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Chromosome 15 maternal uniparental disomy and psychosis in Prader-Willi syndrome

Centre for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium

Correspondence to:
Professor J-P Fryns, Centre for Human Genetics, Herestraat 49, 3000 Leuven, Belgium;
Jean-Pierre.Fryns{at}med.kuleuven.ac.be]

Keywords: chromosome 15; maternal uniparental disomy; psychosis; Prader-Willi syndrome

In the 16 January 2002 issue of the Lancet, Boer et al¹ reported that psychotic illness in Prader-Willi syndrome (PWS) is associated with chromosome 15 maternal uniparental disomy. Here, we report the findings of a 10 year follow up study at the Centre for Human Genetics in Leuven, confirming the results of the previous study.

MATERIALS AND METHODS
Fifty-nine PWS patients with the diagnosis confirmed by DNA methylation testing had regular and long term follow up at the Centre for Human Genetics in Leuven. For more then 10 years, these patients have been seen at least once a year by a clinical geneticist and a psychiatrist skilled in the assessment of people with learning disabilities. Detailed information on clinical and psychiatric history was recorded in the medical files for all patients. For the past two years all patients were offered a DNA methylation test using probes PW71B and KB17 and FISH analysis for 15q11-12 deletion detection. If FISH analysis did not show a deletion, blood samples were taken from the parents to test for uniparental disomy. If no uniparental disomy was found, an imprinting centre deletion was examined (Essen, Germany).

RESULTS AND DISCUSSION
In 51 out of the 59 patients, the exact genetic type was established: 37 patients had a deletion, eight patients had uniparental heterodisomy, and one patient had uniparental isodisomy. Three patients with a typical PWS clinical phenotype showed only a typical PWS methylation abnormality with probes PW71B and KB17 but no further abnormality was detected (no uniparental disomy, no microdeletion, no IC deletion). These three patients presumably have a sporadic imprinting centre defect. A de novo translocation 46,XX,t(11;15)(q25;q11.2) was found in one patient. Blood samples from the parents for analysis of uniparental disomy were not available in one patient.

Key points Prader-Willi syndrome (PWS) is known to be associated with a high rate of psychotic disorders and an association between psychotic illness in PWS and chromosome 15 maternal uniparental disomy has been reported. Fifty-nine patients with the PWS diagnosis confirmed by DNA methylation testing had a full psychiatric assessment. In all patients, the exact genetic subtype (15q11-12 deletion, uniparental disomy, imprinting centre defect) was established. Six patients (15.7%) had experienced a psychotic episode with an age of onset varying from 13 to 19 years. Five out of these six patients had uniparental disomy and the sixth patient had an imprinting centre defect. These data further support the hypothesis that an abnormal imprinting pattern of genes might lead to development of psychotic illness in PWS.

 

Six out of these 59 patients have experienced a psychotic episode with "acute onset and shifting and polymorphous symptomatology" as defined by Perris in 1988² and described in PWS patients by Clarke in 1993.³ The age of onset of the psychotic episodes in the six patients in the present study varied from 13 years to 19 years. In the patient group older than 13 years (mean age 27.7 years), six out of 38 (15.7%) had psychotic episodes. The somewhat higher rate in the English population (28% or 7/25) is probably the result of the older age of that PWS population (28 years and older), but the difference is not statistically significant. Because we have included all patients older than 13, there is a risk that some of them might still develop a psychotic episode.

Table 1 shows the sex, age at onset, genetic status, and symptoms in these six patients. Five out of six patients with psychotic illness had uniparental disomy. Two patients had confirmed maternal heterodisomy. The results in the other three patients were compatible with heterodisomy, but these results could not be proven because the father of these patients had died. None of the psychotic patients had a deletion.

REFERENCES

1. Boer H, Holland A, Whittington J, Butler J, Webb T, Clarke D. Psychotic illness in people with Prader Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet 2002;359:135–6.[CrossRef][Medline]
2. Perris C. The concept of cycloid psychotic disorder. Psychiatr Dev 1988;1:37–56.
3. Clarke DJ. Psychosis and Prader Willi. Br J Psychiatry 1993;163:680–4.[Abstract/Free Full Text]

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