Genetic Subtypes Of Prader-Willi Syndrome Research Articles

Expressive and receptive language in Prader–Willi syndrome: Report on genetic subtype differences

Prader–Willi syndrome (PWS), most recognized for the hallmark hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the q11-13 region of chromosome 15. Since the recognition of PWS as a genetic disorder, most research has focused primarily on the medical, genetic, and behavioral aspects of the syndrome. Extensive research has not been conducted on the cognitive, speech, and language abilities in PWS. In addition, language differences with regard to genetic mechanism of PWS have not been well investigated. To date, research indicates overall language ability is markedly below chronological age with expressive language more impaired than receptive language in people with PWS. Thus, the aim of the present study was to further characterize expressive and receptive language ability in 35 participants with PWS and compare functioning by genetic subtype using the Clinical Evaluation of Language Fundamentals-4 (CELF-IV). Results indicate that core language ability is significantly impaired in PWS and both expressive and receptive abilities are significantly lower than verbal intelligence. In addition, participants with the maternal uniparental disomy (mUPD) genetic subtype exhibit discrepant language functioning with higher expressive vs. receptive language abilities. Future research is needed to further examine language functioning in larger genetic subtype participant samples using additional descriptive measures. Further work should also delineate findings with respect to size of the paternal deletion (Type 1 and Type 2 deletions) and explore how overexpression of maternally expressed genes in the 15q11-13 region may relate to verbal ability.Learning outcomes: After reading this article, the reader will be able to: (1) summarize primary characteristics of Prader–Willi syndrome (PWS), (2) describe differentiating characteristics for the PWS genetic subtypes, (3) recall limited research regarding language functioning in PWS to date, (4) summarize potential genetic variations of language ability in Prader–Willi syndrome, and (5) summarize language ability in PWS with respect to adaptive functioning.

The neuroanatomy of genetic subtype differences in Prader–Willi syndrome

Despite behavioral differences between genetic subtypes of Prader-Willi syndrome (PWS), no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of PWS [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)]. Fifteen individuals with PWS due to a typical deletion [(DEL) type I; n = 5, type II; n = 10], eight with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume (WMV) between groups, covarying for age, sex, and body mass index (BMI). Overall, compared to HWC, PWS individuals had lower gray matter volumes (GMV) that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower WMVs in the brain stem, cerebellum, medial temporal, and frontal cortex. Compared to UPD, the DEL subtypes had lower GMV primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and WMVs in the orbitofrontal and limbic cortices compared to HWC. These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes.

Relationship between the IQ of people with Prader–Willi syndrome and that of their siblings: evidence for imprinted gene effects

Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs. higher performance IQ in the other; slower than normal reaction time in one vs. normal in the other). In a population study of PWS, the IQ distribution of people with PWS was approximately normal. This raises the question of whether this distribution arose from a systematic effect of PWS on IQ (hypothesis 1) or whether it was the fortuitous result of random effects (hypothesis 2). The correlation between PWS and sibling IQ was determined in order to discriminate between the two hypotheses. In the first case we would expect the correlation to be similar to that found in the general population (0.5); in the second case it would be zero. It was found that the overall PWS-sibling IQ correlation was 0.3 but that the two main genetic subtypes of PWS differed in their familial IQ relationships. As expected, the IQs of normal siblings correlated 0.5, and this was also the case with one genetic subtype of PWS (uniparental disomy) and their siblings, while the other subtype IQ correlated -0.07 with sibling IQ. This is a potentially powerful result that gives another clue to the role of genes on chromosome 15 in the determination of IQ. It is another systematic difference between the genetic subtypes of PWS, which needs an explanation in terms of the very small genetic differences between them.

Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome

BackgroundDifferences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)] indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup demonstrates reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses.ObjectiveTo examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating.Design and SubjectsNine individuals with PWS due to UPD and 9 individuals with PWS due to (type 2) deletion, matched for age, gender, and BMI, underwent fMRI scanning while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal.ResultsBoth PWS subgroups demonstrated greater activity in response to food pre- and post-meal compared to the healthy-weight group. Compared to UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex and amygdala. In contrast, the UPD group demonstrated greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex and parahippocampal gyrus.ConclusionThese preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

Assessment of Hyperphagia in Prader‐Willi Syndrome

Prader-Willi syndrome (PWS), the leading known genetic cause of obesity, is characterized by intellectual disabilities, maladaptive and compulsive behaviors, and hyperphagia. Although complications of obesity resulting from hyperphagia are the leading cause of death in PWS, quantifying this drive for food has long been an unmet research need. This study provides factor-analytic and within-syndrome analyses of a new measure of hyperphagia in PWS. A 13-item informant measure, the Hyperphagia Questionnaire, was developed and administered to the parents of 153 persons with PWS, 4 to 51 years of age. The intelligence quotients, genetic subtypes of PWS, and BMIs of offspring were obtained, as were measures of their non-food problem behaviors. Factor analyses with varimax rotation produced three statistically and conceptually robust factors that accounted for 59% of the variance: Hyperphagic Behaviors, Drive, and Severity. Hyperphagic Behavior increased with age, whereas Drive remained stable, and Severity dipped in older adults. Hyperphagic Drive and Severity were positively correlated with non-food behavior problems, and Hyperphagic Drive differentiated the 36% of participants with extreme obesity from those who had overweight/obese (48%) or healthy (16%) BMI classifications. The Hyperphagia Questionnaire is a robust tool for relating breakthroughs in the neurobiology of hyperphagia to in vivo food-seeking behavior and for examining the psychological and developmental correlates of hyperphagia in PWS. The Hyperphagia Questionnaire also offers a nuanced, real-life outcome measure for future clinical trials aimed at curbing the life-threatening drive for food in PWS.

The relationship between compulsive behaviour and academic achievement across the three genetic subtypes of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic syndrome associated with several physical, cognitive and behavioural characteristics. For many individuals with this syndrome, compulsive behaviour is often noted in both food and non-food situations. The focus of this paper is on the non-food-related compulsions in individuals with PWS and comparing differences across the three genetic subtypes of the syndrome. Compulsive behaviours in 73 people with PWS were assessed using the Yale-Brown Obsessive Compulsive Scale and the Compulsive Behavior Checklist. Compulsive behaviour and its relation to IQ and academic achievement also were evaluated. Phenotypic differences were characterized for the three most common genetic subtypes of the disorder: 16 individuals with the long Type I (TI) 15q deletion, 26 individuals with the short Type II (TII) 15q deletion and 31 individuals with maternal disomy 15. There appeared to be important differences between the two deletion subtypes. Specifically, individuals with the TI deletion had more compulsions regarding personal cleanliness (i.e. excessive bathing/grooming), and their compulsions were more difficult to interrupt and interfered with social activities more than the other subtypes. Individuals with the TII deletion were more likely to have compulsions related to specific academic areas (i.e. rereading, erasing answers and counting objects or numbers). These findings may help clinicians and researchers identify possible intervention strategies and supports based on the behavioural phenotype associated with genetic subtype in individuals with PWS.

Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Prader-Willi syndrome is a neurodevelopmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia (leading to obesity in early childhood), learning problems, and behavioral difficulties. A paternal 15q11-q13 deletion is found in approximately 70% of patients with Prader-Willi syndrome, approximately 25% have uniparental maternal disomy 15, and the remaining 2% to 5% have imprinting defects. The proximal deletion breakpoint in the 15q11-q13 region occurs at 1 of 2 sites located within either of 2 large duplicons allowing for the identification of 2 deletion subgroups. The larger, type I (TI) deletion involves breakpoint 1, which is close to the centromere, whereas the smaller, type II (TII) deletion involves breakpoint 2, located approximately 500 kilobases distal to breakpoint 1. Breakpoint 3 is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Analyses of the genetic subtypes of Prader-Willi syndrome to date have primarily compared individuals with typical deletion and uniparental maternal disomy 15 without grouping the individuals with a deletion into TI or TII. Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters. We previously presented the first assessment of clinical differences in individuals with Prader-Willi syndrome categorized as having type I or II deletions. Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15. Four genes (NIPA1, NIPA2, CYFIP1, and GCP5) have been identified in the chromosomal region between breakpoints 1 and 2 and are implicated in compulsive behavior and lower intellectual ability observed in individuals with Prader-Willi syndrome with TI versus TII deletions. We quantified messenger-RNA levels of these 4 genes in actively growing lymphoblastoid cells derived from 8 subjects with Prader-Willi syndrome with the TI deletion (4 males, 4 females; mean: age 25.2 +/- 8.9 years) and 9 with the TII deletion (3 males, 6 females; mean age: 19.5 +/- 5.8 years). Messenger-RNA levels were correlated with validated psychological and behavioral scales administered by trained psychologists blinded to genotype status. Messenger RNA from NIPA1, NIPA2, CYFIP1, and GCP5 was reduced but detectable in the subjects with Prader-Willi syndrome with the TI deletion, supporting biallelic expression. For the most part, messenger-RNA values were positively correlated with assessment parameters, indicating a direct relationship between messenger-RNA levels and better assessment scores, with the highest correlation for NIPA2. The coefficient of determination indicated the quantity of messenger RNA of the 4 genes explained from 24% to 99% of the variation of the behavioral and academic parameters measured. By comparison, the coefficient of determination for deletion type alone explained 5% to 50% of the variation in the assessed parameters. Understanding the influence of gene expression on behavioral and cognitive characteristics in humans is in the early stage of research development. Additional research is needed to identify the function of these genes and their interaction with gene networks to clarify the potential role they play in central nervous system development and function.

Differences in behavioural phenotype between parental deletion and maternal uniparental disomy in Prader–Willi syndrome: an ERP study

Objective Paternal deletion and maternal uniparental disomy are the principal genetic subtypes associated with Prader–Willi syndrome (PWS). Recent clinical findings suggest differences in phenotype between these subtypes. The present experimental study addresses this issue using a cognitive psycho-physiological setup. Methods Behaviour and event-related brain activity (ERP) was recorded by a continuous performance response inhibition task (CPT-AX) in adults with paternal deletion PWS ( n=11), maternal uniparental disomy PWS ( n=11) and normal controls ( n=11). The dependent behavioural variables of the CPT-AX task were reaction time and correct scores. For the ERPs the N200 and P300 components were included which are related to early modality-specific inhibition and late general inhibition, respectively. Results The disomy group had fewer correct scores and increased reaction times as compared to the CPT-AX task than the control and deletion group. Both PWS subgroups differed significantly from the control group for the N200 amplitude. Only the control group showed the typical task modulation for the N200 amplitude. The amplitude of the P300 component was considerably smaller in the uniparental disomy group than in the deletion and control groups. Conclusions The ERP results suggest that early modality specific inhibition is impaired in both PWS genetic subtypes. Late general inhibition is impaired in the uniparental disomy group only. Thus, although the ERP data suggests a common impairment in early visual inhibition processing, uniparental disomy and parental deletion genetic PWS subtypes clearly differ in their behavioural and brain activation phenotypes. Significance The present study is the first experimental demonstration which explains the two principal genetic mechanisms that hinder the expression of the genes at 15q11-q13g in PWS result in different behavioural phenotype.