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Publications, April - June 2017

 

Listed below along with their abstracts are selected papers on PWS newly appearing in PubMed between  1st April  and end of  June  2017 in peer reviewed academic journals.   All papers are initially listed without their summaries to give a quick overview, then for most of the papers the summaries are included later in the document.  They are divided into specific categories: Genetics, general PWS, and brain imaging; Endocrine including GH; Sensory and physical; Behaviour; Cognition and mental health.  Open access is indicated next to the link.

 

This list has been compiled by Joyce Whittington and by members of the IPWSO Scientific Advisory Committee.  If there are papers that you think should have been included please let Joyce Whittington know (tel. +44 (0)1223 465266)

 

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Index

 

Genetics, general PWS, brain imaging

Xu M, Zhang Y, von Deneen KM, Zhu H, Gao JH.   Brain structural alterations in obese children with and without Prader-Willi Syndrome.  Hum Brain Mapp. 2017 May 23. [Epub ahead of print]

 

Riemens RJM, Soares ES, Esteller M, Delgado-Morales R.  Stem Cell Technology for (Epi)genetic Brain Disorders.  Adv Exp Med Biol. 2017;978:443-475.

 

Anglin K.  Prader-Willi Syndrome 101: An Overview for Pediatric Nurses.   J Pediatr Nurs. 2017 May 23. pii: S0882-5963(17)30191-4. [Epub ahead of print]

 

Cao Y, AlHumaidi SS, Faqeih EA, Pitel BA, Lundquist P, Aypar U.   A novel deletion of SNURF/SNRPN exon 1 in a patient with Prader-Willi-like phenotype.   Eur J Med Genet. 2017 May 26. pii: S1769-7212(16)30452-9. [Epub ahead of print]

 

Falaleeva M, Welden JR, Duncan MJ, Stamm S.  C/D-box snoRNAs form methylating and non-methylating ribonucleoprotein complexes: Old dogs show new tricks.  Bioessays. 2017 May 15. [Epub ahead of print]

Purtell L, Qi Y, Campbell L, Sainsbury A, Herzog H.   Adult-onset deletion of the Prader-Willi syndrome susceptibility gene Snord116 in mice results in reduced feeding and increased fat mass.  Transl Pediatr. 2017 Apr;6(2):88-97.

 

Abdilla Y, Andria Barbara M, Calleja-Agius J.  Prader-Willi Syndrome: Background and Management.  Neonatal Netw. 2017 May 1;36(3):134-141.

 

Shao ER, Kiyegi LF, Mwasamwaja AO, Kilonzo K, Hamel BCJ. Respiratory Failure due to Severe Obesity and Kyphoscoliosis in a 24-Year-Old Male with Molecularly Confirmed Prader-Willi Syndrome in Tertiary Hospital in Northern Tanzania.  Case Rep Genet. 2017;2017:2348045. Epub 2017 Apr 9

 

Albuquerque D, Manco L, González LM, Gervasini G, Marcaida Benito G, González JR, Rodríguez-López R. Polymorphisms in the SRNPN gene are associated with obesity susceptibility among Spanish population.  J Gene Med. 2017 Apr 7. [Epub ahead of print]

 

Butler MG.  Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder.

J Intellect Disabil Res. 2017 Apr 7.. [Epub ahead of print]

 

Skrypnik K, Suliburska , Skrypnik D, Pilarski Ł, Reguła J, Bogdański P  The genetic basis of obesity complications.   Acta Sci Pol Technol Aliment. 2017 Jan-Mar;16(1):83-91.

 

 

 

 

 

Endocrine including GH

Mele C   Grugni G, Mai S, Vietti R, Aimaretti G, Scacchi M, Marzullo P.  Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome.  Sci Rep. 2017 Jun 9;7(1):3186.

 

Nishi Y, Tanaka T.  Growth Hormone Treatment and Adverse Events.  Pediatr Endocrinol Rev. 2017 Mar;14(Suppl 1):235-239.

 

Tauber M, Diene G, Molinas C.  Sequelae of GH Treatment in Children with PWS.

Pediatr Endocrinol Rev. 2016 Dec;14(2):138-146

 

Scheermeyer E, Harris M, Hughes I, Crock PA, Ambler G, Verge CF, Bergman P, Werther G, Craig ME, Choong CS, Davies PSW; PWS and OZGROW collaboration.  Low dose growth hormone treatment in infants and toddlers with Prader-Willi syndrome is comparable to higher dosage regimens.  Growth Horm IGF Res. 2017 Mar 24;34:1-7.. [Epub ahead of print]

 

 

Sensory and physical

Blat C, Busquets E, Gili T, Caixàs A, Gabau E, Corripio R.  Gastric Dilatation and Abdominal Compartment Syndrome in a Child with Prader-Willi Syndrome.  Am J Case Rep. 2017 Jun 7;18:637-640.

 

Cimolin V, Cau N, Galli M, Santovito C, Grugni G, Capodaglio P.  Gait initiation and termination strategies in patients with Prader-Willi syndrome.   J Neuroeng Rehabil. 2017 May 23;14(1):44.

 

Esbensen AJ, Schwichtenberg AJ.  Sleep in Neurodevelopmental Disorders.  Int Rev Res Dev Disabil. 2016;51:153-191.

 

 

Behaviour

Dimitropoulos A, Zyga O, Russ S.   Evaluating the Feasibility of a Play-Based Telehealth Intervention Program for Children with Prader-Willi Syndrome.   J Autism Dev Disord. 2017 Jun 13. [Epub ahead of print]

 

McCandless SE, Yanovski JA, Miller J, Fu C, Bird LM5 Salehi P, Chan CL, Stafford D, Abuzzahab MJ, Viskochil D, Barlow SE, Angulo M, Myers SE,Whitman BY, Styne D, Roof E, Dykens EM, Scheimann AO, Malloy J, Zhuang D, Taylor K, Hughes TE, Kim DD, Butler MG.  Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: a randomized, double-blind, placebo-controlled trial.  Diabetes Obes Metab. 2017 May 29.. [Epub ahead of print]

 

Miller JL, Tamura R, Butler MG, Kimonis V, Sulsona C, Gold JA, Driscoll DJ   Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study.  Am J Med Genet A. 2017 Mar 30.. [Epub ahead of print]

 

Jensen KB, Kirsch I, Pontén M, Rosén A, Yang K, Gollub RL, des Portes V, Kaptchuk TJ, Curie A. Certainty of genuine treatment increases drug responses among intellectually disabled patients. Neurology. 2017 Apr 19. pii: 10.1212/WNL.0000000000003934. [Epub ahead of print]

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Cognition and mental health

Briegel W   Neuropsychiatrische Aspekte bei Prader-Willi-Syndrom – eine Übersicht.

Z Kinder Jugendpsychiatr Psychother. 2017 Jun 14:1-8. [Epub ahead of print]

 

Shriki-Tal L, Avrahamy H, Pollak Y, Gross-Tsur V, Genstil L, Hirsch HJ, Benarroch F. Psychiatric disorders in a cohort of individuals with Prader-Willi syndrome.  Eur Psychiatry. 2017 Apr 5;44:47-52. [Epub ahead of print]

 

Dykens EM, Roof E, Hunt-Hawkins H, Dankner N, Lee EB, Shivers CM, Daniell C, Kim SJ. Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome.J Neurodev Disord. 2017 Jun 5;9:18.. eCollection 2017.

 

Lukoshe A, van den Bosch GE, van der Lugt A, Kushner SA, Hokken-Koelega AC, White T.  Aberrant White Matter Microstructure in Children and Adolescents With the Subtype of Prader-Willi Syndrome at High Risk for Psychosis.  Schizophr Bull. 2017 May 16. [Epub ahead of print]

 

 

 

Abstracts

 

 

Genetics, general PWS, brain imaging

 

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Riemens RJM, Soares ES, Esteller M, Delgado-Morales R.  Stem Cell Technology for (Epi)genetic Brain Disorders.  Adv Exp Med Biol. 2017;978:443-475.

 

Abstract  Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).

KEYWORDS: Brain disorders; Disease modeling; Drug screening; Epigenetics; Regenerative medicine; Stem cells; iPSCs

PMID:28523560   DOI:10.1007/978-3-319-53889-1_23

 

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Xu M, Zhang Y, von Deneen KM, Zhu H, Gao JH.   Brain structural alterations in obese children with and without Prader-Willi Syndrome.  Hum Brain Mapp. 2017 May 23. [Epub ahead of print]

 

Abstract  Prader-Willi syndrome (PWS) is a genetic imprinting disorder that is mainly characterized by hyperphagia and childhood obesity. Previous neuroimaging studies revealed that there is a significant difference in brain activation patterns between obese children with and without PWS. However, whether there are differences in the brain structure of obese children with and without PWS remains elusive. In the current study, we used T1-weighted and diffusion tensor magnetic resonance imaging to investigate alterations in the brain structure, such as the cortical volume and white matter integrity, in relation to this eating disorder in 12 children with PWS, 18 obese children without PWS (OB) and 18 healthy controls. Compared with the controls, both the PWS and OB groups exhibited alterations in cortical volume, with similar deficit patterns in 10 co-varying brain regions in the bilateral dorsolateral and medial prefrontal cortices, right anterior cingulate cortex, and bilateral temporal lobe. The white matter integrities of the above regions were then examined with an analysis method based on probabilistic tractography. The PWS group exhibited distinct changes in the reduced fractional anisotropy of white matter fibers connected to the co-varying regions, whereas the OB group did not. Our findings indicated that PWS and OB share similar gray matter alterations that are responsible for the development of eating disorders. Additionally, the distinct white matter alterations might explain the symptoms associated with food intake in PWS, including excessive hyperphagia and constant hunger.

KEYWORDS: Prader-Willi syndrome; childhood obesity; cortical volume; eating disorder; tractography

PMID:28543989   DOI:10.1002/hbm.23660

 

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Anglin K.  Prader-Willi Syndrome 101: An Overview for Pediatric Nurses.   J Pediatr Nurs. 2017 May 23. pii: S0882-5963(17)30191-4. [Epub ahead of print]

PMID:28549751   DOI:10.1016/j.pedn.2017.04.007

 

 

Cao Y, AlHumaidi SS, Faqeih EA, Pitel BA, Lundquist P, Aypar U.   A novel deletion of SNURF/SNRPN exon 1 in a patient with Prader-Willi-like phenotype.   Eur J Med Genet. 2017 May 26. pii: S1769-7212(16)30452-9. [Epub ahead of print]

 

Abstract              Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene. SNURF/SNRPN exon 1, which is methylated on the silent maternal allele, is associated with acetylated histones on the expressed paternal allele. This region also overlaps with the PWS-imprinting center (IC). Subsequent molecular methylation analysis was performed using methylation-specific MLPA (MS-MLPA), which characterized that the deletion of SNURF/SNRPN exon 1 was paternal in origin, consistent with the PWS-like phenotype. Since SNURF/SNRPN gene and the PWS-IC are known to regulate snoRNAs, it is likely that the PWS-like phenotype observed in patients with paternal SNURF/SNRPN deletion is due to the disrupted expression of SNORD116 snoRNAs.

KEYWORDS: Chromosomal microarray; MS-MLPA; PWS-IC; Prader-Willi syndrome; SNURF/SNRPN

PMID:28554868   DOI:10.1016/j.ejmg.2017.05.003

 

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Falaleeva M, Welden JR, Duncan MJ, Stamm S.  C/D-box snoRNAs form methylating and non-methylating ribonucleoprotein complexes: Old dogs show new tricks.  Bioessays. 2017 May 15. [Epub ahead of print]

 

Abstract  C/D box snoRNAs (SNORDs) are an abundantly expressed class of short, non-coding RNAs that have been long known to perform 2'-O-methylation of rRNAs. However, approximately half of human SNORDs have no predictable rRNA targets, and numerous SNORDs have been associated with diseases that show no defects in rRNAs, among them Prader-Willi syndrome, Duplication 15q syndrome and cancer. This apparent discrepancy has been addressed by recent studies showing that SNORDs can act to regulate pre-mRNA alternative splicing, mRNA abundance, activate enzymes, and be processed into shorter ncRNAs resembling miRNAs and piRNAs. Furthermore, recent biochemical studies have shown that a given SNORD can form both methylating and non-methylating ribonucleoprotein complexes, providing an indication of the likely physical basis for such diverse new functions. Thus, SNORDs are more structurally and functionally diverse than previously thought, and their role in gene expression is under-appreciated. The action of SNORDs in non-methylating complexes can be substituted with oligonucleotides, allowing devising therapies for diseases like Prader-Willi syndrome.

KEYWORDS: Prader-Willi syndrome; RNA methylation; RNA processing; RNA therapy; SNORD; alternative splicing; obesity; snoRNA

PMID:28505386   DOI:10.1002/bies.201600264

 

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Purtell L, Qi Y, Campbell L, Sainsbury A, Herzog H.   Adult-onset deletion of the Prader-Willi syndrome susceptibility gene Snord116 in mice results in reduced feeding and increased fat mass.  Transl Pediatr. 2017 Apr;6(2):88-97.

 

Abstract  BACKGROUND: The imprinted small nucleolar RNA (snoRNA) Snord116 is implicated in the aetiology of Prader-Willi syndrome (PWS), a disease associated with hyperphagia and obesity. Germline deletion of Snord116 in mice has been found to lead to increased food intake but not to the development of obesity. To determine the role of Snord116 independent of potential compensatory developmental factors, we investigated the effects of conditional adult-onset deletion of Snord116 in mice.

METHODS: Deletion of Snord116 was induced at 8 weeks of age by oral administration of tamoxifen to male Snordlox/lox; ROSAcre/+ mice, with vehicle-treated mice used as controls. Body weight (BW) was monitored weekly and body composition was measured by dual-energy X-ray absorptiometry and tissue dissection. Non-fasted and fasting-induced food intake was determined, and glucose and insulin tolerance tests were performed. Twenty-four-hour energy expenditure and physical activity were assessed by indirect calorimetry.

RESULTS: Adult-onset deletion of Snord116 led to reduced food intake and increased adiposity, albeit with no concomitant change in BW or lean mass compared to controls. Adult onset Snord116 deletion was also associated with worsened glucose tolerance and insulin sensitivity.

CONCLUSIONS: This study identified a key role for Snord116 in feeding behaviour and growth. Further, it is likely that the effects of this gene are modulated by developmental stage, as mice with adult-onset deletion showed an opposite phenotype, with respect to food intake and body composition, to previously published data on mice with germline deletion.

KEYWORDS: Mouse; Prader-Willi syndrome (PWS); Snord116; neurodevelopmental disorders; small nucleolar RNA (snoRNA)

PMID:28503414   PMCID:PMC5413475   DOI:10.21037/tp.2017.03.06

 

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Abdilla Y, Andria Barbara M, Calleja-Agius J.  Prader-Willi Syndrome: Background and Management.  Neonatal Netw. 2017 May 1;36(3):134-141.

 

Abstract  The imprinting disorder, Prader-Willi syndrome, is a condition associated with the gene region 15q11.2-q.13. The phenotype includes multiple characteristics, most of which are endocrine-related. An accurate diagnosis is done mostly through pre- or postnatal genetic testing. Management is mainly aimed at correcting the endocrine dysfunctions present in these patients. Genetic testing is also important to distinguish between the different causes and to calculate the recurrence risk for parents with affected children. Although a lot has been discovered and this syndrome can be managed to a satisfactory degree, further research is still important especially regarding new potential treatments with greater efficiency and reduced invasiveness. The neonatal nurse has an important role because the management requires thorough monitoring as well as high compliance from both the patient and the carers. Thus, it is essential for the neonatal nurse to have a good knowledge of this condition.

PMID:28494825   DOI:10.1891/0730-0832.36.3.134

 

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Shao ER, Kiyegi LF, Mwasamwaja AO, Kilonzo K, Hamel BCJ. Respiratory Failure due to Severe Obesity and Kyphoscoliosis in a 24-Year-Old Male with Molecularly Confirmed Prader-Willi Syndrome in Tertiary Hospital in Northern Tanzania.  Case Rep Genet. 2017;2017:2348045. Epub 2017 Apr 9.

 

Abstract Obesity, mild intellectual disability, hypotonia, poor sucking, cryptorchidism in males, hypogonadism, and kyphoscoliosis are common features of Prader-Willi syndrome (PWS). We report a case who had severe respiratory complications due to extreme obesity and kyphoscoliosis, which are important causes of morbidity and mortality, and discuss management. Furthermore, this is the first molecularly confirmed PWS case in Sub-Saharan Africa outside South Africa.

PMID:28487784   PMCID:PMC5401720   DOI:10.1155/2017/2348045

 

 

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Albuquerque D, Manco L, González LM, Gervasini G, Marcaida Benito G, González JR, Rodríguez-López R. Polymorphisms in the SRNPN gene are associated with obesity susceptibility among Spanish population.  J Gene Med. 2017 Apr 7. [Epub ahead of print]

 

Abstract  BACKGROUND: SNRPN, which codes for the RNA-binding SmN protein, is a candidate gene for Prader-Willi syndrome. One characteristic of this neuroendocrine disorder is hyperphagia resulting in extreme obesity later in life. In this study we aim to assess whether variability within this gene could be implicated in obesity susceptibility.

MATERIAL AND METHODS: A case-control study was performed including 265 unrelated patients with non-syndromic and early-onset severe obesity, belonging to high risk obesity families from Spanish ancestry; 184 healthy control individuals were included representative of the same genetic background and sex-matched. Forty-nine single nucleotide polymorphisms (SNPs) spanning the entire SNRPN gene were selected and genotyped by using Sequenom MassARRAY platform.

RESULTS:     The four SNPs rs12905653, rs752874, rs1391516, and rs2047433 were found nominally associated with obesity (p < 0.03). The diversity haplotype distribution among cases and controls identified the combination rs12905653-T/rs8028366-A/rs4028395-T strongly and inversely associated with obesity (OR = 0.49; p = 0.0006). A genetic risk score was built based on rs12905653, rs1391516, and rs2047433 SNPs and each unit higher GRS increase the obesity risk by 49% (OR = 1.49; CI95%: 1.24-1.80).

CONCLUSIONS: To our knowledge, this is the first study reporting an association between variability in the SNRPN gene with the risk of being obese. Interestingly, it was the major allele of each SNP, which was found associated with the risk of weight gain. Further studies analyzing this locus, and the possible additive deleterious capability of SNPs combinations, could be useful to demonstrate the obesity development.

KEYWORDS: BMI; SNRPN gene; Spanish population; case-control study; genetic susceptibility; obesity

PMID:28387446   DOI:10.1002/jgm.2956

 

 

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Butler MG.  Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder.

J Intellect Disabil Res. 2017 Apr 7.. [Epub ahead of print]

 

Abstract   BACKGROUND: The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler susceptibility locus) is an emerging condition with over 200 individuals reported in the literature. TUBGCP5, CFYIP1, NIPA1 and NIPA2 genes are located in this chromosome 15 region and when disturbed individually are known to cause neurological, cognitive or behavioural problems as well as playing a role in both Prader-Willi and Angelman syndromes. These syndromes were the first examples in humans of genomic imprinting and typically caused by a deletion but involving the distal chromosome 15q11-q13 breakpoint BP3 and proximally placed breakpoints BP1 or BP2 of different parental origin. The typical 15q11-q13 deletion involves BP1 and BP3 and the typical type II deletion at BP2 and BP3. Several studies have shown that individuals with the larger type I deletion found in both Prader-Willi and Angelman syndromes are reported with more severe neurodevelopmental symptoms compared to those individuals with the smaller type II deletion.

METHODS: The literature was reviewed and clinical and cytogenetic findings summarised in 200 individuals with this microdeletion along with the role of deleted genes in diagnosis, medical care and counseling of those affected and their family members.

RESULTS: Reported findings in this condition include developmental delays (73% of cases) and language impairment (67%) followed by motor delay (42%), attention deficit disorder/attention deficit hyperactivity disorder (35%) and autism spectrum disorder (27%). The de novo deletion frequency has been estimated at 5 to 22% with low penetrance possibly related to subclinical manifestation or incomplete clinical information on family members. A prevalence of 0.6 to 1.3% has been identified in one study for patients with neurological or behavioural problems presenting for genetic services and chromosomal microarray analysis.

CONCLUSIONS: The summarised results indicate that chromosome 15q11.2 BP1-BP2 microdeletion is emerging as one of the most common cytogenetic abnormalities seen in individuals with intellectual impairment, autism spectrum disorder and other related behavioural or clinical findings, but more research is needed.

KEYWORDS: Prader-Willi syndrome; autism; genetics; genotype; intellectual disability; mental health

PMID:28387067   DOI:10.1111/jir.12382

 

 

 

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Skrypnik K, Suliburska , Skrypnik D, Pilarski Ł, Reguła J, Bogdański P  The genetic basis of obesity complications.   Acta Sci Pol Technol Aliment. 2017 Jan-Mar;16(1):83-91.

 

Abstract  Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex- pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1ß and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-γ2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involvedt in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications.

KEYWORDS: genetic background; obesity; obesity complications

PMID:28362475

 

 

 

Endocrine including GH

 

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Mele C   Grugni G, Mai S, Vietti R, Aimaretti G, Scacchi M, Marzullo P.  Circulating angiopoietin-like 8 (ANGPTL8) is a marker of liver steatosis and is negatively regulated by Prader-Willi Syndrome.  Sci Rep. 2017 Jun 9;7(1):3186.

 

Abstract  ANGPTL8 is a liver-derived protein related to insulin-sensitivity. Its relationship with obesity and liver function in Prader-Willi syndrome (PWS) is unknown. The present study investigated circulating ANGPTL8 in PWS and controls with common obesity, assessing its association to liver steatosis. For this purpose, 20 obese PWS and 20 controls matched for body mass index (BMI), sex and age underwent analysis of ANGPTL8 levels, glucose and lipid metabolism. Liver function tests and degree of liver steatosis by ultrasonography (US), fat-free mass (FFM) and fat mass (FM) by dual-energy x-ray absorptiometry (DEXA) were also assessed. In comparison to controls, obese PWS showed lower values of FFM (p < 0.0001) and higher FM (p = 0.01), while harbouring higher HDL cholesterol, lower triglycerides and OGTT-derived insulin levels, as well as a lower prevalence and severity of liver steatosis. With respect to obese controls, ANGPTL8 levels were significantly lower in PWS (p = 0.007) and overall correlated with transaminase levels and the severity of liver steatosis, as well as FFM (p < 0.05 for all). By a stepwise multivariable regression analysis, ANGPTL8 levels were independently predicted by PWS status (p = 0.01) and liver steatosis (p < 0.05). In conclusion, ANGPTL8 levels are lower in PWS than obese controls and are inversely associated with the severity of liver steatosis. Further studies should investigate the potential genetic basis for this observation.

PMID:28600576   DOI:10.1038/s41598-017-03538-7

 

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Nishi Y, Tanaka T.  Growth Hormone Treatment and Adverse Events.  Pediatr Endocrinol Rev. 2017 Mar;14(Suppl 1):235-239.

 

Abstract  We compiled the major adverse events included in the Annual Research Reports of the Foundation for Growth Research published in and after 2000. We conducted a review of approximately 32,000 patients treated with growth hormone (GH) who subsequently developed leukemia and who were registered with the Foundation for Growth Research (from 1975 to December 31 1997). We performed a literature review and found that GH therapy was not associated with leukemia onset in patients with no risk factors for leukemia. We also reported the onset of diabetes mellitus (DM), scoliosis, and respiratory problems in patients with Prader-Willi syndrome who were treated with GH. Osteoporosis, Hashimoto thyroiditis, and hyperlipemia were relatively frequent complications of Turner syndrome (TS).

KEYWORDS: Diabetes mellitus; Growth hormone treatment; Leukemia; Prader-Willi syndrome; Respiratory problems; Scoliosis; Turner syndrome

PMID:28516752   DOI:10.17458/per.vol14.2017.nt.growthhormonetreatment

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Tauber M, Diene G, Molinas C.  Sequelae of GH Treatment in Children with PWS.

Pediatr Endocrinol Rev. 2016 Dec;14(2):138-146

 

Abstract  More than 15 years after rGH was granted marketing authorization for children with PWS, a review of the sequelae, side effects and safety issues of rGH therapy is timely. The publications on issues concerning respiratory function, glucose metabolism, fat mass, and scoliosis at baseline and with rGH treatment are herein presented. We discuss the impact of rGH side effects, make proposals to prevent or treat them, and emphasise the remaining questions and perspectives. As a whole, the benefit /risk ratio is positive, although questions are raised about the role of GH in premature pubarche and its long-term effects, particularly the potential long-term oncogenic risk. The organisation of care in dedicated or reference centres at the national and European level will facilitate the collection and analysis of data and serve as a paradigm for long-term follow-up.

KEYWORDS: Diabetes mellitus; Growth hormone; Impaired glucose tolerance; Safety; Sleep-related disordered breathing

PMID:28508607   DOI:10.17458/PER.2016.TDM.SequelaeofGH

 

Scheermeyer E, Harris M, Hughes I, Crock PA, Ambler G, Verge CF, Bergman P, Werther G, Craig ME, Choong CS, Davies PSW; PWS and OZGROW collaboration.  Low dose growth hormone treatment in infants and toddlers with Prader-Willi syndrome is comparable to higher dosage regimens.  Growth Horm IGF Res. 2017 Mar 24;34:1-7.. [Epub ahead of print]

 

Abstract  OBJECTIVE: Evaluate benefit and risk of low dose growth hormone treatment (GHT, 4.5mg/m2/week) in very young children with Prader-Willi Syndrome (PWS).

DESIGN: Prospective longitudinal clinical intervention.

METHODS: We evaluated 31 infants (aged 2-12months) and 42 toddlers (13-24months) from the PWS-OZGROW database for height, weight and BMI using the World Health Organization standard deviation scores (SDSWHO) and PWS specific BMI (SDSPWS), bone age, insulin-like growth factor 1 (IGF-I) levels and adverse events over 3years of GHT.

RESULTS: At commencement of GHT infants had a lower BMI SDSWHO (-0.88 vs 0.40) than toddlers, while toddlers had a lower height SDSWHO (-1.44 vs -2.09) (both P<0.05). All increased height SDSWHO (2year delta height infants +1.26 SDS, toddlers+1.21 SDS), but infants normalised height sooner, achieving a height SDS of -0.56 within 1year, while toddlers achieved a height SDS of -0.88 in two years. BMI SDSWHO increased, while BMI SDSPWS decreased (both P<0.0001) and remained negative. The GHT response did not differ with gestation (preterm 23%) or genetic subtype (deletion vs maternal uniparental disomy). Bone age advancement paralleled chronological age. All children had low serum IGF-I at baseline which increased, but remained within the age-based reference range during GHT (for 81% in first year). Four children had spinal curvature at baseline; two improved, two progressed to a brace and two developed an abnormal curve over the observation period. Mild to severe central and/or obstructive sleep apnoea were observed in 40% of children prior to GHT initiation; 11% commenced GHT on positive airway pressure (PAP), oxygen or both. Eight children ceased GHT due to onset or worsening of sleep apnoea: 2 infants in the first few months and 6 children after 6-24months. Seven resumed GHT usually after adjusting PAP but five had adenotonsillectomy. One child ceased GHT temporarily due to respiratory illness. No other adverse events were reported. Two children substantially improved their breathing shortly after GHT initiation.

CONCLUSION: Initiation of GHT in infants with 4.5mg/m2/week was beneficial and comparable in terms of auxological response to a dose of 7mg/m2/week. Regular monitoring pre and post GH initiation assisted in early detection of adverse events. IGF-I levels increased with the lower dose but not excessively, which may lower potential long-term risks.

KEYWORDS: Administration & dosage; Adverse effects; Early medical intervention; Insulin-like growth factor (IGF); Paediatric obesity; Prader-Willi Syndrome

PMID:28427039   DOI:10.1016/j.ghir.2017.03.001

 

 

 

 

Sensory and physical

 

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Cimolin V, Cau N, Galli M, Santovito C, Grugni G, Capodaglio P.  Gait initiation and termination strategies in patients with Prader-Willi syndrome.   J Neuroeng Rehabil. 2017 May 23;14(1):44.

 

Abstract  BACKGROUND: Gait Initiation (GI) is a functional task representing one of the first voluntary destabilizing behaviours observed in the development of a locomotor pattern as the whole body centre of mass transitions from a large to a small base of support. Conversely, Gait Termination (GT) consists in the transition from walking to standing which, in everyday life, is a very common movement. Compared to normal walking, it requires higher control of postural stability. For a safe GT, the forward movement of the body has to be slowed down to achieve a stable upright position. Stability requirements have to be fulfilled for safe GT. In individuals with Prader-Willi syndrome (PWS), excessive body weight negatively affects the movement, such as walking and posture, but there are no experimental studies about GI and GT in these individuals. The aim of this study was to quantitatively characterise the strategy of patients with PWS during GI and GT using parameters obtained by the Center of Pressure (CoP) track.

METHODS: Twelve patients with PWS, 20 obese (OG) and 19 healthy individuals (HG) were tested using a force platform during the GI and GT tasks. CoP plots were divided into different phases, and duration, length and velocity of the CoP trace in these phases were calculated and compared for each task.

RESULTS: As for GI, the results showed a significant reduction of the task duration and lower velocity and CoP length parameters in PWS, compared to OG and HG. In PWS, those parameters were reduced to a higher degree with respect to the OG. During GT, longer durations, similar to OG, were observed in PWS than HG. Velocity is reduced when compared to OG and HG, especially in medio-lateral direction and in the terminal part of GT.

CONCLUSIONS: From these data, GI appears to be a demanding task in most of its sub-phases for PWS individuals, while GT seems to require caution only towards the end of the task. Breaking the cycle of gait into the phases of GI and GT and implementing specific exercises focusing on weight transfer and foot clearance during the transition phase from the steady condition to gait will possibly improve the effectiveness of rehabilitation and fall and injury prevention.

KEYWORDS: Center of pressure; Gait initiation; Gait termination; Obesity; Prader-Willi syndrome; Rehabilitation

PMID:28535762   PMCID:PMC5442593   DOI:10.1186/s12984-017-0257-7

 

 

 

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Esbensen AJ, Schwichtenberg AJ.  Sleep in Neurodevelopmental Disorders.  Int Rev Res Dev Disabil. 2016;51:153-191.

 

Abstract  Individuals with intellectual and developmental disabilities (IDD) experience sleep problems at higher rates than the general population. Although individuals with IDD are a heterogeneous group, several sleep problems cluster within genetic syndromes or disorders. This review summarizes the prevalence of sleep problems experienced by individuals with Angelman syndrome, Cornelia de Lange syndrome, Cri du Chat syndrome, Down syndrome, fragile X syndrome, Prader-Willi syndrome, Smith-Magenis syndrome, Williams syndrome, autism spectrum disorder, and idiopathic IDD. Factors associated with sleep problems and the evidence for sleep treatments are reviewed for each neurodevelopmental disorder. Sleep research advancements in neurodevelopmental disorders are reviewed, including the need for consistency in defining and measuring sleep problems, considerations for research design and reporting of results, and considerations when evaluating sleep treatments.

KEYWORDS: genetic syndrome; intellectual disability; sleep

PMID: 28503406   PMCID:PMC5424624   DOI:10.1016/bs.irrdd.2016.07.005

 

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Blat C, Busquets E, Gili T, Caixàs A, Gabau E, Corripio R.  Gastric Dilatation and Abdominal Compartment Syndrome in a Child with Prader-Willi Syndrome.  Am J Case Rep. 2017 Jun 7;18:637-640.

 

Abstract  BACKGROUND Prader-Willi syndrome (PWS) is a genetic disorder characterized by initial muscular hypotonia and feeding difficulties, and later an insatiable appetite, hyperphagia and obesity along with mild to moderate intellectual impairment. Affected individuals' food-seeking behavior and suspected delayed gastric emptying can lead to gastric dilatation with subsequent necrosis and perforation. CASE REPORT We present the case of a 5-year-old boy diagnosed with Prader-Willi syndrome at neonatal age due to muscular hypotonia, who started growth hormone therapy at 20 months. He presented with two episodes of a rapidly progressing gastric dilatation that led to abdominal hypertension and secondary shock at the age of 2 and 5. No large amount of food was eaten before any of the episodes, and he had abdominal pain and vomiting on both occasions. On arrival at the emergency room, a nasogastric tube was placed and aspiration of food material was performed. Abdominal X-ray and CT scan revealed massive gastric dilatation. He was admitted at the Pediatric Intensive Care Unit and after a variable period of fasting, tolerated oral intake and could be discharged. CONCLUSIONS Gastric dilatation due to gastroparesis in PWS is a rare complication. However, it is a life-threatening situation and physicians should therefore maintain a high level of suspicion for gastric dilatation when patients present with warning symptoms such as abdominal pain or discomfort and vomiting.

PMID:28588153

 

 

Behaviour

 

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Dimitropoulos A, Zyga O, Russ S.   Evaluating the Feasibility of a Play-Based Telehealth Intervention Program for Children with Prader-Willi Syndrome.   J Autism Dev Disord. 2017 Jun 13. [Epub ahead of print]

 

Abstract   Here we report the feasibility and acceptability of telehealth for direct intervention in children with Prader-Willi syndrome (PWS). Children with PWS have social-cognitive challenges that are similar to children with ASD. However, developing behavioral interventions for individuals with PWS is faced with the significant challenge of enrolling enough participants for local studies where multiple visits per week are indicated for effective intervention. This study delivered a 6-week play-based intervention via telehealth directly to eight children with PWS (6-12 years). Participants completed the program with minimal behavioral or technological difficulty (#sessions M = 11.875/12). Behavioral Intervention Rating Scale results indicate good acceptability (M = 5.54/6.00). These findings support using telehealth in rare disorders and delivering intervention directly to children with developmental delays through this modality.

KEYWORDS: Play-based intervention; Prader–Willi syndrome; Telehealth; Video conferencing

PMID:28612246   DOI:10.1007/s10803-017-3196-z

 

 

McCandless SE, Yanovski JA, Miller J, Fu C, Bird LM5 Salehi P, Chan CL, Stafford D, Abuzzahab MJ, Viskochil D, Barlow SE, Angulo M, Myers SE,Whitman BY, Styne D, Roof E, Dykens EM, Scheimann AO, Malloy J, Zhuang D, Taylor K, Hughes TE, Kim DD, Butler MG.  Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: a randomized, double-blind, placebo-controlled trial.  Diabetes Obes Metab. 2017 May 29.. [Epub ahead of print]

 

Abstract  AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS trial assessed the efficacy, safety, and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib.

MATERIALS AND METHODS: Participants with PWS (12-65 years) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib, or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Coprimary endpoints were the changes in hyperphagia (measured by Hyperphagia Questionnaire for Clinical Trials [HQ-CT]; possible score 0-36) and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151.

RESULTS: 107 were included in the intention-to-treat analysis: placebo (n = 34), 1.8 mg beloranib (n = 36), or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; p = 0.0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; p = 0.0001) vs placebo. Compared to placebo, weight change was greater with 1.8 mg (mean difference -8.2%, 95% CI -10.8 to -5.6; p < 0.0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; p < 0.0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (two fatal events of pulmonary embolism and two events of deep vein thrombosis) compared to placebo.

CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviors and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

PMID:28556449  DOI:10.1111/dom.13021

 

 

 

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Miller JL, Tamura R, Butler MG, Kimonis V, Sulsona C, Gold JA, Driscoll DJ   Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study.  Am J Med Genet A. 2017 Mar 30.. [Epub ahead of print]

 

Abstract  Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale - Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P < 0.05) between groups at Day 6. The drug effect appeared to be diminished at Day 14. There was no evidence of a difference between oxytocin and placebo in safety lab parameters, 60 min post dose vital signs, weight, or diet parameters. The results from this study suggest that low dose intranasal oxytocin is safe for individuals with PWS and may result in reduction in appetite drive, and improvements in socialization, anxiety, and repetitive behaviors. Further, long-term studies with a larger population of participants are necessary to confirm these findings. The results of this study are encouraging that oxytocin may be a safe and effective treatment for many of the issues that negatively impact individuals with PWS.

KEYWORDS: Prader-Willi syndrome; hyperphagia; oxytocin

PMID:28371242   DOI:10.1002/ajmg.a.38160

 

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Jensen KB, Kirsch I, Pontén M, Rosén A, Yang K, Gollub RL, des Portes V, Kaptchuk TJ, Curie A. Certainty of genuine treatment increases drug responses among intellectually disabled patients. Neurology. 2017 Apr 19. pii: 10.1212/WNL.0000000000003934. [Epub ahead of print]    

 

Abstract   OBJECTIVE: To determine the placebo component of treatment responses in patients with intellectual disability (ID).

METHODS: A statistical meta-analysis comparing bias-corrected effect sizes (Hedges g) of drug responses in open-label vs placebo-controlled clinical trials was performed, as these trial types represent different certainty of receiving genuine treatment (100% vs 50%). Studies in fragile X, Down, Prader-Willi, and Williams syndrome published before June 2015 were considered.

RESULTS: Seventeen open-label trials (n = 261, 65% male; mean age 23.6 years; mean trial duration 38 weeks) and 22 placebo-controlled trials (n = 721, 62% male; mean age 17.1 years; mean trial duration 35 weeks) were included. The overall effect size from pre to post treatment in open-label studies was g = 0.602 (p = 0.001). The effect of trial type was statistically significant (p = 0.001), and revealed higher effect sizes in studies with 100% likelihood of getting active drug, compared to both the drug and placebo arm of placebo-controlled trials. We thus provide evidence for genuine placebo effects, not explainable by natural history or regression toward the mean, among patients with ID.

CONCLUSIONS: Our data suggest that clinical trials in patients with severe cognitive deficits are influenced by the certainty of receiving genuine medication, and open-label design should thus not be used to evaluate the effect of pharmacologic treatments in ID, as the results will be biased by an enhanced placebo component.

PMID:28424273   DOI:10.1212/WNL.0000000000003934                                    

 

 

 

Cognition and mental health

 

Briegel W   Neuropsychiatrische Aspekte bei Prader-Willi-Syndrom – eine Übersicht.

Z Kinder Jugendpsychiatr Psychother. 2017 Jun 14:1-8. [Epub ahead of print]

KEYWORDS: Prader-Willi Syndrome; Prader-Willi-Syndrom; Psychose; Review; Therapie; neuropsychiatric aspects; neuropsychiatrische Aspekte; psychiatric disorders; psychische Störungen; psychosis; review; therapy

PMID:28613110   DOI:10.1024/1422-4917/a000530

 

Shriki-Tal L, Avrahamy H, Pollak Y, Gross-Tsur V, Genstil L, Hirsch HJ, Benarroch F. Psychiatric disorders in a cohort of individuals with Prader-Willi syndrome.  Eur Psychiatry. 2017 Apr 5;44:47-52. [Epub ahead of print]

Abstract  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.

Copyright © 2017 Elsevier Masson SAS. All rights reserved.

KEYWORDS: Behavior; Prader–Willi syndrome; Psychiatry

PMID:28545008   DOI:10.1016/j.eurpsy.2017.03.007

 

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Dykens EM, Roof E, Hunt-Hawkins H, Dankner N, Lee EB, Shivers CM, Daniell C, Kim SJ. Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome.J Neurodev Disord. 2017 Jun 5;9:18.. eCollection 2017.

 

Abstract  BACKGROUND: A small percentage of people with autism spectrum disorders (ASD) have alterations in chromosome 15q11.2-q3, the critical region for Prader-Willi syndrome (PWS). Data are limited, however, on the rates and characteristics of ASD in PWS. Previous estimates of ASD in PWS (25 to 41%) are questionable as they are based solely on autism screeners given to parents. Inaccurate diagnoses of ASD in PWS can mislead intervention and future research.

METHODS: One hundred forty-six children and youth with PWS aged 4 to 21 years (M = 11) were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). An expert clinical team-made best-estimate ASD diagnoses based on ADOS-2 videotapes, calibrated severity scores, and children's developmental histories and indices of current functioning. Children were also administered the Kaufman Brief Intelligence Test-2, and parents completed the Repetitive Behavior Scale-Revised and Vineland Adaptive Behavior Scales. Scores were compared across children with PWS + ASD versus PWS only. The performance of an ASD screener, the Social Communication Questionnaire (SCQ) and the ADOS-2 were evaluated in relation to best-estimate diagnoses.

RESULTS: Best-estimate diagnoses of ASD were made in 18 children, or 12.3% of the sample, and the majority of them had the maternal uniparental disomy (mUPD) PWS genetic subtype. Compared to the PWS-only group, children with PWS + ASD had lower verbal and composite IQ's and adaptive daily living and socialization skills, as well as elevated stereotypies and restricted interests. Regardless of ASD status, compulsivity and insistence on sameness in routines or events were seen in 76-100% of children and were robustly correlated with lower adaptive functioning. The SCQ yielded a 29-49% chance that screen-positive cases will indeed have ASD. The ADOS-2 had higher sensitivity, specificity and predictive values. Communication problems were seen in children who were ADOS-2 positive but deemed not to have ASD by the clinical team.

CONCLUSIONS: Autism screeners should not be the sole index of probable ASD in PWS; children need to be directly observed and evaluated. Compulsivity and insistence on sameness are salient in PWS and likely impede adaptive functioning. Most children with PWS only evidenced sub-threshold problems in social interactions that could signal risks for other psychopathologies.

KEYWORDS: ASD screeners; Autism spectrum disorder (ASD); Best-estimate diagnoses; Insistence on sameness; Prader-Willi syndrome (PWS); Repetitive behavior; Social impairment

PMID: 28592997   PMCID:PMC5458479   DOI:10.1186/s11689-017-9200-2

 

Lukoshe A, van den Bosch GE, van der Lugt A, Kushner SA, Hokken-Koelega AC, White T.  Aberrant White Matter Microstructure in Children and Adolescents With the Subtype of Prader-Willi Syndrome at High Risk for Psychosis.  Schizophr Bull. 2017 May 16. [Epub ahead of print]

 

Abstract  Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder caused by loss of the paternal 15q11.2-q13 locus, due to deletion (DEL), maternal uniparental disomy (mUPD), or imprinting center defects. Individuals with mUPD have up to 60% risk of developing psychosis in early adulthood. Given the increasing evidence for white matter abnormalities in psychotic disorders, we investigated white matter microstructure in children and adolescents with PWS, with a particular emphasis on the DEL and mUPD subtypes. Magnetic resonance diffusion weighted images were acquired in 35 directions at 3T and analyzed using fractional anisotropy (FA), mean, axial, and radial diffusivity (MD, AD, RD) values obtained by tract-based spatial statistics (TBSS) in 28 children and adolescents with PWS and 61 controls. In addition, we employed a recently developed white matter pothole approach, which does not require local FA differences to be spatially co-localized across subjects. After accounting for age and gender, individuals with PWS had significantly lower global FA and higher MD, compared with controls. Individuals with mUPD had lower FA in multiple regions including the corpus callosum, cingulate, and superior longitudinal fasciculus and larger potholes, compared with DEL and controls. The observed differences in individuals with mUPD are similar to the white matter abnormalities in individuals with psychotic disorders. Conversely, the subtle white matter abnormalities in individuals with DEL are consistent with their substantially lower risk of psychosis. Future studies to investigate the specific neurobiological mechanism underlying the differential psychosis risk between the DEL and mUPD subtypes of PWS are highly warranted.

KEYWORDS: 15q11–q13; Prader–Willi syndrome; neurodevelopmental disorders; psychosis; structural connectivity

PMID:28510708   DOI:10.1093/schbul/sbx052