Clinical Features in 27 Patients with Angelman Syndrome Resulting from DNA Deletion J Med Genet: First Published As 10.1136/Jmg.33.2.107 on 1 February 1996

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3rMed Genet 1996;33:107-112 107 Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion J Med Genet: first published as 10.1136/jmg.33.2.107 on 1 February 1996. Downloaded from

A Smith, C Wiles, E Haan, J McGill, G Wallace, J Dixon, R Selby, A Colley, R Marks, R J Trent

Abstract Angelman syndrome (AS) is an intellectual We report the clinical features in 27 Aus- disability disorder with a complex genetic aeti- tralasian patients with Angelman syn- ology. Since the first three children reported drome (AS), all with a DNA deletion 30 years ago,' the clinical phenotype has been involving chromosome 15(qll-13), span- described in many individual cases,26 from ning markers from D15S9 to D15S12, patient surveys,7'-I and reviews of published about 3*5 Mb of DNA. There were nine reports.342 13 The phenotype of AS comprises males and 18 females. All cases were spor- severe intellectual disability, epilepsy, lack of adic. The mean age at last review (end of speech, ataxic movements, easily precipitated 1994) was 11*2 years (range 3 to 34 years). laughter, fair colouring in some patients, large All patients were ataxic, severely retarded, mouth and chin, microcephaly, and an ab- and lacking recognisable speech. In all normal EEG. Phenotypic variability has been patients, head circumference (HC) at birth noted and some cases have been described as was normal but skewed in distribution, atypical."'1' ' The lack of a distinctive early with 62-5% at the 10th centile. At last re- phenotype is reflected by the age of diagnosis view HC was around the 50th centile in in the majority of patients described, ranging from 2 years"6 to adulthood.'6 Department of three patients (12-5%) while 15 had poor Genetics, postnatal head growth. Short stature was The availability ofsophisticated genetic stud- Children's Hospital, not invariable, 5/26 (19%) were on or above ies, including high resolution cytogenetics, Sydney, Australia the 50th centile. fluorescence in situ hybridisation (FISH), and A Smith Hypotonia at birth was DNA testing by methylation C Wiles recorded in 15/24 (63%) and neonatal feed- assays or DNA ing difficulties were in polymorphic markers'72' has enabled a genetic Women and Children's recorded 20/26 classification of AS. Interstitial deletions of Hospital, Adelaide, (77%). Epilepsy was present in 26/27 (96%) chromosome 15(qll-13) comprise about 66% Australia with onset by the third year of life in 20 E Haan of cases, and non-deletional AS about 33% of patients (83%). Improvement in epilepsy cases.22 In the latter group about 2% are the Children's Hospital, was reported in 11/16 patients (69%) with result of uniparental disomy (UPD)'52122 and http://jmg.bmj.com/ Brisbane, Australia age. An abnormal EEG was reported in J McGill a few cases have been described with an im- 25/25 patients. Hypopigmentation was printing mutation.23 The DNA diagnosis is Mater Hospital, present in 19/26 (73%). One patient had highly specific as the AS locus is subject to Brisbane, Australia oculocutaneous albinism. Five G Wallace patients imprinting so that both deletions and UPD could not walk independently. Of the re- show a parent oforigin effect, with the deletions Departments of maining 22 who could walk, age of onset maternal in origin20 and UPD paternal.2'24 Genetics and The of on September 29, 2021 by guest. Protected copyright. Paediatrics, walking ranged from 2 to 8 years. Dis- DNA deletion in AS may be quite small23 but Wellington Hospital, rupted sleep patterns were present in 18/ a large deletion spanning about 3 5 Mb ofDNA New Zealand 21 patients (86%), with improvement in 9/ from D15S9 proximally to D15S12 distally is J Dixon R Selby 12 patients (75%) over 10 years of age. seen in over 90% of deletional cases.2324 The clinical features in this group of Most reported clinical studies have either Hunter Genetics, deletional AS patients were similar to pre- not used DNA diagnosis or have considered Newcastle, Australia A Colley vious reports, but these have not separated all cases together. Other studies have used high patients into subgroups based on DNA resolution cytogenetics to classify patients as Developmental studies. In our group of deletional cases, deleted or non-deleted.5 79 25 High resolution Paediatrics, Starship Children's Health, 100% showed severe mental retardation, cytogenetics has been shown to be in- Auckland, ataxic movements, absent language, ab- accurate.2*28 There are now a number of New Zealand normal EEG, happy disposition (noted in reports describing the DNA types in AS R Marks infancy in 95%), normal birth weight and patients,22 29-31 but these have not included Department of head circumference at birth, and a large, clinical features. Molecular Genetics, wide Laboratory confirmation of the diagnosis of Royal Prince Albert mouth. These features occurred with Hospital, Sydney, a higher frequency than in AS patients as AS has now made it possible to assess clinical Australia a whole. Our study also provided in- features in relation to the DNA based genetic R J Trent formation on the evolution of the pheno- classification. The phenotypic heterogeneity Corrrespondence to: type. The data can act as a benchmark for described in AS may in part be attributable to Dr Smith, Cytogenetics differences in the Department, New Children's comparisons of AS resulting from other underlying genetic mech- Hospital, Hawkesbury Road, genetic mechanisms. anisms. Such evaluations would also provide Westnead, NSW 2145, specific information useful Australia. (J Med Genet 1996;33:107-112) for diagnosis and prognosis. One recent study has reported 61 Received 17 July 1995 Revised version accepted for Key words: chromosome 15(qll-13); pigmentation; patients with AS (37 with sporadic deletion) publication 19 October 1995 epilepsy; intellectual delay. and examined several clinical features in de- 108 Smith, Wiles, Haan, McGill, Wallace, Dixon, Selby, Colley, Marks, Trent

Table 1 Patient data referring geneticist. Consecutive cases (1991- ID Sex ADx ARv BW HC P E W HtRv 1994) with a maternal deletion, extending from

(centile) D15S9 to D15S12, were included in this study. J Med Genet: first published as 10.1136/jmg.33.2.107 on 1 February 1996. Downloaded from 1 F 7 9 3317 34 fam 1 4 3* Clinical assessment of all patients was made 2 M 2 4 3110 36 H 4 4 50 3 M 32 34 3062 unk fam 2 7 <3 before the DNA results were available. Further 4 F 9 11 2523 34 H 2 5 <3 information was sought from hospital records, 5 M 15 17 3402 35 H 1 5 <3 6 M 17 18 2890 33 H 2 3 <3 referring physicians, other physicians involved 7 F 11 12 2892 34 H 1 4 25 with patient care, Baby Health Centre records, 8 M 7 8 2800 unk H 3 7 25 9 F 17 18 3090 N alb 1 5 75t parent interviews, early photographs, and vid- 10 F 3 3 2700 33 H 1 NA unk eos. All patients/records were reviewed at the 11 F 5 5 2910 33 fam 1 4 3 12 M 3 6 2800 35 H 1 3 25 end of 1994. 13 F 10 12 3150 36 H 2 NA <3 14 F 1-4 4-5 2900 34 H NA 2 3 15 M 23 25 3800 unk fam 2 5 3 16 F 4 5 3600 unk H 2 NA 10 GENETIC TESTING 17 F 6 6 2520 unk H 2 NA 10 18 F 5 7 3410 35 H 2 3 75t Cytogenetic analysis was performed on all 19 F 5 5 3800 unk H 3 2 10 probands, on peripheral blood lymphocytes, 20 F 6 7 3130 34 fam 2 2 <3* 21 F 11 14 3000 34 fam 1 8 75 harvested after 72 hour cultures and karyotyped 22 M 24 24 unk unk H unk NA <3 after GTG banding had been performed. Mo- 23 F 9 9 unk unk unk unk 3 75 24 F 5 6 unk 35 H 1 3 3 lecular studies were performed on the patients 25 F 15 16 2523p unk H 1 3 3* and both parents in 26/27 cases. High mo- 26 F 7 7 2560p 34 H 8 5 <3 M lecular weight DNA was prepared from peri- 27 3 6 2810p N fam 1 3 3 pheral blood according to standard methods. M=male, F=female, ADx=age at diagnosis in years, ARv=age at last review (end 1994) in years, BW=birth weight, HC=birth head circumference (cm), E=age of onset of epilepsy Polymorphism analysis was performed with (years), W=age of walking independently (years), HtRv=height at last review (years), P= RFLP, VNTR, and PCR based simple se- pigmentation, H = hypopigmented compared to the family, fam = same as the family pigmentation, quence repeats (SSR) with probes for loci from N = normal, alb = albinism, unk=unknown, NA = not applicable, *both parents small, tboth parents tall, p = preterm delivery. within the PWS/AS chromosome region (D15S18, D15S9, DI5SIl , D15S13, D15S10, D15S113, D15S97, GABRB3, D15S12) and Table 2 Frequency offeatures outside the region distally on chromosome No 15 (D15S24, ACTC, THBS1, D15S87, Severe mental retardation 27/27 100 D15S86). DNA patterns at each polymorphic Ataxic movements 27/27 100 locus were recorded according to the bands Absent language 27/27 100 seen on the or Birth weight in normal range (at term) 24/24 100 autoradiographs polyacrylamide Birth HC in normal range (at term) 18/18 100 gels. Detailed methods and the probe-enzyme Happy disposition at last review 26/26 100 Abnormal EEG 25/25 100 combinations used have been previously de- Epilepsy 26/27 96 scribed for patients AS1-10 and subsequent Large/wide mouth/large chin 24/26 92 32 Paroxysmal laughter 21/23 91 patients were investigated in the same way.31 Happy disposition in infancy 21/22 95 Usually five polymorphisms per patient were Term delivery 22/24 92 http://jmg.bmj.com/ Sleeping problems 18/21 86 sufficiently informative to establish whether a Onset of epilepsy by 3rd year 20/24 83 deletion or UPD was present, the parent of Walking independently 22/27 82 HC<25th centile 21/24 87 origin, the size of the deletion, or if the patient HC>50th centile 3/24 13 was non-deleted, non-disomic. In one case the Microcephaly (<2nd centile) by 2 y 8/15 53 proband (an unbalanced translocation carrier HC approaching 2nd centile from 2-11 y 7/15 47 Height <50th centile 21/26 81 with a cytogenetic deletion) had died and skin Feeding difficulties as infant 20/26 77 Improvement in sleeping 9/12 75 fibroblasts were tested with fluorescence in situ Hypopigmented 19/26 73 hybridisation (FISH) using probe GABR,B3.33 on September 29, 2021 by guest. Protected copyright. Hypotonia at birth 15/24 63 Epilepsy improvement 11/16 69 Floppy infant 15/22 68 Dysmorphic facial features at birth 0/27 0 DEFINITIONS Epilepsy improvement was defined as de- creased frequency of seizures or reduced re- leted and non-deleted patients based on DNA quirement for medication. Disruptive sleep was studies.27 In this report we describe 27 AS sleep truncated to two to three hour periods patients, all with the common large deletion of during the night with wakefulness and activity chromosome 15(ql 1- 13) on DNA testing. in between. Pigmentation of the skin, eye and hair colouring was subjectively assessed by two clinicians and compared with the family. Term Methods deliveries were those between 37 and 42 weeks' PATIENTS gestation. Patients were referred from Australia and New Zealand for genetic testing under a research grant protocol, approved by the institutional Results Ethics Committee. A data sheet accompanied GENETIC TESTING each referral. The data sheet contained ques- Twenty-seven patients had deletional AS. In tions on AS based on the American AS As- 26 patients with karyotype 46,XX or 46,XY, sociation checklist.7 Twenty-two cases were the deletion was de novo, maternal in origin, seen by the senior author (AS) as well as the and spanning markers from D15S9 to referring doctor, while information on five cases Dl5SI2.3' Not all patients were informative (8, 10,19, 23, 24) was obtained only from for each probe or had each one tested, but the data sheets and correspondence with the there was sufficient information in each case Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion 109

to establish that the deletion spanned the whole who were walking, the ataxia manifested vari- AS region and was maternal in origin. In one ously as a wide based gait, unsteadiness with patient the deletion arose as the result of an jerky or clumsy movements, or a thumping J Med Genet: first published as 10.1136/jmg.33.2.107 on 1 February 1996. Downloaded from unbalanced de novo translocation, 45,XY,t(10; heavy gait, more noticeable in the adults when 15)(q26;q13). This patient had died aged 24 excited or running. Jerky movements of the years34 and the cytogenetic deletion was sub- upper limbs with poor coordination were also stantiated with FISH studies on skin fibroblast observed. Up to six single words were reported cells retrieved from liquid nitrogen storage after in five children. One child (patient 20) had use death.33 of 27 single words reported by the parents but not verified by others.

PATIENTS Patient data are shown in table 1. There were PIGMENTATION 18 females and nine males. The mean age at Hypopigmentation relative to family members diagnosis was 8-8 years (range 1-5 years to 32 was considered present in 19/26 patients years) and mean age at last review was 11-2 (73%), while 7/26 had the same colouring as years (range 3 to 34 years). Age distribution is their family, including one dark skinned, black shown in fig 1. All patients were severely men- haired, brown eyed male of Italian descent. tally retarded and had ataxic movements in- One female patient, aged 18 years, had oculo- volving the upper and lower limbs. In patients cutaneous albinism diagnosed in infancy on the basis of characteristic retinal changes. Red 6 hair was present in three girls, although in each case this was familial. 5

a, 4 PREGNANCY Overall there had been 90 pregnancies in the 27 families, with 13 known miscarriages (in 11 0 0 2- families) and 52 normal unaffected sibs. The z mother's age at conception of the AS proband ranged from 23 to 36 years (mean 28, median 25 years) and the father's age at conception 0 ranged from 25 to 44 years (mean 31, median 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 5; 18 30 years). Of the 27 AS pregnancies, 22 con- Age (years) tinued to term, three were preterm (32, 34, Figure 1 Age distibution of the 27 patients at last review. Dark hatching represents the and 36 weeks gestation by dates), and in two females and light hatching the male patients. the gestation was unknown. http://jmg.bmj.com/ 5 ANTHROPOMETRICS AT BIRTH Birth weight was known in 24 patients (fig 2). 0) 4 90th centile For the 21 term infants the mean birth weight 50th centile was 3-1 kg (range 2-5 to 3-8 kg) which fell -c0) a 10tha centile within the normal 2nd to 98th centile range. 3 UL ^ *However, there was clustering below the 50th ._ B - * centile and 2/21 (9 5%) had a birth weight on September 29, 2021 by guest. Protected copyright. m 2 below the 10th centile. The preterm infant born at 32 weeks (by dates) weighed 2500 g, which was above the 90th centile. 3:0 32 34 36 38 40 42 44 Head circumferences (HC) at birth were Gestational age (weeks) measured in 16 patients and in two others were recorded as "normal". These 16 HC were Figure X2 Birth weight measurements in relation to gestational age. The clustering of within normal centiles (2nd to 98th) with mean birth weeight around 40 weeks includes 13 patients. HC 34-2 cm (range 33-36-8 cm). Thus, no child was microcephalic at birth. However, 4UAAn 11/16 (69%) were below the 50th centile, a distribution of birth HC significantly skewed 38 90th centile from the normal (p<0 01) (fig 3). 36 50th centile There were insufficient recorded data on 34 birth lengths for meaningful analysis. -/-1U IVLiInn h cenLIIej 32 30 GROVVTH 0 Height at last review showed that 15/26 were 28 on the 3rd centile or less (58%), six were 26 31 32 34 36 38 40 42 44 between the 3rd and 50th centile (23%), and 5/26 were on the 50th centile or over (19%). 32sta34Gestationalon36 age38e(weeks)40e42s) Although 42% were not short, height dis- Figure 3 Birth HC measurements in relation to gestational age. The clustering below the tribution was significantly skewed from the 50th cen,tile includes seven patients. normal (p<0.01). Four patients were obese, 110 Smith, Wiles, Haan, McGill, Wallace, Dixon, Selby, Colley, Marks, Trent

three males and one female. One male (patient epilepsy was precisely known in 24 cases and 12) weighed 150% of expected weight for epilepsy had developed by 3 years of age in 20

height at 7 years, one male (patient 15) weighed (83%). One girl had her first seizure at 8 years J Med Genet: first published as 10.1136/jmg.33.2.107 on 1 February 1996. Downloaded from 200% of expected weight for height at 24 years, of age, presenting in status epilepticus lasting one male (patient 8) weighed 113% ofexpected 1 -5 hours. From the available histories, an early weight for height at 7 years of age, and one childhood onset of epilepsy seems likely in the female (patient 7) weighed 180% of expected remaining two patients; in one (patient 23) weight for height at 12-5 years. The remainder epilepsy was well established at 9 years, and showed appropriate weight gain for height. The the other, an institutionalised patient (patient HC in 20/24 patients was small (less than the 22), had "always" had epilepsy. 25th centile), in one it was between the 25th Epilepsy improvement was reported in 11/16 and 50th centile, and 3/24 patients (12-5%) (69%) patients; in eight there were insufficient had a HC >50th centile (patients 7, 9, and 15) data to assess this parameter, in two the onset at ages 11, 18, and 24 years. Of 15 patients was recent, and one did not have epilepsy. Of whose serial HC measurements were known, the 11 patients, improvement by the age of 5 eight (53%) were microcephalic by 2 years years was evident in two, by 10 years in a of age and seven (46%) showed downward further five, by 15 years in a further three crossing ofcentiles approaching the 2nd centile patients, and one patient improved as an adult. at last review. The onset of epilepsy was not associated with regression of any developmental skills attained. An EEG had been performed in 25 patients, NEUROBEHAVIOUR of which all were recorded as abnormal. One Neurological abnormalities were non-specific patient had an abnormal EEG but no overt in infancy. Hypotonia at birth (floppy baby) epilepsy. It was not possible to draw con- was reported in 15/24 (63%), one infant was clusions about the type of EEG abnormality hypertonic (4%), and eight (33%) had normal seen, owing to variations in reporting between tone. Feeding difficulties were reported in centres and within centres over the time period 20/26 (77%) babies and included difficulty of the study, or to draw any conclusions about with sucking, breast attachment, tongue thrust, improvement in the EEG patterns, although a vomiting, and reflux. Reflux in one patient (12) number of patients have had repeat EEG stud- was managed by fundoplication at 6 months ies performed. of age. The mothers of two female babies con- Overall the patients slept poorly. Information sidered them "perfect". on sleeping patterns was available for 21/27 Gross motor skills were delayed. No child patients. There were no sleeping problems in walked before 18 months (fig 4). Overall, 22 three, but the remaining 18 had disruptive patients could walk independently and five sleep. A spontaneous improvement in sleep were non-walkers. The ages of the five who patterns was reported in 9/12 of these patients were not walking independently were 3, 5, 6, around the age of 6 to 8 years although there 12, and 24 years. Cumulatively, 10/27 children was no sleep improvement in two 18 year olds. http://jmg.bmj.com/ (37%) were walking independently in their Assessment of Activities of Daily Living third year, 14 (52%) in the fourth year, 19 showed that the teenage children and the five (70%) in the fifth year, and 22 (81%) by 10 adults were all dependent, requiring assistance years of age. with feeding, toileting, and dressing. Epilepsy developed in 26/27 patients (96%). The child without overt epilepsy had an abnormal EEG and at the age of 3 years had Discussion on September 29, 2021 by guest. Protected copyright. night screaming and startles which responded From the referrals for DNA testing in patients to Frisium (clobazam). The age of onset of with AS around Australasia2831 we have fol- lowed up and present here the clinical findings in 27 consecutive patients, all of whom have 7 DNA deletions spanning known genetic loci within the PWS/AS region.222432 The clinical 6 = features of AS patients with proven DNA deletions have previously been documented in c 5 one study of 37 Japanese patients.27 This study 01) (which includes two35 and 1 130 deletional cases is the one 4 previously reported) only providing data comparable to ours. Comparisons can be 0 made for those features documented by both 0 3 = groups. Other features reported here extend 0 the deletional phenotype in AS. z 2 Similarities are apparent in many of the features from our data and those from Japan27 in 1 both occurrence and frequency. The mean age was 0 youngerof the Japanesethan ourspatients( 1 -2(8-6yearsyears)at last review).slightly 0 1 2 3 4 5 6 7 8 Both groups showed severe mental retardation, Age (years) ataxia, epilepsy, abnormal EEG, absent language, paroxysmal laughter, normal birth Figure 4 i4ge of onset of walking in the 22 walkers. weight and head circumference, normal de- Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion illl

liveries at term, and characteristic facial fea- Apart from the diagnostic and prognostic tures in virtually 100% of patients. A similar aspects, the importance of presenting the clin- frequency ofhypopigmentation was also found. ical profile of deletional AS lies in the provision J Med Genet: first published as 10.1136/jmg.33.2.107 on 1 February 1996. Downloaded from The major difference between the two studies of data which can be used as a benchmark was in the anthropometric measurements of against which cases with other genetic mech- HC and height. While the measurements made anisms can be assessed. No differences were are expressed differently making direct com- found in the Japanese data between the de- parison difficult, in our study there was a small letional and non-deletional cases.27 The sug- HC in 83% compared with 10/29 (34 5%) in gestion that the phenotype ofAS resulting from the Japanese group with microcephaly, and UPD is milder than in deletional AS has no conversely 42% of our patients were not short parameters for comparison.38 In the two cases in stature compared with a height of -1 1 SD of UPD reported,38 aged 7-5 and 10-25 years, in 32/37 (86-5%) Japanese patients. There is both were of small height and HC, had seizures also a difference in the sex ratio of patients, and an abnormal EEG, but the ataxia was mild. with equal distribution in the Japanese series, Other cases have been reported with ataxia, but with a male to female ratio in our group but no seizures at ages 3, 3, and 4-5 years3"Al of 1:2. Other studies have reported an excess and one adult had epilepsy.'6 It is of interest of females.7 90 It may be that the syndrome is that, currently, few data are available com- more readily recognised in females than males. paring deletional PWS with PWS resulting Sex differences could affect growth meas- from UPD,42 but the suggestion is that there urements and further studies of deletional are no significant differences. Detailed clinical patients would add data on whether there is a descriptions of further cases of non-deletional growth difference in males and females. AS need to be documented and the features In our group of patients, features not pre- compared with deletional AS patients, to pro- viously described in deletional cases include vide validity to any conclusions drawn. the frequent occurrence of disruptive sleep and the in (85%) subsequent improvement We thank Dr C Burke, Dr A Bye, Dr M Edwards, Dr R Leitner, sleep patterns with age. Sleep problems were Professor G Morgan, Dr J Nelson, Dr M Partington, Dr A common in the whole UK group,'0 but have Turner, Professor G Turner, Dr E Wilkinson, and Dr G Wise for referring patients and help with follow up; Professor D not been discussed in other surveys. Also note- Sillence, Head, Department of Genetics, Children's Hospital, worthy in our deletional cases was the hy- for his support; Reckitt and Colman Pharmaceuticals, sup- porting Angelman Syndrome Research. The DNA work was potonia at birth, early smiling in infancy, and performed under an NH&MRC Grant. happy disposition later. The hypotonia at birth and the subsequent finding of a cytogenetic 1 Angelman H. "Puppet" children: a report on three cases. deletion could lead to a provisional diagnosis Dev Med Child Neurol 1965;7:681-8. of Prader-Willi syndrome (PWS),15 so accurate 2 Bower BD, Jeavons PM. The "happy puppet" syndrome. Arch Dis Child 1967;42:298-302. early diagnosis may require DNA testing for 3 Fisher JA, Burn J, Alexander FW, Gardner-Medwin D. parent oforigin ofthe deletion.3637 Our patients Angelman (happy puppet syndrome) in a girl and her brother. J Med Genet 1987;24:294-8. http://jmg.bmj.com/ had an early age of onset of epilepsy and a late 4 Yamada KA, Volpe JJ. Angelman syndrome in infancy. Dev age of walking. These latter features are well Med Child Neurol 1990;32:1005-10. 5 Fryburg JS, Breg WR, Lindgren V. Diagnosis of Angelman known in AS as a whole.710 Improvement in syndrome in infants. Am _7 Med Genet 199 1;38:58-64. epilepsy in our group ofpatients is an important 6 Van Lierde A, Atza MG, Giardino D, Viani F. Angelman syndrome in the first year of life. Dev Med Child Neurol finding, as it may indicate a degree of brain 1990;32: 1011-15. maturation, a concept supported by the im- 7 Williams CA, Gray BA, Hendrickson JE, Stone JW, Cantu provement in the EEG patterns found in 7/7 ES. Incidence of 15q deletions in the Angelman syndrome:

a survey oftwelve affected persons. Am 7Med Genet 1989; on September 29, 2021 by guest. Protected copyright. cytogenetically deleted patients studied in 32:339-45. 8 Robb SA, Pohl KR, Baraitser M, Wilson J, Brett EM. The Japan.9 The predictions which can be made "happy puppet" syndrome of Angelman: review of the about the improvement in epilepsy and sleep clinical features. Arch Dis Child 1989;64:83-6. 9 Matsumoto A, Kumagai T, Miura K, Miyazaki S. Hawakawa patterns may help some families when a de- C, Yamanaka T. Epilepsy in Angelman syndrome as- letion is found. sociated with chromosome 15q deletion. Epilepsia 1992; 33:1083-90. The data presented here on 27 patients sug- 10 Clayton-Smith J. Clinical research on Angelman syndrome gest that there is a distinct phenotype associated in the United Kingdom: observations on 82 affected in- dividuals. Am J Med Genet 1993;46:12-15. with deletional AS. As a group these patients 11 Clayton-Smith J, Webb T, Cheng XJ, Pembrey ME, Mal- have similar features to those reported in other colm S. Duplication of chromosome 15 in the region 15ql 1-13 in a patient with developmental delay and ataxia reviews but with a higher frequency ofthe some with similarities to Angelman syndrome. Jf Med Genet features. The focused phenotype consists of 1993;30:529-31. 12 Clayton-Smith J, Pembrey ME. Angelman syndrome. JMed severe intellectual disability, ataxia, lack of Genet 1992;29:412-15. speech, happy disposition, and epilepsy in vir- 13 Zori RT, Hendrickson J, Woolven S, Whidden EM, Gray B, Williams CA. Angelman syndrome: clinical profile. _7 tually 100% of patients. There is lack of a Child Neurol 1992;7:270-80. specific neonatal phenotype, with normal birth 14 Stoll C, Alembik Y, Dott B, Fischbach M, Chognot D. Mental retardation, ataxia, seizures, dysmorphia, and weight and head circumference, but hypotonia hydrocephaly in two sibs. Angelman syndrome or new and feeding difficulties are common. With time syndrome. Genet Couns 1993;4: 153-6. 15 Kirkilionis AJ, Chudley AE, Gregory CA, Hamerton JL. there is development of the large mouth/chin, Molecular and clinical overlap of Angelman and Prader- delayed motor milestones, postnatal growth Willi syndrome phenotypes. Am J Med Gener 1991A;40: abnormal 454-9. failure, sleep patterns, paroxysmal 16 Smith A, Deng ZM, Beran R, Woodage T, Trent RJ. Familial laughter, and an abnormal EEG. However, unbalanced translocation t(8;15)(p23.3;qll) with uni- there was still parental disomy in Angelman syndrome. Hum Genet1994; some phenotypic variability in 93:47 1-3. certain features, such as HC, weight, and height 17 Wagstaff J, Knoll JHK, Glatt KA, Shugart YY, Sommer A, and the should not be discarded if Lalande M. Maternal but not paternal transmission of diagnosis 1i5q 1-13-linked nondeletion Angelman syndrome leads these features are not typical. to phenototypic expression. Nature Genet 1992;1:291-4. 112 Smith, Wiles, Haan, McGill, Wallace, Dixon, Selby, Colley, Marks, Trent

18 Nicholls RD. Genomic imprinting and uniparental disomy 30 Zackowski JL, Nicholls RD, Gray BA, et al. Cytogenetic in Angelman and Prader-Willi syndromes: a review. Am and molecular analysis in Angelman syndrome. Am .7 Med JMed Genet 1993;46:16-25. Genet 1993;46:7-1 1. 31 Deng ZM, Woodage TJ, Smart R, Smith A, Trent RJ. Novel 19 Dittrich B, Robinson WP, Knoblauch H, et al. Molecular J Med Genet: first published as 10.1136/jmg.33.2.107 on 1 February 1996. Downloaded from diagnosis of the Prader-Willi and Angelman syndromes patterns of inheritance of genetic disease are illustrated by detection ofparent-of-origin specific DNA methylation by the Angelman syndrome. MedjAust 1993;158:813-16. in 15qll-13. Hum Genet 1992;90:313-15. 32 Woodage T, Deng ZM, Prasad M, et al. A variety of genetic 20 Clayton-Smith J, Webb T, Pembrey ME, Nichols M, Mal- mechanisms are associated with the Prader-Willi syn- colm S. Maternal origin of deletion 15qll-13 in 25/25 drome. Am _7 Med Genet (Neuro Psych Genet) 1994;54: cases ofAngelman syndrome. Hum Genet 1992;88:376-8. 219-26. 21 Malcolm S, J, Nichols M, et 33 Jauch A, Robson L, Smith A. Investigations with fluor- Clayton-Smith al. Uniparental escence in situ hybridisation (FISH) demonstrate loss of disomy in Angelman syndrome. Lancet 1991;337:694-7. the telomeres on the reciprocal chromosome in three 22 Chan CTJ, Clayton-Smith J, Cheng XJ, Buxton J, Pembrey unbalanced translocations involving chromosome 15 in ME, Malcolm S. Molecular mechanisms in Angelman Prader-Willi and Angelman syndrome. Hum Genet 1995; syndrome: a survey of 93 patients. J Med Genet 1993;30: 96:345-9. 895-902. 34 Smith A, den Dulk G. A severely retarded male with deletion 23 Buiting K, Saitoh S, Gross S, et al. Inherited microdeletions of chromosomes 15(pter-ql3) and 10(q26-qter). _7 Med in the Angelman and Prader-Willi syndromes define an Genet 1982;19:77. imprinting centre on human chromosome 15. Nature Genet 35 Imaizumi K, Takada F, Kuroki Y, Naritomi K, Hamabe 1995;9:395-400. J, Niikawa N. Cytogenetic and molecular study of the 24 Nicholls RD. Invited editorial. New insights reveal complex Angelman syndrome. Am _7 Med Genet 1990;35:314-18. mechanisms involved in genomic imprinting. Am J Hum 36 Chu CE, Cooke A, Shephenson JBP, et al. Diagnosis in Genet 1994;54:733-40. Prader-Willi syndrome. Arch Dis Child 1994;71:441-2. 25 Pembrey M, Fennell SJ, van den Berghe J, et al. The 37 Donaldson MDC, Chu CE, Cooke A, Wilson A, Greene association ofAngelman's syndrome with deletions within SA, Stephenson JBP. The Prader-Willi syndrome. Arch 15ql1-13. J Med Genet 1989;26:73-7. Dis Child 1994;70:58-63. 26 Delach JA, Rosengren SS, Kaplan L, Greenstein RM, Cas- 38 Bottani A, Robinson WP, DeLozier-Blanchet CD, et al. sidy SB, Benn PA. Comparison of high resolution chro- Angelman syndrome due to paternal uniparental disomy mosome banding and fluorescence in situ hybridisation of chromosome 15; a milder phenotype? Am _7 Med Genet (FISH) for the laboratory evaluation of Prader-Willi syn- 1994;51:35-40. drome and Am J Med Genet 39 Smeets DFCM, Hamel BCJ, Nelen MR. Prader-Willi syn- Angelman syndrome. 1994; drome and Angelman syndrome in cousins from a family 52:85-91. with a translocation between chromosomes 6 and 15. N 27 Saitoh S, Harada N, Jinno Y, et al. Molecular and clinical Engl _r Med 1992;326:807-1 1. study of 61 Angelman syndrome patients. Am J Med Genet 40 Freeman SB, May KM, Pettay D, Fernhoff PM, Hassold 1994;52: 158-63. TJ. Paternal uniparental disomy in a child with a balanced 28 Smith A, Prasad M, Deng ZM, Robson L, Woodage T, 15; 15 translocation and Angelman syndrome. Am _7 Med Trent RJ. Comparison of high resolution cytogenetics, Genet 1993;45:625-30. fluorescence in situ hybridisation (FISH) and DNA studies 41 Nicholls RD, Pai GS, Gottlieb W, Cantu ES. Paternal to validate the diagnosis of Prader-Willi and Angelman uniparental disomy of chromosome 15 in a child with syndrome. Arch Dis Child 1995;72:397-401. Angelman syndrome. Ann Neurol 1992;32:512-18. 29 Hamabe J, Kuroki Y, Imaizumi K, et al. DNA deletion and 42 Robinson WP, Bottani A, Yagang X, et al. Molecular, cyto- its parental origin in Angelman syndrome patients. Am _7 genetic, and clinical investigation of Prader-Willi syn- Med Genet 1991;41:54-63. drome patients. Am I Hum Genet 1991;49:1219-34. http://jmg.bmj.com/ on September 29, 2021 by guest. Protected copyright.