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Pediatric growth charts are used to monitor children's growth and development, and assist in healthcare delivery and supervision. Researchers have developed syndrome-specific growth charts for several disorders in which affected children grow differently than unaffected children. Typical standardized growth curves have been recently reported in non-growth hormone treated infants with Prader-Willi syndrome (PWS) of both genders from birth to 36 months of age to support monitoring growth and nutritional status during infancy, and to guide growth hormone treatment and follow up. Electronic health record (EHR) systems serving pediatric populations can now incorporate interactive automated growth charts to assist the healthcare providers in clinical settings to monitor growth. The American Academy of Pediatrics has recommended that EHR systems incorporate syndrome-specific growth charts where feasible. This manuscript describes the experiences at two medical centers at different stages of incorporating electronic growth charts into the medical records on infants with rare disorders, using PWS as an illustration. The absence of readily available and accessible syndrome-specific standardized growth charts in other disorders causes challenges for EHR personnel and for healthcare providers who care for these children particularly in the growing electronic medical record environment.
Copyright © 2012 Wiley Periodicals, Inc.

RNA transcripts encoding the 2C-subtype of serotonin (5HT(2C)) receptor undergo up to five adenosine-to-inosine editing events to encode twenty-four protein isoforms. To examine the effects of altered 5HT(2C) editing in vivo, we generated mutant mice solely expressing the fully-edited (VGV) isoform of the receptor. Mutant animals present phenotypic characteristics of Prader-Willi syndrome (PWS) including a failure to thrive, decreased somatic growth, neonatal muscular hypotonia, and reduced food consumption followed by post-weaning hyperphagia. Though previous studies have identified alterations in both 5HT(2C) receptor expression and 5HT(2C)-mediated behaviors in both PWS patients and mouse models of this disorder, to our knowledge the 5HT(2C) gene is the first locus outside the PWS imprinted region in which mutations can phenocopy numerous aspects of this syndrome. These results not only strengthen the link between the molecular etiology of PWS and altered 5HT(2C) expression, but also demonstrate the importance of normal patterns of 5HT(2C) RNA editing in vivo.

Two experiments were conducted to examine differences between people with Prader-Willi syndrome and an obese comparison group in choosing a larger quantity of food delivered after a delay (15, 30, or 60 seconds) or a small quantity of food delivered immediately. Individuals with Prader-Willi syndrome selected the larger food quantity. Choices by the obese comparison group tended to be equally divided between both options. Relative food preference influenced choosing the larger, delayed option in both groups. This effect appeared to be larger in the non-Prader-Willi syndrome group, but was not statistically significant. These results suggest perceived differences in food quantity may be an important determinant of food choice of people with Prader-Willi syndrome.

Seventeen patients with Prader-Willi syndrome (7 with paternal deletion of chromosome 15q11-q13 and 10 with maternal uniparental disomy [UPD]), and 9 controls performed a computerized visual recognition task. A series of color digital photographs were presented; most were presented twice, but the remainder appeared only once. Photographs presented twice were separated in their presentation by either 0, 10, 30, 50 or 100 intervening photographs. Subjects indicated whether each photograph had been presented previously. This procedure was implemented twice, once using photographs of foods, and once using photographs of nonfood objects. As the number of intervening photographs between the first and second presentation increased, subjects were less likely to remember having seen the photograph before. Performance by UPD subjects was less affected by increasing the number of intervening photographs relative to the other two groups, suggesting they had superior visual recognition memory. This raises the possibility of a beneficial effect of having two copies maternally expressed genes on chromosome 15. UBE3A is suggested as a possible candidate for this effect.

Advances in genetic research have led to an increased understanding of genotype-phenotype relationships. Excessive eating and weight gain characteristic of Prader-Willi syndrome (PWS) have been the understandable focus of much of the research. The intense preoccupation with food, lack of satiation, and incessant food seeking are among the most striking features of PWS. It has become increasingly clear that the behavioral phenotype of PWS also includes symptoms similar to obsessive compulsive disorder, which in all probability interact with the incessant hunger and lack of satiation to engender the intense preoccupation and food seeking behavior that is characteristic of this disorder. Several lines of evidence suggest that genetic material on chromosome 15 may alter synthesis, release, metabolism, binding, intrinsic activity, or reuptake of specific neurotransmitters, or alter the receptor numbers and/or distribution involved in modulating feeding. Among the likely candidates are GABAnergic, serotonergic, and neuropeptidergic mechanisms. This review summarizes what is known about the appetitive behavior and compulsivity in PWS and discusses the possible mechanisms underlying these behaviors. MRDD Research Reviews 2000;6:125-130.
Copyright 2000 Wiley-Liss, Inc.

Prader-Willi syndrome and Angelman syndrome are associated with parent-of-origin-specific abnormalities of chromosome 15q11-q13, most frequently a deletion of an approximately 4-Mb region. Because of genomic imprinting, paternal deficiency of this region leads to PWS and maternal deficiency to AS. Additionally, this region is frequently involved in other chromosomal rearrangements including duplications, triplications, or supernumerary marker formation. A detailed physical map of this region is important for elucidating the genes and mechanisms involved in genomic imprinting, as well as for understanding the mechanism of recurrent chromosomal rearrangments. An initial YAC contig extended from D15S18 to D15S12 and was comprised of 23 YACs and 21 STSs providing an average resolution of about one STS per 200 kb. To close two gaps in this contig, YAC screening was performed using two STSs that flank the gap between D15S18 and 254B5R and three STSs located distal to the GABRA5-149A9L gap. Additionally, we developed 11 new STSs, including seven polymorphic markers. Although several groups have developed whole-genome genetic and radiation hybrid maps, the depth of coverage for 15q11-q13 has been somewhat limited and discrepancies in marker order exist between the maps. To resolve the inconsistencies and to provide a more detailed map order of STSs in this region, we have constructed an integrated YAC STS-based physical map of chromosome 15q11-q13 containing 118 YACs and 118 STSs, including 38 STRs and 49 genes/ESTs. Using an estimate of 4 Mb for the size of this region, the map provides an average STS spacing of 35 kb. This map provides a valuable resource for identification of disease genes localized to this region as well as a framework for complete DNA sequencing.

The gene encoding the small nuclear ribonucleoprotein-associated polypeptide N (SNRPN) maps to the Prader-Willi syndrome critical region on chromosome 15 and is expressed preferentially from the paternal allele. A CpG island encompassing the first exon of SNRPN is methylated on the inactive maternal allele. DNA sequence was determined for a cosmid containing the first three exons of SNRPN and extending 20 kb upstream and 15 kb downstream from the CpG island. This region is extremely rich in Alu elements and other repetitive sequences and contains a single CpG island, which includes numerous short direct repeat sequences. Functional analysis of the first exon revealed strong promoter activity for a 260-bp fragment extending 207 bp upstream from the exon. In vitro methylation of this 260-bp fragment abolished promoter activity completely, suggesting that the silencing of the maternal SNRPN allele may be a direct consequence of methylation of the promoter region.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct clinical phenotypes resulting from maternal and paternal deficiencies, respectively, in human chromosome 15qll-q13. Although several imprinted, paternally expressed transcripts have been identified within the PWS candidate region, no maternally expressed gene has yet been identified within the AS candidate region. We have developed an integrated physical map spanning the PWS and AS candidate regions and localized two breakpoints, including a cryptic t(14;15) translocation associated with AS and a non-AS 15q deletion, which substantially narrow the AS candidate region to approximately 250 kb. Mapping data indicate that the entire transcriptional unit of the E6-AP ubiquitin-protein ligase (UBE3A) gene lies within the AS region. The UBE3A locus expresses a transcript of approximately 5 kb at low to moderate levels in all tissues tested. The mouse homolog of UBE3A was cloned and sequenced revealing a high degree of conservation at nucleotide and protein levels. Northern and RT-PCR analysis of Ube3a expression in mouse tissues from animals with segmental, paternal uniparental disomy failed to detect substantially reduced or absent expression compared to control animals, failing to provide any evidence for maternal-specific expression from this locus. Recent identification of de novo truncating mutations in UBE3A taken with these observations indicates that mutations in UBE3A can lead to AS and suggests that this locus may encode both imprinted and biallelically expressed products.