Prader-Willi and Angelman Syndromes: Sister Imprinted Disorders

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 97:136–146 (2000) ARTICLE

SUZANNE B. CASSIDY,* ELISABETH DYKENS, AND CHARLES A. WILLIAMS

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are clinically distinct complex disorders mapped to chromosome 15q11-q13. They both have characteristic neurologic, developmental, and behavioral phenotypes plus other structural and functional abnormalities. However, the cognitive and neurologic impairment is more severe in AS, including seizures and ataxia. The behavioral and endocrine disorders are more severe in PWS, including obsessive–compulsive symptoms and hypothalamic insufficiency. Both disorders can result from microdeletion, uniparental disomy, or an imprinting center defect in 15q11-q13, although the abnormality is on the paternally derived chromosome 15 for PWS and the maternally derived 15 for AS because of genomic imprinting. Although the same gene may control imprinting for both disorders, the gene(s) causing their phenotypes differ. AS results from underexpression of a single gene, UBE3A, which codes for E6-AP, a protein that functions to transfer small ubiquitin molecules to certain target proteins, to enable their degradation. The genes responsible for PWS are not determined, although several maternally imprinted genes in 15q11-q13 are known. The most likely candidate is SNRPN, which codes for a small nuclear ribonucleoprotein, a ribosome-associated protein that controls gene splicing and thus synthesis of critical proteins in the brain. Animal models exist for both disorders. The genetic relationship between PWS and AS makes them unique and potentially highly instructive disorders that contribute substantially to the population burden of cognitive impairment. Am. J. Med. Genet. (Semin. Med. Genet.) 97:136–146, 2000 ᮊ 2000 Wiley-Liss, Inc.

KEY WORDS: Prader-Willi syndrome; Angelman syndrome; genetic imprinting; behavioral phenotype; uniparental disomy; microdeletion; chromosome disorder; mental retardation

INTRODUCTION neurologic phenotype. These disorders them thus represents an important occupy an important place in the con- pathogenetic mechanism of cognitive Prader-Willi syndrome (PWS) and An- temporary history of human genetic impairment. gelman syndrome (AS) are two clini- disorders because of their unusual and PWS and AS are different in many cally distinct disorders each with a char- partially shared genetic basis. They are ways. Patients with PWS generally have acteristic cognitive, behavioral, and sometimes called sister disorders be- mild mental retardation, and individuals cause they are both the result of the with AS have severe impairment with absence or lack of expression of one absent speech. Multiple endocrine ab- Suzanne B. Cassidy, M.D., is a medical ge- parent’s contribution to the same re- normalities occur in PWS, whereas sig- neticist who is a Professor of Pediatrics and Director of Human Genetics at Uni- gion of the proximal long arm of chro- nificant neurologic deficits, including versity of California, Irvine. She has a mosome 15q (15q11-q13, the PWS/AS seizures and ataxia, are characteristic of long-standing interest in Prader-Willi region). The absent contribution to this AS. The affect of people with AS is syndrome, and has had a major hand in delineating its clinical, diagnostic, and region is invariably paternal in the case happy, with unprovoked laughter and genetic basis. of PWS and maternal in the case of AS. preference for water play, whereas Elisabeth Dykens, Ph.D., is a behavioral psychologist who is an Associate This phenomenon of parent-of-origin those with PWS tend to be relatively Professor of Psychiatry and Biobehav- difference in the expression of genes is discontent and have temper tantrums ioral Sciences at the U.C.L.A. Neuropsy- chiatric Institute. She has played a signifi- the consequence of genomic imprint- and obsessive–compulsive behavior. cant role in the delineation of cognitive ing in this region. Thus, the gene for However, they also share some clinical characteristics and behavioral phenotypes of genetic syndromes. AS and the gene(s) for PWS exhibit dif- findings, including the presence of Charles Williams, M.D., is a medical ferential expression depending on the infantile hypotonia and sometimes hy- geneticist who is Professor of Pediatrics sex of the parent from whom they were popigmentation, and they have in com- at University of Florida. He has been in- strumental in delineating the clinical inherited. Because PWS and AS each mon the presence in each of a distinc- characteristics and genetic basis for An- occurs in approximately 1/10,000– tive (although different) behavioral gelman syndrome. *Correspondence to: Division of 1/15,000 individuals, together they phenotype. In addition, they both dem- Human Genetics, Department of Pediat- represent a substantial contribution to onstrate similar genotype–phenotype rics, UCI Medical Center, Bldg. 2, 101 The City Drive, Orange, CA 92868. cognitive disability, and the nontradi- correlations. Thus, it is appropriate that tional form of inheritance that causes they be discussed together.

The Common Genetic Basis of et al., 1999], although a few patients mechanism is unknown but could be PWS and AS have smaller or larger deletions. The sporadic. All families with recurrence of difference in frequency of UPD be- PWS studied to date have had an im- AS and PWS map to the same genetic tween PWS and AS is, in large part, printing mutation, but this is not true region at 15q11-q13. They each can be presumably because paternal nondis- the result of three shared genetic de- of AS. In AS, approximately 10–15% of junction is much less common than fects: microdeletion, uniparental di- cases are the result of a single gene maternal. Approximately 2–5% of pa- somy (UPD), and imprinting defects. mutation in one gene within 15q11- tients with either disorder have their Also, they share similar diagnostic q13, UBE3A, which codes for a ubiq- deletion or their UPD as a consequence methodologies, including analysis of uitin protein ligase [Kishino et al., of a translocation or other structural ab- the degree of methylation of the gene 1997; Matsuura et al., 1997]. In the re- normality involving chromosome 15. SNRPN within the PWS/AS region. maining 10%, the cause has not yet PWS is known to be caused by been identified. lack of expressed paternally inherited A number of imprinted and non- genes in chromosome 15q11-q13, . . . [P]atients with UPD imprinted genes have been found to ex- whereas AS is caused by lack of a single or imprinting defects [in ist within the PWS/AS critical region expressed gene, UBE3A, from the ma- (Table II; Figs. 1 and 2) [Nicholls, ternally inherited chromosome 15. In PWS or AS] have milder 1993; Buiting et al., 1994; Glenn et al., this region, the maternally inherited manifestations than those 1997]. However, for none of these genes is it clear how underexpression is genes related to PWS are normally not with deletions. expressed, having been rendered inac- involved in causing the disease pheno- tive because of genetic imprinting; like- types. The major exception is the non- wise, the paternally inherited UBE3A is imprinted P gene [Lee et al., 1994], normally not expressed because of im- Among those with a defect in the im- which codes for a tyrosine transporter printing. Table I reviews the genetic printing process, a proportion have gene whose deficiency results in the mechanisms that are known to cause been shown to have a very small dele- skin and ocular hypopigmentation that these two disorders, and the frequencies tion, mutation, or other abnormality in occur in 50–70% of those with PWS with which they occur. In approxi- the center that controls imprinting and AS with deletions. P protein defi- mately 70% of patients with PWS and a within 15q11-q13, the imprinting cen- ciency also causes strabismus, attribut- comparable number in AS, there is a ter (IC) [Ohta et al., 1999]. Others have able to aberrant chiasmal crossing of op- cytogenetically small deletion in chro- not had a detectable mutation or dele- tic nerve fibers that depend on normal mosome 15 between bands 15q11-q13, tion in the IC but nonetheless have bi- retinal pigment for proper growth and which is paternal in PWS and maternal parental-inheritance and a maternal- routing [Wiesner et al., 1987; King et in AS. In most cases, the same break- only (PWS) or paternal-only (AS) al., 1993]. Although AS is known to points on the chromosome have re- expression pattern [Buiting et al., result from a single gene defect, PWS is sulted in the same 4-Mb deletion 1998]. These individuals are said to caused by at least two genes. The best [Christian et al., 1995; Amos-Landgraf have an imprinting defect, and the candidate gene is SNRPN, discussed below. Upstream of the SNRPN gene, in a region called SNURF (SNRPN upstream reading frame), is a putative im- TABLE I. Genetic Abnormalities in Prader-Willi (PWS) and printing control element (IC) for the Angelman Syndromes (AS) region [Gray et al., 1999] (Fig. 2). Very Frequency of genetic cause small deletions within it have been Recurrence risk identified in a few patients with AS or PWS (%) AS (%) (%) PWS despite biparental inheritance Deletion 15q11-q13 70 70 <1a [Saitoh et al., 1996]. GABRB3, Uniparental disomy 25–28 (maternal) 3–5 (paternal) <1a GABRA5, and GABRG3, are all non- Imprinting center defect 2–5 2–5 50b imprinted receptor subunit genes for ␥ Translocation within <1 <1 5–50b the neurotransmitter GABA ( -amino PWS/AS critical region butyric acid). There are also several Single gene mutation 0? 10–15 (UBE3A) 50b identified maternally imprinted genes Unknown 0? ∼10 ? and transcripts whose function is unknown. ZNF127 is an imprinted zinc- a Not yet reported. finger gene of unknown function. Nec- b Magnitude and disorder of risk dependent on the parent of origin. din (NDN) is an imprinted gene that encodes a DNA-binding protein. IPW 138 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

is an imprinted gene that does not en- TABLE II. Maternally Imprinted Genes/Transcripts in the Prader-Willi code a protein. Two imprinted anony- Syndrome (PWS) Deletion Region mous transcripts, PAR1 and PAR5, have been identified. PW71 is another Gene Protein Function imprinted gene of unknown function; SNRPN SmN Involved in translational control it has been used as a methylation probe (small nuclear ribonuclear protein) and alternative splicing for some clinical and research studies. A SNURF ? Possibly the PWS imprinting center number of other genes and transcripts PW71 ? ? in this region have been identified, with IPW None ? no known pathogenetic relationship to Necdin A DNA-binding protein ? AS or PWS. ZNF127 ? Zinc finger gene of unknown Genotype–phenotype correlations function have been found for both disorders. In Par 1 None Read-through transcript general, patients with UPD or imprint- Par 5 None Read-through transcript ing defects have milder manifestations than those with deletions. Although the reason is not identified, potential expla- nations include incompleteness (“leaki- ness”) of the imprinting process, haplo- insufficiency of nonimprinted gene(s) in those with deletion, and overexpres- sion of some gene(s) in patients with UPD. Animal models exist for both disorders, although they have as yet pro- vided only pathogenetic insight for AS. The discussion that follows will detail these findings.

ANGELMAN SYNDROME

Physical, Neurologic, and Developmental Phenotype

The hallmarks of Angelman syndrome are mental retardation with jerky, ataxic gait, seizures, and absent speech. In addition, the presence of microcephaly, a flat occiput (microbrachycephaly), excessive laughter with protruding tongue, prognathism, and skin hypopigmentation usually present a distinctive clinical picture [Williams et al., Figure 1. Genetic map of human chromosome 15q11-13, that extends over 4Mb. 1995a, 1995b] (Fig. 1). Developmental Dotted horizontal arrows indicate the mechanisms that lead to AS and solid arrows delay is evident by age 6–12 months, illustrate mechanisms for PWS. The jagged lines indicate the common large deletion but forward progression occurs. There breakpoints. Deletion of the entire q11-13 region leads to either AS or PWS depending on the parental chromosome of origin (maternal deletion for AS and paternal for is a structurally grossly normal brain, al- PWS). Vertical lines represent other critical regions in which either gene deletions or though mild cortical atrophy or dysmy- mutations cause AS or PWS. The imprinting control region (IC) is depicted as bipar- elination may be seen on magnetic tite, illustrating that IC deletions more proximal to SNRPN cause PWS. Its vertical line indicates mutations in the UBE3A gene. The region from ZNF127 to the telomeric resonance scans. The prenatal history side of SNRPN represents the critical region presumed to contain the presumptive and birth parameters are normal. Some PWS gene(s). Paternal uniparental disomy (UPD) causing AS and maternal UPD manifestations may be absent or late to ;(P gene (tyrosine transporter ס causing PWS is also depicted. Other abbreviations: P gamma emerge (e.g., seizures and protruding ס Human End Repeat 2 gene; GABRB3, GABRA5, GABRG3 ס HERC2 Zinc finger protein tongue), so that the syndrome may not ס Necdin; ZNF127 ס aminobutyric acid receptor genes; NDN 127 gene. be considered or diagnosed until later in childhood. Diagnostic consensus crite- ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 139

interaction. Although many individuals seem to show unfocused, non-goal- related actions, and a lack of sustained attention to others, others show some babbling, use of gestures, turn-taking, and relatively well-developed receptive language skills [Williams et al., 1995b]. Clayton-Smith [1993] found that 90% of 82 people with AS used some type of signing or gesturing, but only 20% could be taught standardized sign language, and 70% had from one to three words. Beginning with Angelman’s [1965] Figure 2. Genetic map of 15q11-13 to illustrate imprinted genes. The PWS bracket indicates those genes that may play a role in pathogenesis of PWS. The imprinting first observations, descriptions of be- control (IC) region is indicated by the horizontal bar, indicating its close proximity havior in AS have been remarkably and/or contiguousness with the SNRPN gene. Genes are indicated by open arrows and consistent. These include bouts of maternal and paternal expression patterns are noted under each. The +/− notation for UBE3A indicates selective tissue imprinting (e.g., restricted to brain). Adapted from laughter unrelated to context, mouth- Ohta et al. [1999]. ing objects, problems falling or staying asleep, feeding problems during infancy, motoric hyperactivity and inat- ria are helpful in understanding the ment in their seizure disorders over tention, and stereotypies such as hand- spectrum of abnormalities and in decid- time, and a subsiding of abnormal EEG flapping or twirling [e.g., Summers et ing which individuals are candidates for patterns [Buntinx et al., 1995; Glayton- al., 1995; Summers and Feldman, definitive genetic testing (Table III) Smith, 1993]. However Laan et al. 1999]. Table IV summarizes rates of [Williams et al., 1995a]. [1996], found that 82% of their sample these and other behaviors across various Seizures occur in most children of 28 adults with AS still manifested studies. Hyperactivity may diminish with AS, in most before 3 years, but regular seizure activity. Others have with age, and patients may also calm occurrence in older children or in teen- identified patients who have a more down and show less sleep disturbance as agers is not exceptional. The seizures variable course, showing periods of in- they get older [Clayton-Smith, 1993; can be severe, often major motor type, activity or “silence,” followed by a sud- Buntinx et al., 1995], and have fewer and may require multiple anticonvul- den reemergence of hard-to-control bouts of laughter [e.g., Laan et al., sant medications [Zori et al., 1992]. seizures [Buckley et al., 1998; Buntinx 1996; Buckley et al., 1998]. Seizures may be difficult to recognize et al., 1995]. Although temper tantrums were or distinguish from the child’s usual noted in 5 of 11 (45%) children with AS tremulousness, hyperkinetic limb [Summers et al., 1995], tantrums, irri- Cognitive and Behavioral Aspects movements, or attention deficits. The tability, and social withdrawal were sig- typical electroencephalogram (EEG) is Although most people with AS show nificantly lower among 27 children often more abnormal that expected. It severe levels of delay, few studies have with AS compared to age, and IQ- usually has symmetrical high-voltage been conducted that actually document matched controls [Summers and Feld- slow-wave activity (four to six cycles/ these delays using standardized tests. man, 1999]. This is consistent with sec) persisting for most of the record Recently, Penner et al. [1993] admin- long-noted “happy disposition,” and unrelated to drowsiness; and very istered a series of Piagetian tasks to marked by frequent smiling. Clinical large amplitude slow activity at two to seven institutionalized adults with AS. observations suggest that many people three cycles/sec occurring in runs and Use of objects was better developed in with AS love water, shiny objects such more prominent anteriorly. In addition, all patients than their vocal and gestural as mirrors or plastic, and musical toys or spikes or sharp waves, mixed with large imitation skills. None engaged in imi- objects that make loud sounds [Clay- amplitude three to four cycles/sec com- tative vocalizations or spontaneous ton-Smith, 1993]. ponents, are seen posteriorly and are speechlike babbling, instead producing usually provoked by passive eye closure single-sound, open-mouth vowel-like Genetics of Angelman Syndrome [Boyd et al., 1988; Clayton-Smith and sounds. None was able to imitate AS is caused by deficiency of Pembrey, 1992; Sugimoto et al., 1992]. mouth motor acts; thus, the researchers protein E6-AP Other EEG anomalies, including corti- proposed that AS may involve an oral– cal myoclonus, have been described motor or developmental verbal dys- AS is now known to be caused by mu- [Guerrini et al., 1996]. praxia. Furthermore, most did not have tations or dysfunction in the ubiquitin Many individuals show improve- prerequisite skills for successful social ligase gene, UBE3A [Kishino et al., 140 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

TABLE III. Manifestations in Angelman Syndrome*

Consistent Developmental delay, functionally severe Speech impairment, none or minimal use of words; receptive and nonverbal communication skills higher than verbal ones Movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs Behavioral uniqueness: any combination of frequent laughter/smiling; apparent happy demeanor; easily excitable personality, often with hand-flapping movements; hypermotoric behavior; short attention span Frequent (more than 80%) Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2 years Seizures, onset usually <3 years of age Abnormal EEG, characteristic pattern with large-amplitude slow-spike waves Associated (20–80%) Stabismus Hypopigmented skin and eyes Tongue thrusting; suck/swallowing disorders Hyperactive tendon reflexes Feeding problems during infancy Uplifted, flexed arms during walking Prominent mandible Increased sensitivity to heat Wide mouth, wide-spaced teeth Sleep disturbance Frequent drooling, protruding tongue Attraction to/fascination with water Excessive chewing/mouthing behaviors Brachycephaly *Adapted from Williams et al., 1995.

1997; Matsuura et al., 1997]. The (Table II). The conceptually simplest UBE3A protein product, E6-AP, func- mechanisms involve chromosomal mi- tions to transfer small ubiquitin mol- crodeletions (70% of cases), intragenic ecules to certain target proteins, to UBE3A mutations, and paternal UPD. TABLE IV. Behavioral Traits enable their degradation through the A more provocative mechanism in- of Persons With cytoplasmic proteosome complex volves disruption of the IC located ap- Angelman Syndrome* [Scheffner et al., 1995]. Almost all proximately 1 Mb centromeric to known UBE3A mutations cause trun- UBE3A [Dittrich et al., 1996; Saitoh et Behavior % cation of E6-AP, leading to haploinsuf- al., 1996; Farber et al., 1999; Buiting et ficiency of the protein [Fang et al., al., 1999]. The precise DNA structure Grabs people or things 100 1999]. Reduced cellular amounts of the and function of the IC is currently un- Ataxic movements 100 E6-AP appear to have no effect in so- known, but it appears that the IC con- Absent or sparse language 95–100 matic cells because the other normal al- trols a turn-on/turn-off regulator of Frequent smiling 95–100 lele on the paternal chromosome 15 is UBE3A in the brain. The IC also ap- Characteristic EEG 92–100 Hand flapping 84 active and produces an apparently suf- pears to control other genes in this re- Bouts of inappropriate ficient amount of protein. However, gion that may cause PWS (Fig. 2). laughter 77–91 there is little or no expression of E6-AP Theoretical mechanisms for this regu- Excessive mouthing 75–100 from the paternal chromosome 15 in lation include the action of a second Overactive, restless 64–100 certain brain regions, reflecting the im- protein mediator or long-range changes Sleeping difficulty 57–100 printed status of UBE3A (see below). in chromatin configuration [Barlow, Eating problem 45–64 Thus, these regions depend solely on 1997]. Such distant regulation by the maternally transcribed UBE3A. IC could affect DNA sequences located *Figures derived from Clayton- AS is caused by several genetic near or within the UBE3A gene. One Smith, 1993; Laan et al., 1996; Smith mechanisms that perturb UBE3A ex- such element could be a recently dis- et al., 1996; Summers et al., 1995; pression on the normal, maternally de- covered antisense gene that overlaps Zori et al., 1992. rived chromosome 15 [Jiang et al., UBE3A. It has been speculated that 1999; Mann and Bartolomei, 1999] transcription of the antisense gene in ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 141 the central nervous system could com- genes within the region of 15q11-q13, Kandel, 1969; Hegde et al., 1997]. In pete with and/or shut off transcription such as UBE3A [Jiang et al., 1998] or the human, UBE3A might function to of UBE3A [Rougeulle et al., 1998]. GABRB3 [DeLorey et al., 1998]. degrade proteins that would normally UBE3A knockout mice with mater- inhibit or repress nuclear transcriptional nally derived null mutations exhibit events associated with phenomena such Those with maternal easily inducible seizures (e.g., by rat- as LTP. In addition to mental retarda- deletion show most of the tling a cage) and have mild abnormali- tion, UBE3A disruption could alter ties in gait and motor coordination but synaptic function in a manner that in- “classic” features of AS. are not obviously hypermotoric or creases paroxysmal bursting and neuro- tremulous [Jiang et al., 1998]. Wild nal synchronization, accounting for type (m+/p+) and paternal-derived abnormal EEG patterns and seizures Genotype–phenotype correlations mutant mice (m+/p−) are normal. The in AS. AS mice (m−/p+) appear to have nor- Certain phenotypic differences be- mal brain size, morphology, and histol- PRADER-WILLI tween people with AS due to different ogy, and these findings are consistent SYNDROME genetic causes were recently identified. with limited human pathology studies Physical, Neurologic, and Those with maternal deletion show in AS [Jiang et al., 1998]. Decreased Developmental Phenotype most of the “classic” signs of AS. Ex- expression of mouse UBE3A occurred amining 27 individuals with confirmed only in Purkinje cells, in the CA3 re- The major findings in PWS are infantile deletions, Smith et al. [1996] found that gion of the hippocampus, and in the central hypotonia with poor suck and all had severe mental retardation, ataxic olfactory nerve, indicating that only a early failure to thrive, global develop- movements, absent speech, abnormal limited area of the mouse brain dem- mental delay with ultimate mild cogni- EEG, a happy disposition, normal birth onstrates silencing of the paternal tive impairment, early childhood onset weight and head circumference at birth, UBE3A allele [Albrecht et al., 1997; obesity, hypogonadotrophic hypogo- and a large, wide mouth. In contrast, a Jiang et al., 1998]. Precise localization nadism with genital hypoplasia and pu- milder phenotypic picture is found of regional brain imprinting is not yet bertal insufficiency, mild short stature, among the relatively few cases with AS known in the human [Rougeulle et al., and a characteristic behavior disorder due to paternal UPD [Bottani et al., 1997; Vu and Hoffman, 1997]. [Prader et al., 1956]. There is a charac- 1994; Gillessen-Kaesbach et al., 1995a; Two types of synaptic phenomena teristic facial appearance, with narrow Smith et al., 1997, 1998]. Those with have been evaluated by Jiang et al., in bifrontal diameter, almond-shaped pal- paternal UPD have better growth, less hippocampal neurons from Angelman pebral tissues, and down-turned mouth hypopigmentation, more subtle facial syndrome mouse brain slices [1998]. with a thin upper lip [Fig. 1], often changes, walk at earlier ages, have less Short-term synaptic potentiation results evolving over time. These and the severe or frequent seizure disorders, less in modification of existing proteins more minor but often more distinctive ataxia, and a greater facility with rudi- without a requirement of RNA synthe- anomalies are well described in a num- mentary communication such as sign- sis. Long-term potentiation (LTP) was ber of reviews [Butler, 1990; Holm et ing or gesturing. Those with imprinting markedly diminished in the AS mouse al., 1993; Cassidy, 1997]. Diagnostic center mutations are less apt to show hippocampal neurons, and LTP is criteria have been published [Holm et microcephaly or hypopigmentation, known to be dependent on nuclear al., 1993]. and they also appear to have a less se- transcription and RNA synthesis. LTP There is marked neonatal lethargy vere seizure disorder [Saitoh et al., has been implicated as an important el- with weak cry, decreased arousal, poor 1997; Burger et al., 1996; Minassian et ement in learning and memory, espe- reflexes, and the need to awaken the al., 1998]. Milder epilepsy is also noted cially in the limbic system [Nayak and infant to feed. Hypotonia can be severe, among those AS cases with UBE3A ab- Browning, 1999]. Furthermore, behav- although it gradually improves some- normalities [Minassian et al., 1998]. Ul- ioral conditioning experiments in AS what with age. Special feeding tech- timately, data from different genotypes mice did show learning deficits that re- niques (e.g., gavage tube feeding, need have the potential to refine gene- quired “memory” of the prior days’ for special nipples) are generally re- behavior understandings as well as aversive environment [Jiang et al., quired in early infancy to avoid severely treatment and prognosis. 1998]. It is possible that the deficits in impaired weight gain. Sucking slowly LTP in the hippocampus could be the improves during weeks to months, and Animal models provide clues about central reason for this learning problem and a period of relatively normal eating en- nervous system E6-AP actions may have direct relevance to the mental sues. Motor milestones are delayed, and retardation seen in AS. Interestingly, average age of sitting is 12 months and Mouse models have been made that al- activation of the ubiquitin proteolytic walking is 24 months. Adults remain low study of the common 4-Mb dele- pathway is essential for the maintenance mildly hypotonic with decreased tion region [Gabriel et al., 1999], or of LTP in Aplysia [Kupfermann and muscle bulk and tone. 142 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

Hyperphagia generally occurs be- high pain threshold, skin picking, and a tween ages 1 and 6 years, most often high threshold for vomiting may repre- TABLE V. Percentage of 100 between 2 and 4 years, and obesity soon sent autonomic nervous system dys- Subjects With Prader-Willi follows if uncontrolled. Food-seeking function [DiMario et al., 1994]. Sleep Syndrome Aged 4 to 46 Years behavior, with hoarding or foraging for disturbances, especially excessive day- Showing Selected food, eating of unappealing substances time sleepiness and oxygen desaturation Maladaptive Behaviors* such as garbage, pet food, and frozen in rapid eye movement sleep, are com- food, and stealing of food or money to mon even in the absence of obesity Behavior % buy food, is common. The hyperphagia [Hertz et al., 1995]. Strabismus is often Overeats 98 is likely of hypothalamic origin and present. Scoliosis may develop at any Skin-picking 97 manifests as lack of sense of satiety [Zipf age, and kyphosis is common in early Stubborn 95 and Bernston, 1987; Holland et al., adulthood. Osteoporosis is frequent but Obsessions 94 1993]. Obesity is the major cause of as yet poorly studied. Tantrums 88 morbidity in PWS. Disobedient 78 Hypothalamic hypogonadism is Cognitive and Impulsive 76 prenatal in onset, and is evident at birth Behavioral Phenotype Labile 76 as genital hypoplasia. It is manifested Excessive sleep 75 by cryptorchidism, scrotal hypoplasia Most people with PWS function in the Talks too much 74 (small, hypopigmented, and poorly ru- mild to moderate range of mental re- Compulsions 71 gated) and sometimes a small penis in tardation, with most IQs ranging from Anxious, worried 70 males, and by hypoplasia of the labia 60 to 70 [e.g., Curfs, 1992; Dykens et Gets teased a lot 65 minora and/or clitoris in females. Hy- al., 1992a]. A few show severe to pro- Hoards (nonfood) 55 pogonadism also results in incomplete found delays, and as many as 30% have Steals (food, money for food) 54 pubertal development [Cassidy, 1984, IQs in the borderline (IQ 70–84) to av- Withdrawn 53 1997]. Adult males only occasionally erage (IQ 85 and above) ranges. There Unhappy, sad 51 have voice change, male body habitus, is no evidence that IQ declines over or substantial facial or body hair, and time. Adaptively, even high-function- *Adapted from Dykens and Cassidy, females have amenorrhea or oligomen- ing individuals rarely function at a level 1999 orrhea. Menarche may occur as late as commensurate with their IQ. Although the 30s. In both males and females, sex- early clinical observations suggest rela- ual activity is rare, and infertility is the tive strengths in reading and weaknesses as many as 70–85% of the population rule, although one exception has re- in arithmetic, formal studies do not [Stein et al., 1994; Dykens and Cassidy, cently been reported [Akefeldt et al., support this profile [Taylor, 1988; 1995; Dykens and Kasari, 1997]. Al- 1999]. This end-organ understimula- Dykens et al., 1992a]. Many do show though people with PWS are variably tion is treatable with pituitary or go- relative strengths in certain visual pro- preoccupied with food, many show a nadal hormones. cessing tasks, especially those requiring variety of obsessive and compulsive Short stature is almost always pres- perceptual closure and attention to vi- symptoms unrelated to food. Examin- ent by the second half of the second sual detail, such as jigsaw puzzles [e.g., ing 91 subjects with PWS, Dykens et al. decade if untreated. Growth hormone Gabel et al., 1986; Dykens et al., [1996] found high rates of compulsive deficiency, caused by insufficiency of 1992a]. In contrast, many show relative symptoms and symptom-related adap- hypothalamic pulsatile growth hor- weaknesses in auditory or visual se- tive impairment, suggesting high rates mone production, has been demon- quential processing tasks that tap their of obsessive–compulsive disorder strated in most tested patients with short-term memory, or that require (OCD) in this condition. Some adults PWS, and treatment with growth hor- them to place stimuli in serial or tem- with PWS are similar to nonretarded mone increases height and lean body poral order, including poor arithmetic adult patients with OCD in the number mass [Lindgren et al., 1997, 1998; Car- skills in some [Gabel et al., 1986; and degree of severity of their symp- rel et al., 1999]. Dykens et al., 1992a]. There is no cor- toms [e.g., Dykens and Kasari, 1997; relation between IQ and body mass in- State et al., 1999]. Such symptoms be- dices [Dykens et al., 1992a]. gin early in childhood [Dimitropoulos There is no evidence that Behavior problems are variable but et al., 1999]. Aberrant levels of oxyto- IQ declines over time frequent (Table V), and include: temper cin have been implicated, and may also tantrums, impulsivity, disobedience, ar- be associated with the impaired satiety [among people with PWS]. guing with others, stealing food or response characteristic of the syndrome money to buy food, skin-picking, com- [Swaab et al., 1995; Dykens, 1998; pulsivity, mood lability, worry, with- Martin et al., 1998]. Thick, viscous saliva related to un- drawal, and anxiety. Such problems Case reports suggest that 6–17% of derstimulation of the salivary glands, may reach clinically significant levels in patients with PWS have atypical psy- ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 143 chosis, especially with a depressive printed in the brain, is the best de- deletions. Dykens et al. [1999] found component [Clarke, 1993; Beardsmore scribed gene that is likely to cause some more frequent and severe skin-picking et al., 1998; Clarke et al., 1998]. Sad- of the manifestations of PWS. This [as did Symons et al., 1999], with- ness, depression, withdrawal, disorga- gene codes for a small nuclear ribonu- drawal, hoarding, aggression, and over- nized thinking, and atypical psychosis cleoprotein, which is a ribosome- eating in those with deletions. These become more prominent with increas- associated protein that functions in con- differences must be considered in the ing age [Dykens et al., 1992b]. Adults trolling gene splicing and therefore may context of within-group variability in with good weight control and lower be pivotally involved in the control of findings. A few patients with UPD have body mass indices may experience synthesis of some proteins, particularly also been diagnosed as having autism, as more sadness, withdrawal, and disorga- those related to hypothalamic function. well as very low IQs, and more severe nized thinking [Dykens and Cassidy, It is the most frequently used gene for behavioral problems [Dykens and Cas- 1995], and more psychopathology in clinical testing purposes, because it sidy, 1999]. Associations between au- general [Whitman and Accardo, 1987]. demonstrates deletion or maternal-only tism and chromosome 15 duplica- expression in virtually all affected indi- tions involving the PWS/AS region viduals. There is another gene in the [Cook et al., 1998] are intriguing in this Genetics of upstream reading frame of SNRPN, context. Prader-Willi Syndrome SNURF (SNRPN upstream reading PWS is caused by lack of paternally frame), which consists of exons 1–3. Animal models of PWS do not contributed 15q11-q13 SNURF is thought to play a key role in survive long Many of the manifestations of PWS the control of imprinting throughout represent hypothalamic insufficiency, 15q11-q13, and disruption of this gene, Attempts to create mouse models of although no structural defect of the hy- e.g., through chromosomal transloca- PWS have used a number of ap- pothalamus has been documented on tion, results in failure to imprint the proaches. The SNRPN knock-out postmortem examination. However, SNRPN gene. mouse appears normal [Yang et al., recent studies have demonstrated de- When all the genes in this region 1998]. Mice with an intragenic deletion creased number and size of cells in the have been identified, and when better that included the mouse homologs of anterolateral hypothalamic nucleus, identification of which genes contrib- SNRPN and the putative PWS-im- whose normal function is secretion of ute to the PWS phenotype has oc- printing center lacked expression of the oxytocin [Swaab et al., 1995]. curred, it is hoped that the pathogenesis homologs of ZNF127, NECDIN and of PWS will be better understood, and IPW [Yang et al., 1998]. They had hy- treatment can be direct accordingly. potonia and poor suck, and died at a The actual genetic few days of age with failure to thrive. Similar findings occur with mice het- Genotype–phenotype correlations haploinsufficiencies that erozygous for the paternally inherited cause the phenotypic effects Patients with deletions and those IC-deletion. Mice with a large deletion in PWS have not been with UPD display subtle differences of 15q11-q13, spanning the SNRPN [Gillessen-Kaesbach et al., 1995b; and UBE3A homologs, manifest identified as yet. Mitchell et al., 1996; Cassidy et al., growth retardation, hypotonia, and le- 1997; Gunay et al., 1997; Dykens and thality before weaning [Tsai et al., Cassidy, 1999]. In general, manifesta- 1999]. Necdin knock-out mice have The genetic basis for PWS has tions are somewhat milder in those failure to thrive and respiratory prob- been intensely investigated, although with UPD. In addition to statistically lems in the neonatal period [Gerard et the correlation between part or all of significant physical differences, such as al., 1999]. Thus, attempted mouse the phenotype and specific genes in the more subtle facial phenotype, larger models have not survived sufficiently region, and the involved pathogenetic hands and feet, and fewer speech prob- long to learn whether they are, indeed, mechanisms, are still obscure. How- lems, preliminary findings suggest sig- appropriate models, nor whether infor- ever, PWS is known to be caused by nificant though subtle differences in IQ mation on pathogenesis can be gleaned the absence of normally active pater- across persons with paternal deletion from them. nally inherited genes at chromosome versus maternal UPD. Comparing 23 15q11-q13 (Table II, Fig. 1). The ac- age- and gender-matched subjects with SUMMARY tual genetic haploinsufficiencies that deletions versus UPD, Dykens et al. cause the phenotypic effects in PWS [1999] found that the UPD group had Prader-Willi and Angelman syndromes have not been identified as yet. Given an average IQ of 71, whereas those are two complex disorders due to ab- the absence of single gene causes of with deletions showed average IQ normalities in the imprinted region of PWS, it is presumed to result from scores of 63. Similarly, Thompson et al. chromosome 15q11–q13. Although absence of at least two genes, and prob- [1999] found lower verbal (but not per- they are distinct, they both have char- ably more. SNRPN, which is im- formance) IQs in subjects with paternal acteristic neurologic, developmental, 144 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE and behavioral phenotypes as well as syndrome reduces the shortest region of de- syndrome and other 15q deletion disorders other structural and functional abnor- letion overlap to 880 bp. Hum Genet 105: (pp. 211–222). Berlin: Springer-Verlag. 665–666. DeLorey TM, Handforth A, Anagnostaras SG, malities. 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