Psychiatric disorders in a cohort of individuals with Prader-Willi syndrome.

BACKGROUND: Psychiatric manifestations in Prader-Willi Syndrome (PWS) are common and often are the most debilitating problem in these individuals. We present an epidemiological nation-wide survey of psychiatric diagnoses in the PWS population, based on full-range psychiatric interviews. METHODS: We studied the distribution of psychiatric diagnoses (as opposed to a symptom-based approach) in the Israel national cohort of adolescents and adults with PWS. There was a total of 53 (32 males) ages 12 years and older. All individuals and their caretakers were interviewed using standardized psychiatric questionnaires. Demographic and clinical variables, Clinical Global Impression (CGI) score, IQ, severity of hyperphagia and quality of life (QOL) were also assessed and correlations with NPD (number of psychiatric diagnoses) calculated. RESULTS: An overwhelming majority (89%) of the study participants had at least one psychiatric diagnosis. The most common were disruptive behavior disorders (DBD) (68%), obsessive compulsive disorder (OCD) (45%) and skin picking (35%). Individuals with DBD were at increased risk for OCD and skin picking. Psychotic disorders were found in 11%. NPD had a significant negative influence on QOL. There was no correlation between NPD and BMI, IQ, hyperphagia severity, hormonal profile or genetic subtypes. CONCLUSIONS: Psychiatric diagnoses are very frequent in PWS and strongly influence QOL. Furthermore, characterizing the profile of psychiatric comorbidity in PWS is crucial for planning effective interventions. Precise behavioral phenotyping in PWS in combination with a well-defined genetic etiology may aid biological research linking biological correlates to behavior.

Anthropometric adjustments are helpful in the interpretation of BMD and BMC Z-scores of pediatric patients with Prader-Willi syndrome.

Anthropometric adjustments of bone measurements are necessary in Prader-Willi syndrome patients to correctly assess the bone status of these patients. This enables physicians to get a more accurate diagnosis of normal versus abnormal bone, allow for early and effective intervention, and achieve better therapeutic results. INTRODUCTION: Bone mineral density (BMD) is decreased in patients with Prader-Willi syndrome (PWS). Because of largely abnormal body height and weight, traditional BMD Z-scores may not provide accurate information in this patient group. The goal of the study was to assess a cohort of individuals with PWS and characterize the development of low bone density based on two adjustment models applied to a dataset of BMD and bone mineral content (BMC) from dual-energy X-ray absorptiometry (DXA) measurements. METHODS: Fifty-four individuals, aged 5-20 years with genetically confirmed PWS, underwent DXA scans of spine and hip. Thirty-one of them also underwent total body scans. Standard Z-scores were calculated for BMD and BMC of spine and total hip based on race, sex, and age for all patients, as well as of whole body and whole-body less head for those patients with total-body scans. Additional Z-scores were generated based on anthropometric adjustments using weight, height, and percentage body fat and a second model using only weight and height in addition to race, sex, and age. RESULTS: As many PWS patients have abnormal anthropometrics, addition of explanatory variables weight, height, and fat resulted in different bone classifications for many patients. Thus, 25-70 % of overweight patients, previously diagnosed as normal, were subsequently diagnosed as below normal, and 40-60 % of patients with below-normal body height changed from below normal to normal depending on bone parameter. CONCLUSIONS: This is the first study to include anthropometric adjustments into the interpretation of BMD and BMC in children and adolescents with PWS. This enables physicians to get a more accurate diagnosis of normal versus abnormal BMD and BMC and allows for early and effective intervention.

Sexual dichotomy of gonadal function in Prader-Willi syndrome from early infancy through the fourth decade.

STUDY QUESTION: At what age does the type of hypogonadism, namely hypothalamic or primary gonadal defect, become established in men and women with Prader-Willi syndrome (PWS)? SUMMARY ANSWER: The type of hypogonadism becomes established only in late adolescence and early adulthood. WHAT IS KNOWN ALREADY: The etiology of hypogonadism in PWS is heterogeneous and the clinical expression is variable. Primary testicular failure is common in PWS men, while combinations of ovarian dysfunction and gonadotrophin deficiency are seen in women. STUDY DESIGN, SIZE, DURATION: This is a prospective study of a cohort of 106 PWS patients followed for a mean duration of 4.5 years. Serial blood samples were obtained and assayed for gonadotrophins, inhibin B, anti-Mullerian hormone (AMH), dehydroepiandrosterone sulfate (DHEAS), testosterone (males), and estradiol (females). Results were compared with normal reference values obtained from the literature. For the purpose of this study, we defined the following age groups: infants <1 year; children 1-10 years; adolescents 11-20 years and adults >20 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study participants were 49 males (aged 2 months to 36 years) and 57 females (aged 1 month to 37 years) with genetically confirmed diagnoses of PWS (deletions 60, uniparental disomy 54, imprinting center defect 2) followed in the Israel national multidisciplinary PWS clinic. MAIN RESULTS AND THE ROLE OF CHANCE: Serum LH levels were in the normal range (1.0-6.0 mIU/ml) for 7/10 adult men, and high in 3, while FSH (normal range 1.0-6.1 mIU/ml) was elevated (34.4 ± 11.5 mIU/ml) in 6 and normal (3.5 ± 1.6 mIU/ml) in 4 men. Testosterone was low (5.7 ± 3.4 nmol/l) compared with the normal range of 12.0-34.5 nmol/l in the reference population in all men >20 years. AMH showed a normal decrease with age, despite low testosterone levels. Inhibin B was normal (241 ± 105 pg/ml) in infant boys, but low or undetectable in most adult men. Hormonal profiles were more heterogeneous in women than in men. Estradiol was consistently detectable in only 7/13 adult women. Inhibin B was low or undetectable in all PWS females although occasional samples showed levels within the normal range of 15-95 pg/ml. Vaginal bleeding was reported to occur for the first time in eight women at a median age of 20 years (13-34 years), but only one had regular monthly menses. The type of hypogonadism (primary or secondary) in PWS can be determined only after age 20 years. LIMITATIONS, REASONS FOR CAUTION: The study cohort was heterogeneous, showing variability in BMI, cognitive disability and medical treatment. WIDER IMPLICATIONS OF THE FINDINGS: Demonstration of the natural history of reproductive hormone development in PWS suggests that androgen replacement may be indicated for most PWS boys in mid-adolescence. Recommendations for hormone replacement in PWS women need to be individually tailored, serial measurements of inhibin B should be performed, and contraception should be considered in those women who may have the potential for fertility.

Isolated mild white matter signal changes in preterm infants: a regional approach for comparison of cranial ultrasound and MRI findings.

OBJECTIVE: To compare echogenicity detected using cranial ultrasound (cUS) and diffuse excessive high signal intensity (DEHSI) detected using magnetic resonance imaging (MRI) by identical region-based scoring criteria in preterm infants. To explore the association between these white matter (WM) signal changes with early neurobehavior. STUDY DESIGN: Forty-nine pre-selected premature infants with only echogenicity on a first routine cUS1 underwent MRI and a repeated cUS2 at term equivalent age. Echogenicity and DEHSI were graded in various brain areas and diffusivity values were calculated. Neurobehavior was assessed using the Rapid Neonatal Neurobehavioral Assessment Procedure. RESULT: WM signal changes were significantly higher on cUS1 than cUS2; and higher in MRI than cUS2 in posterior regions. Infants with DEHSI demonstrated reduced tissue integrity. Imaging findings were not correlated with early neurobehavior. CONCLUSION: Echogenicity and DEHSI likely represent the same phenomenon. Reduction of over-interpretation of WM signal changes may help define criteria for the judicious use of imaging in routine follow-up of premature infants.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Accidental injuries are more common in children with attention deficit hyperactivity disorder compared with their non-affected siblings.

BACKGROUND: Accidental injuries are a leading cause of paediatric morbidity and mortality. We hypothesized that attention deficit hyperactivity disorder (ADHD), a common childhood disorder characterized by behaviours such as hyperactivity and impulsivity, is a risk factor for accidental injuries. Previous retrospective studies suggested that children with ADHD have an increased injury rate, but controlled prospective studies are lacking. METHODS: We conducted a prospective case-control study of 29 school-aged children with ADHD and their same-sex, similarly aged, non-ADHD-affected siblings. All diagnoses were made by a paediatric neurologist according to DSM-IV criteria and the children and their parents underwent a structured psychiatric interview and a battery of complementary assessments including: Child Behavior Checklist (CBCL), ADHD Rating scale and Developmental Coordination Disorder Questionnaire (DCDQ). The parents were contacted by telephone every 3 months during a 9-month follow-up period and all injuries requiring medical attention were recorded. Incidence of injuries was compared between the pairs of siblings. RESULTS: During the follow-up period, a total of 13 injuries in 13 children with ADHD were reported, compared with six injuries in six children from the control group (Z=-2.11, P < 0.05). ADHD severity and subtype, CBCL, DCDQ and IQ scores were not predictive of injury risk. CONCLUSIONS: School-aged children with ADHD are at higher risk of accidental injuries than their non-ADHD siblings, regardless of ADHD subtype, co-morbid psychiatric conditions, developmental co-ordination problems and environmental/familial conditions. Awareness and adequate education of parents and caregivers of children with ADHD concerning the increased injury risks are thus warranted.

Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons(3,4) and modulation of central monoaminergic reactivity.(5) We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) polymorphism,(6) in a sample of 86 children with DSM-IV ADHD and their parents. Transmission disequilibrium analysis showed increased transmission of the IL-1Ra 4-repeat allele (chi(2) = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele (chi(2) = 4.59, P = 0.03) to affected children. The 4-repeat allele was associated with a significantly increased risk for ADHD (chi(2) = 4.46, df 1, P = 0.035, RR = 1.292, 95% CI 1.01-1.66). The IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD (chi(2) = 4.65, df 1, P = 0.03, RR = 0.763, 95% CI 0.59-0.98). If replicated, this finding may point to a role for brain cytokine activity in the etiopathogenesis of ADHD.

Arithmetic skills in kindergarten children with developmental language disorders.

Although arithmetic is not a language-based skill, a specific learning disability in arithmetic--dyscalculia--is commonly seen in children with developmental language disorders (DLD). The object of this study was to assess whether kindergarten children with DLD have impaired arithmetic skills and, if so, to correlate the pattern of dysfunction with language syndromes. Forty-two children with DLD attending mainstream kindergartens, and their matched controls, underwent an arithmetic battery, neurological examination, intelligence quotient (IQ) test (WPPSI/WISC-R) and language assessment (CELF-R).* Attention deficit hyperactivity disorder (ADHD) was diagnosed by psychological assessment and behaviour questionnaires. Results showed that children with DLD were similar to controls on performance IQ (104.2+/-12.1 and 109.4+/-12.7 respectively, p = NS), but inferior on both the CELF-R expressive (74.8+/-9.3 vs 95.2+/-15.1, p < 0.01) and receptive (77.5+/-10.0 vs 87.8+/-12.3, p < 0.01) language scores. Their performance on the arithmetic battery was also significantly poorer: 61.2+/-17.7 vs 77.4+/-13.7, p < 0.01. Low scores in reasoning principles and arithmetic operations were associated with both receptive and expressive language impairment, while poor performance on counting principles was primarily associated with expressive deficits. Mild motor signs and ADHD were more frequent in children with DLD (p < 0.01 and < 0.05, respectively). We concluded that the arithmetic impairment in children with DLD is pervasive, affecting a broad spectrum of skills. Whereas impairment of most arithmetic skills is associated with global language disturbances, counting correlates primarily with expressive language deficits. Anticipatory guidance by physicians will better prepare parents and educators for the multiple challenges facing children with DLD.

Developmental dyscalculia.

Developmental dyscalculia is a specific learning disability affecting the acquisition of arithmetic skills in an otherwise-normal child. Although poor teaching, environmental deprivation, and low intelligence have been implicated in the etiology of developmental dyscalculia, current data indicate that this learning disability is a brain-based disorder with a familial-genetic predisposition. The neurologic substrate of developmental dyscalculia is thought to involve both hemispheres, particularly the left parietotemporal areas. Developmental dyscalculia is a common cognitive handicap; its prevalence in the school population is about 5-6%, a frequency similar to those of developmental dyslexia and attention-deficit-hyperactivity disorder. Unlike these, however, it is as common in females as in males. Developmental dyscalculia frequently is encountered in neurologic disorders, examples of which include attention-deficit-hyperactivity disorder, developmental language disorder, epilepsy, and fragile X syndrome. The long-term prognosis of developmental dyscalculia is unknown; it appears, however, to persist, at least for the short-term, in about half of affected preteen children. The consequences of developmental dyscalculia and its impact on education, employment, and psychologic well-being of affected individuals are unknown.

Cognition, attention, and behavior in Prader-Willi syndrome.

We studied the academic, cognitive, and behavior profile of 18 patients with Prader-Willi syndrome. All had severe learning disabilities in arithmetic and writing, and the majority were also dyslexic. Their average Full-Scale IQ was 73.7 +/- 8.9, which was 1 SD below normal range, whereas their performance on executive, memory, and visuospatial tasks ranged from 2.1 to 7.0 SD below the expected means. Behavioral problems were measured using the Child Behavior Checklist, on which the majority scored in the pathologic range for social and attention problems, delinquent and aggressive behavior, somatic complaints, and thought problems. Genotypes of the children did not predict cognitive or behavioral profile, nor could behavior be associated with parameters of weight or IQ. In summary, we found that patients with Prader-Willi syndrome have profound learning disabilities and cognitive deficits, greater than expected for their IQ. Behavioral problems, including attention-deficit hyperactivity disorder (ADHD), are also prevalent and impede the overall management of this group of patients. The genotypes were not helpful in predicting cognitive or behavioral patterns.

Developmental dyscalculia is a familial learning disability.

Whereas current evidence attests to a genetic component in the etiology of dyslexia and attention-deficit/hyperactivity disorder (ADHD), little is known about the role of genetics in developmental dyscalculia (DC). The objective of this study was to determine the familial aggregation of DC. Siblings and parents of children with DC were assessed for arithmetic, reading and attention disorders. The criteria for DC were an IQ higher than 85, poor performance in arithmetic, and a significant discrepancy between arithmetic achievement and IQ. The study group was composed of 39 children with DC, 21 mothers, 22 fathers, 90 siblings, and 16 second-degree relatives. We found that 66% of mothers, 40% of fathers, 53% of siblings, and 44% of second-degree relatives had DC. The intraclass correlation between the sib pairs was .27. A 95% confidential interval (CI) for the prevalence of DC among siblings of DC probands (see Note 1) ranged from 40% to 64%, indicating a familial prevalence almost tenfold higher than expected for the general population. IQ and attention problems were not risk factors for DC. We conclude that DC, like other learning disabilities, has a significant familial aggregation, suggesting a role for genetics in the evolution of this disorder.

Visual impairment in children with epilepsy treated with vigabatrin.

Vigabatrin is an anti-epileptic drug particularly useful for drug-resistant partial seizures and infantile spasms. Recently, vigabatrin-induced visual field constriction (VFC) and abnormal ocular electrophysiological studies were reported. In this study, we assessed visual fields, visual evoked potentials (VEPs), and electroretinography (ERG) in children treated with vigabatrin. Twenty-four visually asymptomatic children underwent a clinical ophthalmological examination, perimetry when appropriate, and VEP and ERG. Thirteen patients had at least one abnormal study. VFC was seen in 11 of 17 patients who had perimetry; 5 of 15 patients who underwent VEP testing and 4 of 11 who underwent ERG testing had abnormal examinations. For the most part, abnormal VEPs and ERGs were found in children who also had VFC. There was a consistent trend for longer treatment periods to correlate with VFC, abnormal ERGs, and VEPs. In summary, over half of the children treated with vigabatrin demonstrated VFC or abnormal ocular electrophysiological studies. Perimetry seemed to be the most sensitive modality for identifying vigabatrin toxicity. Abnormal ERGs and VEPs were primarily seen in children with VFC and may be useful in monitoring children who are not appropriate candidates for perimetry. Although the incidence of vigabatrin-induced VFC is worrisome, in the context of intractable seizures or infantile spasms, therapeutic benefits must be weighed against risks.

[Prader-Willi syndrome: medical, emotional and cognitive facets].

Prader-Willi syndrome, first described in 1956, is characterized by marked hypotonia, hyperphagia, severe obesity, short stature, hypogonadism, orthopedic problems, breathing-related sleep disorders, mild to moderate mental retardation and behavioral abnormalities. The incidence of this syndrome, an expression of a genetic imprinting error in chromosome 15, is 1:10,000-1:25,000. We describe the medical, emotional and cognitive parameters of 34 patients in our multidisciplinary clinic for Prader-Willi syndrome. Their ages range from 5 months to 40 years and 20 are males. Excessive weight gain started at the age of 6 years, increasing to 170-370% of that predicted by height and age and short stature started after the age of 12. All males have hypogonadism; 6 patients have scoliosis. Breathing-related sleep disorders have occurred in 15. Children above the age of 8 years underwent neuropsychological assessment: half (9/18) have borderline intelligence while a quarter have low-normal intelligence and the remainder mild to moderate mental retardation. Behavioral and social problems are common, and become more prominent during adolescence. ADHD was diagnosed in 10/18.

Developmental dyscalculia: prevalence and prognosis.

The prevalence of developmental dyscalculia (DC) in the school population ranges from 3-6 %, a frequency similar to that of developmental dyslexia and ADHD. These studies fulfilled the criteria for an adequate prevalence study, i.e., were population based, using standardized measures to evaluate arithmetic function. Although the variation in prevalence is within a narrow range, the differences are probably due to which definition of dyscalculia was used, the age the diagnosis was made and the instrument chosen to test for DC. The relative predominance of girls with DC may reflect a greater vulnerability to environmental influences alone or in addition to a biological predisposition. DC is not only encountered as a specific learning disability but also in diverse neurological disorders, examples of which include ADHD, developmental language disorder, epilepsy, treated phenylketonuria and Fragile X syndrome. Although the long-term prognosis of DC is as yet unknown, current data indicate that DC is a stable learning disability persisting, at least for the short term, in about half of affected children. The long-term consequences of DC and its impact on education, employment and psychological well-being have yet to be determined.

Attention-deficit hyperactivity disorder and developmental right-hemisphere syndrome: congruence and incongruence of cognitive and behavioral aspects of attention.

We studied clinical aspects of attention in three groups: children with developmental right-hemisphere syndrome and attention-deficit hyperactivity disorder (ADHD), children with ADHD only, and normal controls. The three groups (N = 54) were case-matched for age, sex, IQ, hand dominance, and socioeconomic status. ADHD was diagnosed clinically using the Diagnostic and Statistical Manual of Mental Disorders-III-Revised criteria and the Conners' Abbreviated Teacher Questionnaire. Additional aspects of attention and behavior were measured by the Child Behavior Checklist, a low-cognitive-load continuous performance task, and the visual target cancellation test (paper and pencil). Although the Child Behavior Checklist profile of attentional deficits in the two clinical groups was similar, we found that the developmental right-hemisphere syndrome group was more severely impaired on parameters of attention measured by the continuous performance task and visual target cancellation test than the children with ADHD. We conclude that the profile of attentional deficits in developmental right-hemisphere syndrome is different than that seen in children with ADHD only, possibly reflecting disparate neurologic underpinnings for the two syndromes.

[Attention deficit disorder: attentional characteristics of developmental right hemisphere syndrome].

Developmental right hemisphere syndrome (DRHS) is characterized by emotional and interpersonal difficulties, attention deficit hyperactivity disorder (ADHD), visuo-spatial handicaps, subtle left body neurologic signs and failure in nonverbal academic domains, especially arithmetic. Concurrence of ADHD and DRHS is not surprising because research has implicated dysfunction of the right hemisphere in both syndromes. Furthermore, the right hemisphere has more brain areas devoted to attentional processing, making it more important and more vulnerable in attentional problems. We describe the clinical parameters of DRHS as exemplified by 2 cases, a boy and a girl, both 13 years old. They participated in a study group in which attention and speed of performance were assessed in children with DRHS and were compared to children with ADHD and to a control group. A tendency to overfocusing, difficulty in inhibition, perseverative behaviors, stereotypy, and slowness and absence of hyperactivity characterized the DRHS group. These behaviors led us to hypothesize that the attentional symptoms in DRHS define a specific subgroup of ADHD which requires a different therapeutic approach.

Persistence of developmental dyscalculia: what counts? Results from a 3-year prospective follow-up study.

OBJECTIVE: To study the natural history of developmental dyscalculia (DC), a specific learning disability affecting approximately 5% of the normal school age population and to identify factors that contribute to persistence. STUDY DESIGN: Of a cohort of 3029 fourth-grade students, 185 children were classified as having DC; 140 participated in phase 1 in which they underwent IQ testing; arithmetic, reading, and writing evaluations; and an assessment for attention-deficit/hyperactivity disorder over a 3-year period. Three years later (phase 2), 88% of the children (123 of 140) were retested. RESULTS: The arithmetic scores of 95% of the 123 children with DC fell within the lowest quartile for their class. At phase 2, 47% (57 of 123) of the children were reclassified as having persistent DC, scoring in the lowest 5% for their age group (13 to 14 years old). Factors significantly associated with persistence of DC in a multivariate model were severity of the arithmetic disorder and arithmetic problems in siblings of the probands. Factors that were not associated with persistence included socioeconomic status, gender, the presence of another learning disability, and educational interventions. CONCLUSIONS: The outcome of DC is similar to that of other learning disabilities, with a persisting course in almost half of affected children; the remainder continue to perform poorly in arithmetic. The ultimate outcome of children with dyscalculia and the effect on education, employment, and psychologic well-being have yet to be determined.