males and circles denote females. Black symbols indicate definitive psychiatric disorders affecting family members and half-black symbols denote the family members with plausible psychiatric symptoms. The age of each individual is shown below the symbols. N, normal; M, mutant allele. The first identified patient was individual number 12.

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.