Frontal behavioral syndromes in Prader-Willi syndrome

BACKGROUND: Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder presenting with behavioral problems including hyperphagia, emotional aberration, and compulsion-like behaviors. This combination of behavioral problems is likely to be caused by damage to the orbitofrontal cortices and anterior temporal lobes or to circuits involving them. OBJECTIVES: To investigate the prevalence of eating and non-eating behavioral disturbances in PWS by using assessment tools developed originally for patients with frontotemporal dementia and with frontal lobe injury. METHOD: The questionnaire consisted of 35 questions related to three categories of behavior: eating behaviors (including four domains: appetite, food preference, eating habits, and other oral behaviors), stereotypy (including four domains: roaming, speaking, movements, and daily rhythm), and collecting behaviors. It was administered in Japan to the parents of 250 individuals aged 1-42 years with a clinical diagnosis of PWS. RESULTS: The prevalence rates of symptoms in all categories were high. Each domain involved in eating behaviors was significantly correlated with stereotypy and collecting behaviors. The prevalence rates and severity scores of some eating and non-eating behaviors were higher in the older groups. CONCLUSION: Abnormal eating behaviors, stereotyped behaviors, and collecting behaviors were common in the PWS subjects. There was also a potential link between abnormal eating and non-eating behaviors related to frontal behavioral syndromes. It is likely that these behavioral abnormalities reflect dysfunction of the orbitofrontal cortices and anterior temporal lobes.     

Prader-Willi syndrome

People with Prader-Willi syndrome exhibit infantile hypotonia and failure to thrive, genital hypoplasia, childhood-onset obesity, mental deficiency and behavioral abnormalities, hypogonadism, short stature, and characteristic dysmorphology. In over half the affected individuals, prometaphase chromosome analysis reveals a small interstitial deletion of chromosome 15q, del 15(q11-q12); with most of the remaining patients showing apparently normal chromosomes. Molecular genetic technology is currently being applied to the relevant region of chromosome 15 to determine if there is etiologic heterogeneity and to seek a consistent diagnostic marker. Diagnosis at this time is primarily based upon clinical criteria.     

Prader-Willi syndrome

Prader Willi Syndrome (PWS) is a neuro-genetic disorder. It has been reported that cases due to paternal deletion 15q11-13 (Del) behave differently to cases due to uniparental disomy (UPD). Comparison of the two forms of PWS has, to date, not included the frequency of autistic behaviours, even though there are reports of an association between maternal duplications of 15q11-13 and autism spectrum disorders (ASD). It was predicted that maternal UPD PWS cases would be more prone to ASD than Del PWS cases due to their duplicated maternally expressed genes. A preliminary test of the hypothesis was conducted using postal and telephone surveys of matched, genetically verified, UPD and Del cases using the Autism Screening Questionnaire (ASQ) and the Vineland Adaptive Behaviour Scales (VABS). As predicted, UPD cases were reported as exhibiting significantly more autistic symptomatology. They also were born to older mothers and were reported on the VABS to have more deficits in motor control problems and fewer adaptive skills in the Daily Living Skills domain. Del cases were reportedly more skilled at jigsaw puzzles. The results lend further support to the notion that abnormality in the expression of maternal imprinted 15q11-13 genes may confer a susceptibility to ASD. They also suggest that there may be cognitive differences between the groups in processing visuo-spatial information.     

Individuals with Smith-Magenis syndrome display profound neurodevelopmental behavioral deficiencies and exhibit food-related behaviors equivalent to Prader-Willi syndrome

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder associated with intellectual disability, sleep disturbances, early onset obesity and vast behavioral deficits. We used the Behavior Problems Inventory-01 to categorize the frequency and severity of behavioral abnormalities in a SMS cohort relative to individuals with intellectual disability of heterogeneous etiology. Self-injurious, stereotyped, and aggressive/destructive behavioral scores indicated that both frequency and severity were significantly higher among individuals with SMS relative to those with intellectual disability. Next, we categorized food behaviors in our SMS cohort across age using the Food Related Problems Questionnaire (FRPQ) and found that problems began to occur in SMS children as early as 5–11 years old, but children 12–18 years old and adults manifested the most severe problems. Furthermore, we evaluated the similarities of SMS adult food-related behaviors to those with intellectual disability and found that SMS adults had more severe behavioral problems. Many neurodevelopmental disorders exhibit syndromic obesity including SMS. Prader-Willi syndrome (PWS) is the most frequent neurodevelopmental disorder with syndromic obesity and has a well-established management and treatment plan. Using the FRPQ we found that SMS adults had similar scores relative to PWS adults. Both syndromes manifest weight gain early in development, and the FRPQ scores highlight specific areas in which behavioral similarities exist, including preoccupation with food, impaired satiety, and negative behavioral responses. SMS food-related behavior treatment paradigms are not as refined as PWS, suggesting that current PWS treatments for prevention of obesity may be beneficial for individuals with SMS.     

Klinefelter's syndrome and Prader-Willi syndrome: a rare combination

In this paper a review is presented of the rare combination of Klinefelter's syndrome and Prader-Willi syndrome (PWS) and a second case of this combination with a uniparental disomy (UPD) etiology of PWS is described. Patients outlined in all other 8 reports and the present case have a PWS phenotype. Virtually no information is available on the behavioral and psychopathological phenotype in this combination. The latter may be explained by the observation that psychiatric syndromes are especially prevalent in PWS patients with a UPD. It is concluded that instability in mood and behavior in this and other syndromes should be preferentially treated with mood stabilizing agents.     

Refining behavioral phenotypes: personality-motivation in Williams and Prader-Willi syndromes

Despite behavioral differences, individuals with Williams or Prader-Willi syndrome share a proneness to certain personality characteristics. We hypothesized that there are qualitative differences in these shared personality features. Personality-motivation (measured using the Reiss Profiles) was compared for equal numbers of age- and gender-matched individuals with Williams or Prader-Willi syndrome or mental retardation due to nonspecific causes. Each syndrome featured aberrant motivational profiles, and similarities were found across groups in various domains. Significant differences emerged in the specific stimuli that motivated behavior in several Reiss Profile domains. Implications are discussed for the "classic" sociable personality in Williams syndrome and for compulsivity in Prader-Willi syndrome. Recommendations are made for treatment and more refined phenotypic research.     

Prader-Willi syndrome and acute psychosis

Prader-Willi Syndrome (PWS) is a genetically determined disorder, with characteristic physical and behavioural phenotypes. We describe a girl with PWS who developed a psychotic illness, and summarize the course, treatment and outcome. We suggest that the development of a psychotic illness in PWS may be an association of disorders that paediatricians and child mental health professionals should be aware of, and that the cornerstone of management of this kind of case is a multi-professional interdisciplinary approach. Important aspects of the assessment process which are occasionally overlooked are discussed.     

Genetics and mathematics: evidence from Prader-Willi syndrome

Mathematical abilities were tested in people with Prader-Willi syndrome (PWS), using a series of basic mathematical tasks for which normative data are available. The difference between the deletion and the disomy variants of this condition was explored. While a wide phenotypic variation was found, some basic findings emerge clearly. As expected from previous literature, deletion and disomy participants were found to differ in their degree of impairment, with disomy being overall the most spared condition. However, the tasks selectively spared in the disomy condition are not necessarily the easiest ones and those that discriminate less the PWS group from controls. It rather seems that disomy patients are spared, with respect to deletion, in tasks entailing transcoding and comparison of numbers in the Arabic code. Overall a particular difficulty was detected in reliably performing parity judgments. This task has been shown to be very frequently spared after a brain injury, even in severe aphasic conditions. The most interesting result is the sparing in analog number scale, whereby PWS seem, overall, to outperform controls. This finding may help in understanding previously reported, surprising results about cognitive skills in PWS. Elevated performances in PWS may result from life-long hyper-reliance on one visuo-spatial system in presence of underdevelopment of the other.     

Mortality in Prader-Willi syndrome

Persons with Prader-Willi syndrome have been known to have a high mortality rate. However, intellectual disability, which usually accompanies Prader-Willi syndrome, is also associated with a higher mortality rate than in the general population. In this study, the death rates in a longitudinal cohort of people with Prader-Willi syndrome are compared with those for an epidemiologically derived control sample of people with intellectual disability from other causes. We found that those with Prader-Willi syndrome had a higher mortality rate than did controls. After the protective effect of mild intellectual disability or average intellectual function was accounted for, the hazard ratio for Prader-Willi syndrome versus controls was 6.07. Obesity and its complications were factors contributing to the mortality identified in this study.     

Topiramate effectiveness in Prader-Willi syndrome

Prader-Willi syndrome is a neurologic disorder caused by a mutation on chromosome 15. It is characterized by short stature, obesity, mild-to-moderate mental retardation, and multiple behavior problems including mood, self-abusive behavior, and compulsive-eating disorder. These behaviors have detrimental effects on the mental and physical health of patients with Prader-Willi syndrome. This study evaluates the effectiveness of a new antiepileptic medication, topiramate, on behavior, mood, and compulsive-eating disorder associated with Prader-Willi syndrome. Recent studies have indicated that topiramate affects behavior, as well as reducing appetite and weight in some patients. We evaluated seven patients with Prader-Willi syndrome and determined that, in these patients, topiramate appeared to have a positive effect on reducing self-abusive behavior, improving mood, and stabilizing weight.     

Hypogonadism in Prader-Willi syndrome.

Sexual development was evaluated in 9 female and 2 male subjects with Prader-Willi syndrome. The process of sexual development and degree of genital development attained were found to be variable but abnormal in all subjects. Hypothalamic-pituitary-gonadal functions were evaluated by measurement of serum Luteinizing Hormone and plasma testosterone responses to stimulation by clomiphene citrate and plasma testosterone responses to stimulation by human chorionic gonadotrophin. The degree of vaginal estrogenization was variable. The testicular biopsies showed abnormalities mainly in the germinal epithelium. In agreement with previous studies, it was concluded that the abnormalities of sexual development in this syndrome are mainly due to a defect in the hypothalamic pituitary axis. Adrenal function was not found to be grossly abnormal. The 17 ketosteroid excretion values were low, probably explaining the rather sparse pubic and axillary hair observed in these patients. The urinary 17-hydroxycorticosteroid creatinine ratios were found to be elevated, probably due to decreased creatinine excretion, reflecting the muscular abnormalities of these subjects.     

Dermatoglyphics in Prader-Willi syndrome.

The finger-, palm-and sole-prints of thirteen patients with Prader-Willi syndrome have been analysed. Some information has also been obtained from another case. The topological classification has been used for describing palms and soles. Frequencies of finger pattern types, data on finger ridge-count and maximal atd angles are included. Relevant published data has also been considered in making assessments. It is concluded from the evidence available that the dermatoglyphics of patients with the syndrome differ little, if at all, from those of the normal population. Pattern intensity on hands, and particularly feet, is low. Dermatoglyphics, therefore, are not a useful criterion in the diagnosis of the syndrome.     

Prader-Willi syndrome in old age

ABSTRACT. This case report describes a person with Prader-Willi syndrome who recently died, aged 71 years. It is suggested that her longevity was helped by being female, with a moderate degree of mental handicap and a degree of weight control which reduced the problems of diabetes and hypertension.     

Growth and developmental patterns in Prader-Willi syndrome

Eleven Japanese patients with Prader-Willi syndrome were studied from infancy, and examined with respect to their growth and development. The chromosomal aberration was observed in 40% ofthe patients using a high-resolution chromosome banding technique. The birth weight in 10 out of the 11 patients was below the mean and the rate of body weight gain was severely retarded by 6 months in all cases, which suggested an insufficient utilization of nutrients in uterine life and in early infancy. The rate of height increase as well as that of body weight increase were also transiently retarded from 10 to 18 months of age in eight cases, and the body weight gain increased dramatically after 10–18 months due to hyperphagia. The patients' mean milestones of development were delayed (the mean developmental quotient was 50) in comparison with those of control patients; there was no difference between the developmental milestones of the two groups with and without the chromosomal aberration.     

Growth hormone treatment for Prader-Willi syndrome: A review

The Prader-Willi Syndrome (PWS) is a rare developmental disorder that contributed by multiple genes. Phenotypically, infants with PWS exhibit hypotonia and developmental delay, whilst older children and adults have cognitive impairments, neuropsychiatric symptoms, impaired motor development, neurological anomalies, endocrine dysfunctions like growth hormone (GH) deficiency, and hyperphagia that leads to obesity. Although mechanisms remain elusive, GH treatment has been recommended as the standard treatment for PWS children. In addition to better motor development, improved body composition and linear growth have been well established, but mental flexibility and behavioural problems remained largely untouched. This review will systemically analyze the recent clinical trials of GH treatment on PWS patients. The emphasis is on the mental and behavioural improvements by GH treatment, and a few concerns to initiate GH treatment. This review will finally propose possible future explorations on basic studies that may shed new light on clinical trials of GH treatment on PWS.     

Psychopharmacogenetic aspects of Prader-Willi syndrome.

The study of genes, drugs, and behavior in three male adolescents with Prader-Willi syndrome (PWS) revealed a clinical profile that raises questions about the indications for neuroleptic and appetite-suppressing medications in this condition. Evidence of the inadvisability of neuroleptic medication and of the pathophysiology of PWS has led to a remarkable control of violent outbursts and hyperphagia by carbamazepine in one patient afflicted with both PWS and Klinefelter's syndrome. Testosterone and behavioral therapy proved to be useful in the management of two patients. The present observations, which are supported by recent advances in the pathophysiology of satiety, suggest that PWS should be understood as a metabolic disorder and subjected to psychopharmacogenetic study.     

The Prader-Willi syndrome: Neuroendocrine study of identical twins

Identical twins with the Prader-Willi syndrome are reported. Apart from hypogonadism, hypomentia, hypotonia and obesity, they presented shorter than normal stature and the peculiar facies of this syndrome. Both twins also suffered from arterial hypertension with secondary hyperaldosteronism, an abnormality never previously recorded. The endocrinological study showed the presence of hypogonadotropic hypogonadism in both twins. The GnRH and clomiphene tests suggested a hypothalamic disorder. Although the vast majority of cases with the Prader-Willi syndrome are isolated, the expression of this disorder in two identical twins enhances the possibility of a genetic determination.