Angelman Syndrome: Clinical Profile Jill Hendrickson, MS; Sheila Woolven, Elaine M. Whidden, MSN, ARNP; Brian Gray, MS; Charles A. Williams, MD Roberto T. Zori, MD;
Abstract To further delineate the clinical and developmental features of Angelman syndrome, we collected data through three sources of information: (1) physical examinations; (2) laboratory data and family questionnaire data of affected individuals; and (3) literature review. The questionnaire data describes a generally normal prenatal and birth history. Feeding difficulties, developmental delay, or seizures were the presenting problems in all infants. The diagnosis of Angelman syndrome, however, was not made in any infant prior to 1 year of age. Except for seizures, no medical or surgical complication was common, although a variety of visual complaints or findings were common. Sixty percent of Angelman syndrome children had a cytogenetically demonstrated deletion of chromosome 15q11-q13. The individuals with and without a deletion could not be differentiated clinically. Diagnosis in early childhood is therefore difficult, and a high index of suspicion is recommended. ( J Child Neurol 1992;7:270-280).
syndrome is a neurogenetic disorder with a unique behavioral phenotype. Affected children have a rigid, jerky ataxia, and their facial expression is unusually happy. All are severely mentally retarded, most with microbrachycephaly and abnormal electroencephalographic (EEG) findings. They generally cannot speak or, at most, can say a few words. Harry Angelman, an English pediatrician, first described the syndrome in 1965,1 referring to these children as &dquo;puppetlike&dquo; because the children walked like a puppet and because they reminded him of a painting he had seen in Italy by Giovanni Francesco Caroto depicting a happy, young boy holding a puppet (Fanciullo con pupazzo). His observations were confirmed by other clinicians over the next decade, but a pejorative term, &dquo;happy puppet syndrome,&dquo; began to characterize the syndrome. In 1987, a deletion of chromosome 15qll-ql3 in patients with Angelman syndrome was discovered and
Angelman
reported. 2,3 Recently,
clinical review of a series of Angelman individuals has been published.4 The emergence of parent support groups in the United Kingdom and the United States has helped supply missing pieces of knowledge about the developmental history of Angelman syndrome. Established in 1987, the Florida-based Angelman Research Group (ARG) has served as a registry for Angelman syndrome patients, a clearing house for Angelman a
syndrome-related information, a parent support group, and a focus for clinical study. In this report, we summarize information collected by the Angelman Research Group registry regarding developmental and clinical profiles of Angelman syndrome. We also summarize selected information from the UK-based Angelman Syndrome Support Group (ASSG) and descriptions published in the literature.
Methods Information Received
cepted for From
July 15, 1991. Received revised Nov 25, 1991. Acpublication Nov 26, 1991. the Raymond C. Philips Research and Education Unit
(Drs Zori and Williams,
Ms Hendrickson and Whidden, and Mr Division of Genetics, Department of Pediatrics, University of Florida, Gainesville, FL, and the Angelman Syndrome Support
Gray),
Group (Ms Woolven), Waterlooville, England. Address correspondence to Dr Roberto Zori, University Florida, JHMHC, Box J-296, Gainesville, FL 32610.
of
children with Angelman four methods: physical and
syndrome was developmental evaluation of Angelman syndrome patients, questionnaires completed by families in the United States, information provided by the Angelman Syndrome Support Group in the United Kingdom, and literature review. 1-3,5-34 Thirty-six American families with a child with Angelman syndrome were given questionnaires and were asked to provide photographs. The questionnaire included data gathered by
on
270
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’
and developmental variables. The child’s physician was asked to complete a physical examination form to be returned with the family questionnaire. Twenty-six of these patients underwent physical and developmental evaluation. This included high-resolution chromosome studies in which the criterion for chromosome 15 deletion was absence of band q12. A directed physical examination was performed. Children participating in either the questionnaire or physical examination group were judged by the authors (C.A.W. and R.T.Z.) to have a diagnosis of Angelman syndrome using the following criteria: (1) microbrachycephaly; (2) abnormal EEG consisting of diffuse, markedly abnormal sharp and slow waves of the 2- to 4-Hz type; (3) stiff and jerky gait with flexed upper arms; (4) severe language impairment ; (5) characteristic face with prognathia, macrosomia, and protruding tongue; and (6) frequent laughter on
clinical, cytogenetic,
(Figure 1). families in the ASSG in the United Kingasked to complete a general developmental questionnaire, and the following information was summarized : birth and pregnancy data, medical and behavioral problems in the first year of life, attainment of self-help skills, and seizure activity. One of the 38 families had two Angelman syndrome children.
Thirty-eight
dom
were
Results The American questionnaire data were used to compile Tables 1 through 7. Results of high-resolution chromosome studies are included in Table 7. The physical examination data were used to compile Table 8. Information was not available for all questionnaire or physical examination items for all patients. The N values as presented in the tables do not equal the total number of patients evaluated but rather the number of families who adequately answered that question or patients who were adequately examined
TABLE 2 Time of Presentation of
Feeding Problems,
Seizures in American Children with Angelman Syndrome
Developmental Delay,
or
*The denominator represents the number of quately answered for item.
questionnaires
ade-
for that item. For example, in the US questionnaire, if only 28 of the 36 families adequately answered the question of interest, then the N value for this item was considered to be 28. Children with Angelman syndrome generally had uncomplicated prenatal and perinatal histories (Table 1). The children were first brought to medical attention because of one of the following problems: failure to thrive, feeding problems, seizures, or developmental delay. The problems first appeared during the child’s 1st year of life (Table 2). All children were
had
profoundly mentally retarded, although some developed skills necessary for self-care (Table
3). One of
the UK families had two affected chilof the American families had more than one affected child. Of the 39 children in the United Kingdom, eight could say a few words, compared with one in the US cohort. However, 18 of the American children understood speech to some extent, and 12 used gestures to communicate. One child was easily taught to use five gestures after many years of futile speech
dren, and
none
TABLE 1
Prenatal and Birth Data of
Angelman Syndrome
Children
*Data obtained from questionnaire; each denominator in these two columns represents the number of questionnaires adequately answered for item. tPerinatal problems in UK patients include: maternal hypertension (two cases), fetal distress (three cases), floppy (one case), placenta previa (one case); for US patients: toxemia (one case), required O2 neonatally (one case), failure to progress (one case); in literature: polyhydramnios (one case), abruptio (one case).
271
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FIGURE 1 Children with
Angelman syndrome showing typical face
and
Downloaded from jcn.sagepub.com at MCMASTER UNIV LIBRARY on December 21, 2014
posture.
TABLE 3
Developmental Milestones of Angelman Syndrome Children
*N represents the number of
questionnaires adequately
The parents of several other children also commented on the ability of their children to communicate nonverbally. Many children with Angelman syndrome had some feeding difficulty in infancy or early childhood. Feeding problems ranged from frequent spitting up to refusing to feed and failure to thrive. By their first birthday, most infants were notable for their cheerfulness and frequent outbursts of laughter (generally inappropriate for the situation). They also seemed to have less need for sleep than other children, napping only for short intervals. They were also often hyperactive, although generally without accompanying aggressive behavior (Table 4). A few children from the United Kingdom had hearing difficulties related to middle ear disease. Eight children in this group had either adenoids removed or middle ear tubes placed, and four had surgery for inguinal hernias. We did not document similar problems in our American group. Ophthalmologic abnormalities such as strabismus, optic atrophy, and keratoconus were common (Table 5). Most children had seizures that were difficult to control or intractable; seizures were of several types (Table 6). However, at the time of interview only two still had seizures. They both had infrequent absence seizures. Of the remaining ten, two were on no medications, five were on valproic acid alone, one on
therapy.
TABLE 4 Behavioral Attributes of
-
-
.
_
___.___
valproic
acid and
and two
on
clonazepam, one on phenytoin, phenobarbital. Neuroimaging studies, when abnormal, showed cortical atrophy, preventricular leukomalacia, or some dysmyelination; the study of one child showed cerebellar hypoplasia. No consistent central nervous system imaging anomaly was found. Urine organic acids and serum and urine amino acids screening results were normal. A deletion of chromosome 15 was found in 62% of the individuals studied (Table 7). When children with and without the deletion
compared by anthropometric, craniofacial, musculoskeletal, auditory, and visual examinations, were
the
only significant finding was the more frequent of widely spaced teeth in the children lacking the deletion (P < .05, Fisher’s exact test) (Taoccurrence
ble
_.__
*The denominator represents the number of
8).
Discussion is difficult to diagnose in the 3 years of life; no pathognomonic findings are evident, and the phenotype is subtle at first (Figure 2). The first sign of abnormalities in children with Angelman syndrome usually appears around age 6 months with the onset of nonspecific problems such as feeding difficulties and developmental delay. By the time these children reach their first birth-
Angelman syndrome first 2
Angelman Syndrome
uu
answered for item.
or
Children
-
-
questionnaires adequately
-
_r
.
answered for item.
273
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FIGURE 2
Progression of physical features
of
a woman
with
Angelman syndrome
adulthood.
Downloaded from jcn.sagepub.com at MCMASTER UNIV LIBRARY on December 21, 2014
from
infancy to
TABLE 5 Medical and
Surgical
Problems of
Angelman Syndrome
Children
*Data obtained from questionnaire; each denominator in these two columns number of questionnaires adequately answered for item. EEG electroencephalographic.
represents the
=
days, developmental delay is obvious; only the severity of the delay is uncertain. We have found the behavioral profile, seizure history, and physical findings in the young child as a whole very characteristic and sufficient to make the diagnosis. The diagnosis can be supported by EEG findings35 as well as prometaphase chromosome studies to demonstrate a cytogenetic deletion in 15qll-ql3. Other studies are helpful only in that they exclude other diagnoses such as inborn errors of metabolism and structural brain lesions. A recent pathologic description of a brain from an autopsy study of an individual with Angelman syndrome also showed only cortical and cerebellar atrophy. 31 Children with Angelman syndrome typically have a characteristic behavioral profile consisting of
TABLE 6 Seizures in American Children With
happy affect, hyperactivity, short attention span, sleep disorders, and feeding problems in infancy. They have a happy countenance and exhibit frequent laughter, with some having persistent outbursts of laughter. Most parents feel that cheerfulness is the most positive aspect of their child’s personality. Howa
a cheerful affect is so common among children that this aspect of the syndrome may be overemphasized as a distinguishing trait in Angelman syndrome. Another behavioral feature is hypermotoric or hyperactive behavior. Children with Angelman syndrome are often overexcitable and extremely active, with short attention spans, often not showing interest in any one thing for more than a few moments. Sleeping is also a problem in that most parents find that the child apparently requires a decreased amount
ever,
Angelman Syndrome
275
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drug or combination of drugs is clearly superior. The EEG findings can be distinctive. Most Angelman syndrome individuals have both ocular and cutaneous hypopigmentation. Hypopigmentation of skin, eyes, and hair are major
TABLE 7
Diagnostic Studies of American Angelman Syndrome Children
features of oculocutaneous albinism, which is usually seen as an isolated finding, frequently with an autosomal dominant inheritance pattern or associated Hittner et al documented with different deletion in another chromosome 15 this association Ocular Prader-Willi condition, hypopigmentation is consistent with a neural crest developmental abnormality, since the neural crest is intimately involved in the development of uveal pigmentation. Neural crest cells are precursors of many different tissues, especially nervous structures and mesenchymal derivatives. Much of the facial mesenchyme is also derived from cranial neural crest cells, as are the dermal and epidermal melanoblasts. Cranial nerve crest disorders can theoretically arise because of a deficient number of cells, disordered migration, or
syndromes.3~
syndrome.38
*Data obtained
by questionnaire except for the cytogenetic study; denominator represents the number of questionnaires adequately answered for item except for cytogenetics, where it represents the number of individuals studied. CT computed tomographic; MRI magnetic resonance imag=
=
ing.
0
of sleep. This was a serious disruptive factor in many families because some children needed only a few hours of sleep. Feeding problems consisting mainly of inadequate motor control of chewing and swallowing appear to be transient and seem not to affect all children; only five case reports in the literature note this
problem. However,
most
previous
re-
ports have been of older children, and their parents may not recall infant feeding difficulties. At a recent meeting, 19 of 21 families with an Angelman syndrome child reported having one or more of the following feeding problems in infancy: frequent spitting up, refusal to nurse or feed, and failure to thrive (unpublished data). Therefore, we believe feeding difficulties during infancy are common.
Middle ear problems, adenoidectomies, and inguinal hernia surgery were reported in some of the English children with Angelman syndrome but not in any of the American children. This may be due to a lower threshold for diagnosis and treatment or, alternatively, better primary care for multihandicapped children in England, with better detection and intervention for minor problems. In about half of all Angelman syndrome children, seizures are initially severe and difficult to control but they tend to become milder and easier to control in later childhood. A variety of seizure types are exhibited, including Lennox-Gastaut, and no one
inadequate proliferation. 39,40 Rieger syndrome,41 neurofibromatosis,42 incontinentia pigmenti,39 and hypomelanosis of Ito39 have all been considered neurocrestopathies. However, so many tissues are derived from neural crest cells that the spectrum of neurocrestopathies is certainly very broad and may well also include Angelman syndrome. Angelman syndrome can be confused with Prader-Willi syndrome in the first year of life if ascertainment is made by developmental delay, feeding difficulty, and presence of a chromosome 15 deletion, since a cytogenetically similar deletion has been found in about 60% of patients with PraderWilli syndrome.43-45 Feeding problems and hypotonia, however, are generally more involved in Prader-Willi syndrome than in Angelman syndrome, usually resulting in failure to thrive. Two infants initially reported as having Prader-Willi syndrome were, on later evaluation, found to have Angelman syndrome.46 Only after the 1st year of life do these
syndromes clearly diverge clinically. Developdelay and mental retardation continue to be a main feature of both, although Angelman syndrome children will be more delayed and never develop speech. Both Angelman and Prader-Willi syndrome individuals have pleasant and friendly dispositions, but children with Angelman syndrome appear more cheerful and ready to laugh. The face of an Angelman syndrome child with macrognathia, macrosomia, and a protruding tongue is easily distinguished from that of a Prader-Willi child with almond-shaped eyes and a narrow bifrontal diametwo
mental
276
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TABLE 8 Clinical Findings: Grouped According to Presence in Children With Angelman Syndrome
.
--
-
----
-
--
--.--
--
or
-.
*The denominator represents the number of individuals tP < .5 by Fisher exact test. DTR deep tendon reflexes.
--
Absence of 15 Band
--
physically
-.
q12
,
--
examined for item.
=
ter.
Angelman syndrome
males have normal
genita-
lia, while males with Prader-Willi syndrome will small penis and cryptorchidism. Fiand obesity, a constant finding in children with Prader-Willi syndrome, is on the other hand uncommon in children with Angelman syndrome. Therefore, while Angelman syndrome infants and Prader-Willi infants have many similarities, qualitative and quantitative differences in their neurologic insult becomes evident in childhood. The cause, in most cases of both Angelman and Prader-Willi syndromes, seems to involve the loss of a similar area of chromosome 15.24 The genetic mechanism in either syndrome is unknown. Contiguous gene involvement or a single gene defect is possible for both. Differences in phenotype in individuals with and without deletions and subgroups with partial phenotypes would argue for a contiguous gene model. Attempts to differentiate Prader-
often have
a
nally, overeating
Willi syndrome individuals with and without the chromosome 15 deletion have found a correlation between decreased pigmentation and the deletion. 47,48 This suggests that there is a pigmentation gene(s) on the proximal 15q segment. Our Angelman syndrome study did not show any difference between individuals with and without a chromosome 15 deletion. Molecular studies have so far also failed to demonstrate any differences in the regions involved in the Angelman and Prader-Willi syndromes. 24,49,50 One recent study of a family with multiple members with Angelman syndrome suggested different loci for the genes causing the Angelman and Prader-Willi The only consistent finding has been the different parental inheritance of the deleted chromosome in the two conditions. The parental origin of the deleted chromosome in Angelman syndrome is maternal, while the parental origin of the deleted chromosome in Prader-Willi syndrome is paternal. 52-54 The paren-
syndromes.51
277
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tal inheritance data implies that imprinting or germline modification of genes is causing different or modified expression of genes. A parental origin effect could then govern transcription at various times in development and therefore control the expression of a genetic insult. Uniparental chromosomal disomy of chromosome 15 has been found in some individuals with nondeletion Angelman and Prader-Willi syndromes.55,56 Uniparental disomy is the condition in which both homologous chromosomes are inherited from the same parent. In other words, there is lack of contribution for that chromsome from the other parent. This information suggests that at least some regions of the genome require contributions from both
should therefore be considered in any indevelopmental delay who is more lightly pigmented than his first-degree relatives. A delayed child that does not develop speech, although his understanding of language would suggest the contrary, must also be watched for further signs consistent with Angelman syndrome. Marked ataxia in a developmentally delayed child would also warrant suspicion. Since verbal language is more severely impaired than other communication skills, any treatment approach should emphasize nonverbal communication, such as sign language. Since most children are unable to walk at the appropriate time, early physical therapy is also recommended.
diagnosis fant with
parents. We have no explanation yet for individuals with Angelman syndrome without a deletion. Even when cytogenetic studies are complemented by molecular probing, about 20% fail to show a deletion .57 Interestingly, all sibling cases with Angelman syndrome, up to this date, have not had cytogenetic or molecu-
Acknowledgments Editing and acknowledged.
clerical assistance of
lar deletions. 5,17,23,29,32 Autosomal recessive genes on 15qll-ql3, autosomal recessive genes on other
loci, gonadal mosaicism, submicroscopic deletions, chromosomal translocations, and autosomal dominant genes modified by proposed to explain these
imprinting
have all been
cases.
Rett syndrome is a condition that has clinical similarities to Angelman syndrome. Children with Rett syndrome are also born without complications and initially appear to be healthy. Their development stagnates during their lst year, seizures and hyperventilation develop, and their behavior becomes increasingly autisticlike .58 They are distinguished from children with Angelman syndrome by their normal facial appearance and their midline stereotypic hand movements. In many cases, their behavior may be similar to that seen in Angelman syndrome. Rett syndrome children can be pleasant and have sleep disturbances. Their walk is often jerky, with truncal ataxia. Further understanding of the mechanisms determining Rett syndrome and Angelman syndrome will reveal what common denominators underlie the clinical similarities. It will be especially interesting to see whether an inappropriate imprint (eg, disomy) could be implicated as a causative factor of Rett syndrome. Because of nonspecificity of the early findings, the level of suspicion must be very high if early diagnosis of Angelman syndrome is to be made accurately. Early diagnosis is important because individualized treatment modalities can be initiated and appropriate directive counseling offered. This
Sandy
Glazer is
gratefully
References 1.
Angelman H: "Puppet" children: A report on three cases. Dev Med Child Neurol 1965;7:681-688. 2. Kaplan LC, Wharton R, Elias E, et al: Clinical heterogeneity associated with deletions in the long arm of chromosome 15: Report of 3 new cases and their possible genetic significance. AmJ Med Genet 1987;28:45-53. 3. Magenis RE, Brown MG, Lacy DA, et al: Is Angelman syndrome an alternative result of del(15)(q11-q13)? Am J Med Genet 1987;28:829-838. 4. Robb SA, Pohl KRE, Baraitser M, et al: The "happy puppet" syndrome of Angelman: Review of the clinical features. Arch Dis Child 1989;64:83-86. 5. Baraitser M, Patton M, Lam STS, et al: The Angelman (happy puppet) syndrome: Is it autosomal recessive? Clin Genet
1987;31:323-330. 6. 7.
Batenburg-Plenter AM: Een zeldzaam (?) "vrolijk" oligofreen syndrome. Ned Tijdschr Geneeskd 1976;120:1528-1530. Berg JM, Pakula Z: Angelman’s ("happy puppet") syndrome. AmJ Dis Child 1972;123:72-74.
8.
Berggreen
S:
"Happy puppet" syndrome. Ugeskr Laeger
1972;134:1174. 9. Bjerre I, Fagher B,
Ryding E, Rosen I: The Angelman or "happy puppet" syndrome. Clinical and electroencephalographic features and cerebral blood flow. Acta Paediatr Scand 1984;73:398-402.
10. Bower BD, Jeavons PM: The "happy puppet" syndrome. Arch Dis Child 1967;42:298-302. 11. Comas AP: Sindrome de Angelman o de la marioneta alegre. Bol Asoc Med P R 1976;68:257-260. 12. Dickinson AJ, Fielder AR, Young ID, Duckett DP: Ocular findings in Angelman’s (happy puppet) syndrome. Ophthalmic Paediatr Genet 1989;11:1-6. 13. Dooley JM, Berg JM, Pakula Z, MacGregor DL: The puppetlike syndrome of Angelman. Am JDis Child 1981;135: 621-624. 14. Dorries A, Spohr H-L, Kunze J: Angelman ("happy puppet")
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syndrome—seven new cases documented by cerebral computed tomography: Review of the literature. EurJ Pediatr 1988;148:270-273. 15. Eber SW, Joost S, Gabriel M: Angelman syndrome. Monatsschr Kinderheilkd 1986;134:158-160. 16. Elian M: Fourteen happy puppets. Clin Pediatr 1975;14: 902-908. 17. Fisher JA, Burn J, Alexander FW, Gardner-Medwin D: Angelman (happy puppet) syndrome in a girl and her brother. J Med Genet 1987;24:294-298. 18. Ganji S, Duncan MC: Angelman’s (happy puppet) syndrome: Clinical, CT scan and serial electroencephalographic study. Clin Electroencephalogr 1989;20:128-140. 19. Godfrey M: Happy puppet syndrome. Nurs Mirror 1976;143: 45-46. 20. Halal F, Chagnon J: Le syndrome de la "marionnette joyeuse." Union Med Can 1976;105:1077-1083. 21. Hersh JH, Bloom AS, Zimmerman AW, et al: Behavioral correlates in the happy puppet syndrome: A characteristic profile ? Dev Med Child Neurol 1981;23:792-800. 22. Kibel MA, Burness FR: The "happy puppet" syndrome. Centr Afr J Med 1973;19:91-93. 23. Kuroki Y, Matsui I, Yamamoto Y, leshima A: The "happy puppet" syndrome in two siblings. Hum Genet 1980;56: 227-229. 24. Magenis RE, Toth-Fegel S, Allen LJ, et al: Comparison of the 15q deletions in Prader-Willi and Angelman syndromes : Specific regions, extent of deletions, parental origin and clinical consequences. AmJ Med Genet 1990;35: 333-349. 25. Massey JY, Roy FH: Ocular manifestations of the happy pup26.
pet syndrome.J Pediatr Ophthalmol 1973;10:282-284. Mayo O, Nelson MM, Townsend HRA: Three more "happy
puppets." 27. Moore
Dev Med Child Neurol 1973;15:63-74. PM: The "happy puppet" syndrome: Two and a review of five previous cases. Neuropäediatrie
JR, Jeavons
new cases
1973;4:172-179. 28. Pascual Pascual SI, Campos Tullot R, Escudero B, GarciáSimón R: Sindrome (happy puppet) o de Angelman. Revisión a propósito de tres casos. An Esp Pediatr 1986;24: 311-316. 29. Pashayan H, Singer W, Bove C, Eisenberg E, et al: The Angelman syndrome in two brothers. AmJ Med Genet
1982;13: 295 - 298. 30. Pelc S, Levy J, Point G: "Happy puppet" syndrome ou syndrome du "pantin hilare." Helv Paediatr Acta 1976;31: 183-188. 31. Rolando S, Schenone R, Schappapieta M: La sindrome di Angelman. Minerva Pediatr 1983;35:727-731. 32. Willems P, Dijkstra 1, Brouwer O, Smit P: Recurrence risk in the Angelman ("happy puppet") syndrome. AmJ Med Genet
1987;27:773- 780. 33. Williams C, Frias JL: The Angelman ("happy puppet") syndrome. AmJ Med Genet 1982;11:543-460. 34. Williams CA, Hendrickson JE, Cantu ES, Donlon TA: Angelman syndrome in a daughter with del(15)(q11-q13) associated with brachycephaly, hearing loss, enlarged foramen magnum and ataxia in the mother. AmJ Med Genet 1989; 32:333-338. 35. Boyd SG, Harden A, Patton MA: The electroencephalogram in early diagnosis of the Angelman (happy puppet) syndrome. EurJ Pediatr 1988;147:508-513. 36. Jay V, Becker LE, Chan FW, Perry TL: Puppet-like syndrome
of Angelman: A pathologic and neurochemical study. Neurology 1991;41:416-422. 37. Witkop CJ, Quevedo WC, Fitzpatrick TB, King RA: Albinism, in Scriver CR, Beaudet AL, Sly WS, Valle D (eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1989, pp 2905-2947. 38. Hittner HM, King RA, Riccardi VM, et al: Oculocutaneous albinoidism as a manifestation of reduced neural crest derivatives in the Prader-Willi syndrome. Am J Ophthalmol 1982;94: 328-337. 39. Kissel P, Andre JM, Jacquier A: The Neurocristopathies. New York, Masson, 1982. 40. Bolande RP: The neurocristopathies: A unifying concept of disease arising in neural crest maldevelopment. Hum Pathol
1974;5:409-429. 41.
Beauchamp GR, Knepper PA: Role of neural crest in anterior segment development and disease.J Pediatr Ophthalmol Stra-
bismus 1984;21:209-214. 42. Bolande RP: Neurofibromatosis—the quintessential neurocristopathy : Pathogenetic concepts and relationships. Adv Neurol 1981;29:67-75. 43. Butler MG, Meaney FJ, Palmer CG: Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. AmJ Med Genet 1986;23:793-809. 44. Ledbetter DH, Mascarello JT, Riccardi VM, et al: Chromosome 15 abnormalities and the Prader-Willi syndrome. Am J Hum Genet 1982;34:278-285. 45. Ledbetter DH, Riccardi VM, Youngbloom SA, et al: Deletion of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med 1981;304:325-329. 46. Zori R, Williams C, Mattel JF, Moncla A: Prenatal origin of del(15)(q11-q13) in Angelman and Prader-Willi syndromes. AmJ Med Genet 1990;37:294-295. 47. Butler MG: Hypopigmentation: A common feature of PraderLabhart-Willi syndrome. AmJ Hum Genet 1989;45:140-146. 48. Wiesner GL, Bendel CM, Olds DP, et al: Hypopigmentation in the Prader-Willi syndrome. Am J Hum Genet 1987;40: 431-442. 49. Knoll JHM, Nicholls, RD, Magenis RE, et al: Angelman syndrome : Three molecular classes identified with chromsome 15q11q13 specific DNA markers. Am J Hum Genet 1990;47:
149-154. 50. Nicholls
RD, Knoll JH, Glatt K,
length polymorphisms molecular cytogenetics
et al: Restriction fragment within proximal 15q and their use in and the Prader-Willi syndrome. Am J
Med Genet 1989;33:66-77. 51. Niikawa N, Hamabe J: Possible genomic imprinting at the Angelman syndrome gene locus, abstract. Presented at the Prader-Willi Syndrome and Other Chromosome 15q Deletion Disorders Conference, Noordwijkerhout, The Netherlands, May 1991. 52. Butler MG, Palmer CG: Parental origin of chromosome 15 deletion in Prader-Willi syndrome. Lancet 1983;1:1285-1286. 53. Knoll JHM, Nicholls RD, Magenis RE, et al: Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet 1989;32:285-290. 54. Williams CA, Zori RT, Stone JW, et al: Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting. AmJ Med Genet 1990;35:350-353. 55. Malcolm S, Clayton-Smith J, Nichols M, et al: Uniparental paternal disomy in Angelman’s syndrome. Lancet 1991;337: 694-697.
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56. Nicholls
57.
RD, Knoll JHM, Butler MG, et al: Genomic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature 1989;342:281-285. Nicholls RD, Gotlieb W, Zori R, et al: Molecular analysis in Angelman syndrome, abstract. Presented at the PraderWilli Syndrome and Other Chromosome 15q Deletion Dis-
orders Conference, Noordwijkerhout, The Netherlands, May 1991. 58. Moeschler JB, Charman CE, Berg SZ, Graham JM: Rett syndrome : Natural history and management. Pediatrics 1988;82: 1-10.
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Abstract To further delineate the clinical and developmental features of Angelman syndrome, we collected data through three sources of information: (1) physical examinations; (2) laboratory data and family questionnaire data of affected individuals; and (3) literature review. The questionnaire data describes a generally normal prenatal and birth history. Feeding difficulties, developmental delay, or seizures were the presenting problems in all infants. The diagnosis of Angelman syndrome, however, was not made in any infant prior to 1 year of age. Except for seizures, no medical or surgical complication was common, although a variety of visual complaints or findings were common. Sixty percent of Angelman syndrome children had a cytogenetically demonstrated deletion of chromosome 15q11-q13. The individuals with and without a deletion could not be differentiated clinically. Diagnosis in early childhood is therefore difficult, and a high index of suspicion is recommended. ( J Child Neurol 1992;7:270-280).
syndrome is a neurogenetic disorder with a unique behavioral phenotype. Affected children have a rigid, jerky ataxia, and their facial expression is unusually happy. All are severely mentally retarded, most with microbrachycephaly and abnormal electroencephalographic (EEG) findings. They generally cannot speak or, at most, can say a few words. Harry Angelman, an English pediatrician, first described the syndrome in 1965,1 referring to these children as &dquo;puppetlike&dquo; because the children walked like a puppet and because they reminded him of a painting he had seen in Italy by Giovanni Francesco Caroto depicting a happy, young boy holding a puppet (Fanciullo con pupazzo). His observations were confirmed by other clinicians over the next decade, but a pejorative term, &dquo;happy puppet syndrome,&dquo; began to characterize the syndrome. In 1987, a deletion of chromosome 15qll-ql3 in patients with Angelman syndrome was discovered and
Angelman
reported. 2,3 Recently,
clinical review of a series of Angelman individuals has been published.4 The emergence of parent support groups in the United Kingdom and the United States has helped supply missing pieces of knowledge about the developmental history of Angelman syndrome. Established in 1987, the Florida-based Angelman Research Group (ARG) has served as a registry for Angelman syndrome patients, a clearing house for Angelman a
syndrome-related information, a parent support group, and a focus for clinical study. In this report, we summarize information collected by the Angelman Research Group registry regarding developmental and clinical profiles of Angelman syndrome. We also summarize selected information from the UK-based Angelman Syndrome Support Group (ASSG) and descriptions published in the literature.
Methods Information Received
cepted for From
July 15, 1991. Received revised Nov 25, 1991. Acpublication Nov 26, 1991. the Raymond C. Philips Research and Education Unit
(Drs Zori and Williams,
Ms Hendrickson and Whidden, and Mr Division of Genetics, Department of Pediatrics, University of Florida, Gainesville, FL, and the Angelman Syndrome Support
Gray),
Group (Ms Woolven), Waterlooville, England. Address correspondence to Dr Roberto Zori, University Florida, JHMHC, Box J-296, Gainesville, FL 32610.
of
children with Angelman four methods: physical and
syndrome was developmental evaluation of Angelman syndrome patients, questionnaires completed by families in the United States, information provided by the Angelman Syndrome Support Group in the United Kingdom, and literature review. 1-3,5-34 Thirty-six American families with a child with Angelman syndrome were given questionnaires and were asked to provide photographs. The questionnaire included data gathered by
on
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’
and developmental variables. The child’s physician was asked to complete a physical examination form to be returned with the family questionnaire. Twenty-six of these patients underwent physical and developmental evaluation. This included high-resolution chromosome studies in which the criterion for chromosome 15 deletion was absence of band q12. A directed physical examination was performed. Children participating in either the questionnaire or physical examination group were judged by the authors (C.A.W. and R.T.Z.) to have a diagnosis of Angelman syndrome using the following criteria: (1) microbrachycephaly; (2) abnormal EEG consisting of diffuse, markedly abnormal sharp and slow waves of the 2- to 4-Hz type; (3) stiff and jerky gait with flexed upper arms; (4) severe language impairment ; (5) characteristic face with prognathia, macrosomia, and protruding tongue; and (6) frequent laughter on
clinical, cytogenetic,
(Figure 1). families in the ASSG in the United Kingasked to complete a general developmental questionnaire, and the following information was summarized : birth and pregnancy data, medical and behavioral problems in the first year of life, attainment of self-help skills, and seizure activity. One of the 38 families had two Angelman syndrome children.
Thirty-eight
dom
were
Results The American questionnaire data were used to compile Tables 1 through 7. Results of high-resolution chromosome studies are included in Table 7. The physical examination data were used to compile Table 8. Information was not available for all questionnaire or physical examination items for all patients. The N values as presented in the tables do not equal the total number of patients evaluated but rather the number of families who adequately answered that question or patients who were adequately examined
TABLE 2 Time of Presentation of
Feeding Problems,
Seizures in American Children with Angelman Syndrome
Developmental Delay,
or
*The denominator represents the number of quately answered for item.
questionnaires
ade-
for that item. For example, in the US questionnaire, if only 28 of the 36 families adequately answered the question of interest, then the N value for this item was considered to be 28. Children with Angelman syndrome generally had uncomplicated prenatal and perinatal histories (Table 1). The children were first brought to medical attention because of one of the following problems: failure to thrive, feeding problems, seizures, or developmental delay. The problems first appeared during the child’s 1st year of life (Table 2). All children were
had
profoundly mentally retarded, although some developed skills necessary for self-care (Table
3). One of
the UK families had two affected chilof the American families had more than one affected child. Of the 39 children in the United Kingdom, eight could say a few words, compared with one in the US cohort. However, 18 of the American children understood speech to some extent, and 12 used gestures to communicate. One child was easily taught to use five gestures after many years of futile speech
dren, and
none
TABLE 1
Prenatal and Birth Data of
Angelman Syndrome
Children
*Data obtained from questionnaire; each denominator in these two columns represents the number of questionnaires adequately answered for item. tPerinatal problems in UK patients include: maternal hypertension (two cases), fetal distress (three cases), floppy (one case), placenta previa (one case); for US patients: toxemia (one case), required O2 neonatally (one case), failure to progress (one case); in literature: polyhydramnios (one case), abruptio (one case).
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FIGURE 1 Children with
Angelman syndrome showing typical face
and
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posture.
TABLE 3
Developmental Milestones of Angelman Syndrome Children
*N represents the number of
questionnaires adequately
The parents of several other children also commented on the ability of their children to communicate nonverbally. Many children with Angelman syndrome had some feeding difficulty in infancy or early childhood. Feeding problems ranged from frequent spitting up to refusing to feed and failure to thrive. By their first birthday, most infants were notable for their cheerfulness and frequent outbursts of laughter (generally inappropriate for the situation). They also seemed to have less need for sleep than other children, napping only for short intervals. They were also often hyperactive, although generally without accompanying aggressive behavior (Table 4). A few children from the United Kingdom had hearing difficulties related to middle ear disease. Eight children in this group had either adenoids removed or middle ear tubes placed, and four had surgery for inguinal hernias. We did not document similar problems in our American group. Ophthalmologic abnormalities such as strabismus, optic atrophy, and keratoconus were common (Table 5). Most children had seizures that were difficult to control or intractable; seizures were of several types (Table 6). However, at the time of interview only two still had seizures. They both had infrequent absence seizures. Of the remaining ten, two were on no medications, five were on valproic acid alone, one on
therapy.
TABLE 4 Behavioral Attributes of
-
-
.
_
___.___
valproic
acid and
and two
on
clonazepam, one on phenytoin, phenobarbital. Neuroimaging studies, when abnormal, showed cortical atrophy, preventricular leukomalacia, or some dysmyelination; the study of one child showed cerebellar hypoplasia. No consistent central nervous system imaging anomaly was found. Urine organic acids and serum and urine amino acids screening results were normal. A deletion of chromosome 15 was found in 62% of the individuals studied (Table 7). When children with and without the deletion
compared by anthropometric, craniofacial, musculoskeletal, auditory, and visual examinations, were
the
only significant finding was the more frequent of widely spaced teeth in the children lacking the deletion (P < .05, Fisher’s exact test) (Taoccurrence
ble
_.__
*The denominator represents the number of
8).
Discussion is difficult to diagnose in the 3 years of life; no pathognomonic findings are evident, and the phenotype is subtle at first (Figure 2). The first sign of abnormalities in children with Angelman syndrome usually appears around age 6 months with the onset of nonspecific problems such as feeding difficulties and developmental delay. By the time these children reach their first birth-
Angelman syndrome first 2
Angelman Syndrome
uu
answered for item.
or
Children
-
-
questionnaires adequately
-
_r
.
answered for item.
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FIGURE 2
Progression of physical features
of
a woman
with
Angelman syndrome
adulthood.
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from
infancy to
TABLE 5 Medical and
Surgical
Problems of
Angelman Syndrome
Children
*Data obtained from questionnaire; each denominator in these two columns number of questionnaires adequately answered for item. EEG electroencephalographic.
represents the
=
days, developmental delay is obvious; only the severity of the delay is uncertain. We have found the behavioral profile, seizure history, and physical findings in the young child as a whole very characteristic and sufficient to make the diagnosis. The diagnosis can be supported by EEG findings35 as well as prometaphase chromosome studies to demonstrate a cytogenetic deletion in 15qll-ql3. Other studies are helpful only in that they exclude other diagnoses such as inborn errors of metabolism and structural brain lesions. A recent pathologic description of a brain from an autopsy study of an individual with Angelman syndrome also showed only cortical and cerebellar atrophy. 31 Children with Angelman syndrome typically have a characteristic behavioral profile consisting of
TABLE 6 Seizures in American Children With
happy affect, hyperactivity, short attention span, sleep disorders, and feeding problems in infancy. They have a happy countenance and exhibit frequent laughter, with some having persistent outbursts of laughter. Most parents feel that cheerfulness is the most positive aspect of their child’s personality. Howa
a cheerful affect is so common among children that this aspect of the syndrome may be overemphasized as a distinguishing trait in Angelman syndrome. Another behavioral feature is hypermotoric or hyperactive behavior. Children with Angelman syndrome are often overexcitable and extremely active, with short attention spans, often not showing interest in any one thing for more than a few moments. Sleeping is also a problem in that most parents find that the child apparently requires a decreased amount
ever,
Angelman Syndrome
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drug or combination of drugs is clearly superior. The EEG findings can be distinctive. Most Angelman syndrome individuals have both ocular and cutaneous hypopigmentation. Hypopigmentation of skin, eyes, and hair are major
TABLE 7
Diagnostic Studies of American Angelman Syndrome Children
features of oculocutaneous albinism, which is usually seen as an isolated finding, frequently with an autosomal dominant inheritance pattern or associated Hittner et al documented with different deletion in another chromosome 15 this association Ocular Prader-Willi condition, hypopigmentation is consistent with a neural crest developmental abnormality, since the neural crest is intimately involved in the development of uveal pigmentation. Neural crest cells are precursors of many different tissues, especially nervous structures and mesenchymal derivatives. Much of the facial mesenchyme is also derived from cranial neural crest cells, as are the dermal and epidermal melanoblasts. Cranial nerve crest disorders can theoretically arise because of a deficient number of cells, disordered migration, or
syndromes.3~
syndrome.38
*Data obtained
by questionnaire except for the cytogenetic study; denominator represents the number of questionnaires adequately answered for item except for cytogenetics, where it represents the number of individuals studied. CT computed tomographic; MRI magnetic resonance imag=
=
ing.
0
of sleep. This was a serious disruptive factor in many families because some children needed only a few hours of sleep. Feeding problems consisting mainly of inadequate motor control of chewing and swallowing appear to be transient and seem not to affect all children; only five case reports in the literature note this
problem. However,
most
previous
re-
ports have been of older children, and their parents may not recall infant feeding difficulties. At a recent meeting, 19 of 21 families with an Angelman syndrome child reported having one or more of the following feeding problems in infancy: frequent spitting up, refusal to nurse or feed, and failure to thrive (unpublished data). Therefore, we believe feeding difficulties during infancy are common.
Middle ear problems, adenoidectomies, and inguinal hernia surgery were reported in some of the English children with Angelman syndrome but not in any of the American children. This may be due to a lower threshold for diagnosis and treatment or, alternatively, better primary care for multihandicapped children in England, with better detection and intervention for minor problems. In about half of all Angelman syndrome children, seizures are initially severe and difficult to control but they tend to become milder and easier to control in later childhood. A variety of seizure types are exhibited, including Lennox-Gastaut, and no one
inadequate proliferation. 39,40 Rieger syndrome,41 neurofibromatosis,42 incontinentia pigmenti,39 and hypomelanosis of Ito39 have all been considered neurocrestopathies. However, so many tissues are derived from neural crest cells that the spectrum of neurocrestopathies is certainly very broad and may well also include Angelman syndrome. Angelman syndrome can be confused with Prader-Willi syndrome in the first year of life if ascertainment is made by developmental delay, feeding difficulty, and presence of a chromosome 15 deletion, since a cytogenetically similar deletion has been found in about 60% of patients with PraderWilli syndrome.43-45 Feeding problems and hypotonia, however, are generally more involved in Prader-Willi syndrome than in Angelman syndrome, usually resulting in failure to thrive. Two infants initially reported as having Prader-Willi syndrome were, on later evaluation, found to have Angelman syndrome.46 Only after the 1st year of life do these
syndromes clearly diverge clinically. Developdelay and mental retardation continue to be a main feature of both, although Angelman syndrome children will be more delayed and never develop speech. Both Angelman and Prader-Willi syndrome individuals have pleasant and friendly dispositions, but children with Angelman syndrome appear more cheerful and ready to laugh. The face of an Angelman syndrome child with macrognathia, macrosomia, and a protruding tongue is easily distinguished from that of a Prader-Willi child with almond-shaped eyes and a narrow bifrontal diametwo
mental
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TABLE 8 Clinical Findings: Grouped According to Presence in Children With Angelman Syndrome
.
--
-
----
-
--
--.--
--
or
-.
*The denominator represents the number of individuals tP < .5 by Fisher exact test. DTR deep tendon reflexes.
--
Absence of 15 Band
--
physically
-.
q12
,
--
examined for item.
=
ter.
Angelman syndrome
males have normal
genita-
lia, while males with Prader-Willi syndrome will small penis and cryptorchidism. Fiand obesity, a constant finding in children with Prader-Willi syndrome, is on the other hand uncommon in children with Angelman syndrome. Therefore, while Angelman syndrome infants and Prader-Willi infants have many similarities, qualitative and quantitative differences in their neurologic insult becomes evident in childhood. The cause, in most cases of both Angelman and Prader-Willi syndromes, seems to involve the loss of a similar area of chromosome 15.24 The genetic mechanism in either syndrome is unknown. Contiguous gene involvement or a single gene defect is possible for both. Differences in phenotype in individuals with and without deletions and subgroups with partial phenotypes would argue for a contiguous gene model. Attempts to differentiate Prader-
often have
a
nally, overeating
Willi syndrome individuals with and without the chromosome 15 deletion have found a correlation between decreased pigmentation and the deletion. 47,48 This suggests that there is a pigmentation gene(s) on the proximal 15q segment. Our Angelman syndrome study did not show any difference between individuals with and without a chromosome 15 deletion. Molecular studies have so far also failed to demonstrate any differences in the regions involved in the Angelman and Prader-Willi syndromes. 24,49,50 One recent study of a family with multiple members with Angelman syndrome suggested different loci for the genes causing the Angelman and Prader-Willi The only consistent finding has been the different parental inheritance of the deleted chromosome in the two conditions. The parental origin of the deleted chromosome in Angelman syndrome is maternal, while the parental origin of the deleted chromosome in Prader-Willi syndrome is paternal. 52-54 The paren-
syndromes.51
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tal inheritance data implies that imprinting or germline modification of genes is causing different or modified expression of genes. A parental origin effect could then govern transcription at various times in development and therefore control the expression of a genetic insult. Uniparental chromosomal disomy of chromosome 15 has been found in some individuals with nondeletion Angelman and Prader-Willi syndromes.55,56 Uniparental disomy is the condition in which both homologous chromosomes are inherited from the same parent. In other words, there is lack of contribution for that chromsome from the other parent. This information suggests that at least some regions of the genome require contributions from both
should therefore be considered in any indevelopmental delay who is more lightly pigmented than his first-degree relatives. A delayed child that does not develop speech, although his understanding of language would suggest the contrary, must also be watched for further signs consistent with Angelman syndrome. Marked ataxia in a developmentally delayed child would also warrant suspicion. Since verbal language is more severely impaired than other communication skills, any treatment approach should emphasize nonverbal communication, such as sign language. Since most children are unable to walk at the appropriate time, early physical therapy is also recommended.
diagnosis fant with
parents. We have no explanation yet for individuals with Angelman syndrome without a deletion. Even when cytogenetic studies are complemented by molecular probing, about 20% fail to show a deletion .57 Interestingly, all sibling cases with Angelman syndrome, up to this date, have not had cytogenetic or molecu-
Acknowledgments Editing and acknowledged.
clerical assistance of
lar deletions. 5,17,23,29,32 Autosomal recessive genes on 15qll-ql3, autosomal recessive genes on other
loci, gonadal mosaicism, submicroscopic deletions, chromosomal translocations, and autosomal dominant genes modified by proposed to explain these
imprinting
have all been
cases.
Rett syndrome is a condition that has clinical similarities to Angelman syndrome. Children with Rett syndrome are also born without complications and initially appear to be healthy. Their development stagnates during their lst year, seizures and hyperventilation develop, and their behavior becomes increasingly autisticlike .58 They are distinguished from children with Angelman syndrome by their normal facial appearance and their midline stereotypic hand movements. In many cases, their behavior may be similar to that seen in Angelman syndrome. Rett syndrome children can be pleasant and have sleep disturbances. Their walk is often jerky, with truncal ataxia. Further understanding of the mechanisms determining Rett syndrome and Angelman syndrome will reveal what common denominators underlie the clinical similarities. It will be especially interesting to see whether an inappropriate imprint (eg, disomy) could be implicated as a causative factor of Rett syndrome. Because of nonspecificity of the early findings, the level of suspicion must be very high if early diagnosis of Angelman syndrome is to be made accurately. Early diagnosis is important because individualized treatment modalities can be initiated and appropriate directive counseling offered. This
Sandy
Glazer is
gratefully
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