TPH2 polymorphisms and expression in Prader-Willi syndrome subjects with differing genetic subtypes

Prader-Willi syndrome (PWS) is a genetic imprinting disease that causes developmental and behavioral disturbances resulting from loss of expression of genes from the paternal chromosome 15q11-q13 region. In about 70% of subjects, this portion of the paternal chromosome is deleted, while 25% have two copies of the maternal chromosome 15, or uniparental maternal disomy (UPD; the remaining subjects have imprinting center defects. There are several documented physical and behavioral differences between the two major PWS genetic subtypes (deletion and UPD) indicating the genetic subtype plays a role in clinical presentation. Serotonin is known to be disturbed in PWS and affects both eating behavior and compulsion, which are reported to be abnormal in PWS. We investigated the tryptophan hydroxylase gene (TPH2), the rate-limiting enzyme in the production of brain serotonin, by analyzing three different TPH2 gene polymorphisms, transcript expression, and correlation with PWS genetic subtype. DNA and RNA from lymphoblastoid cell lines derived from 12 PWS and 12 comparison subjects were used for the determination of genetic subtype, TPH2 polymorphisms and quantitative RT-PCR analysis. A similar frequency of TPH2 polymorphisms was seen in the PWS and comparison subjects with PWS deletion subjects showing increased expression with one or more TPH2 polymorphism. Both PWS deletion and PWS UPD subjects had significantly lower TPH2 expression than control subjects and PWS deletion subjects had significantly lower TPH2 expression compared with PWS UPD subjects. PWS subjects with 15q11-q13 deletions had lower TPH2 expression compared with PWS UPD or control subjects, requiring replication and further studies to identify the cause including identification of disturbed gene interactions resulting from the deletion process

Uncommon genetic syndromes and narrative production - Case Studies with Williams, Smith-Magenis and Prader- Willi Syndromes

This study compares narrative production among three syndromes with genetic microdeletions: Williams syndrome (WS), Smith-Magenis syndrome (SMS), and Prader-Willi syndrome (PWS), characterized by intellectual disabilities and relatively spared language abilities. Our objective is to study the quality of narrative production in the context of a common intellectual disability. To elicit a narrative production, the task Frog! Where Are You was used. Then, structure, process, and content of the narrative process were analysed in the three genetic disorders:WS (n52), SMS (n52), and PWS (n52). Data show evidence of an overall low narrative quality in these syndromes, despite a high variability within different measures of narrative production. Results support the hypothesis that narrative is a highly complex cognitive process and that, in a context of intellectual disability, there is no evidence of particular ‘hypernarrativity’ in these syndromes.This research was supported by the grants FEDER –

Prader-Willi syndrome: A primer for clinicians

The advent of sensitive genetic testing modalities for the diagnosis of Prader-Willi syndrome has helped to define not only the phenotypic features of the syndrome associated with the various genotypes but also to anticipate clinical and psychological problems that occur at each stage during the life span. With advances in hormone replacement therapy, particularly growth hormone children born in circumstances where therapy is available are expected to have an improved quality of life as compared to those born prior to growth hormone

Different distribution of the genetic subtypes of the Prader–Willi syndrome in the elderly

The Prader–Willi syndrome (PWS) is a genetic disorder caused by the absent expression of the paternal copy of maternally imprinted genes in chromosome region 15q11–13. The frequencies of different subtypes in PWS are usually given in literature as 70% deletion, 25–30% maternal uniparental disomy (mUPD) and 3–5% others (imprinting centre (IC) defects and translocations). Little is known about factors that influence the frequency of genetic subtypes in PWS. The study sample comprised 102 adults with clinically and genetically confirmed PWS, contacted through the Dutch Prader–Willi Parent Association and through physicians specialized in treating persons with intellectual disabilities. Genetic testing showed 55 persons (54%) with a paternal deletion, 44 persons (43%) with an mUPD and 3 persons (3%) with a defect of the IC. The observed distribution in our study differed from that in literature (70% deletion, 30% mUPD), which was statistically significant (z-score: P<0.05). This was mainly caused by a higher proportion of mUPD in the advanced age groups. Differences in maternal age and BMI of persons with PWS could not explain the differences in distribution across the age groups. Our study population had a much broader age range, compared with other studies, because of a predominance of elderly people (40+ years) with PWS. In other studies, these elderly persons might have been undiagnosed and/or underreported because of a lack of genetic diagnosis. The results underline both the need for correct genetic diagnosis in all persons with PWS and adjustment of the guidelines for preventive management in adulthood