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Angelman syndrome(AS)

MedGen UID:
58144
Concept ID:
C0162635
Disease or Syndrome
Synonyms: Angelman syndrome-like; AS; HAPPY PUPPET SYNDROME; Happy puppet syndrome (formerly)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Inheritance with unknown mechanism
MedGen UID:
831588
Concept ID:
CN227389
Intellectual Product
Source: Orphanet
Describes an inherited disorder with unknown mode of inheritance.
not inherited
MedGen UID:
832438
Concept ID:
CN227390
Intellectual Product
Source: Orphanet
Describes a disorder that is not inherited.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
not inherited (Orphanet)
SNOMED CT: Angelman's syndrome (76880004); Angelman syndrome (76880004); Happy puppet syndrome (76880004)
 
Gene (location): UBE3A (15q11.2)
OMIM®: 105830
Orphanet: ORPHA72

Disease characteristics

Excerpted from the GeneReview: Angelman Syndrome
Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year, and it can take several years before the correct clinical diagnosis is obvious. [from GeneReviews]
Authors:
Aditi I Dagli  |  Jennifer Mueller  |  Charles A Williams   view full author information

Additional descriptions

From OMIM
Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, movement or balance disorder, typical abnormal behaviors, and severe limitations in speech and language. Most cases are caused by absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Prader-Willi syndrome (PWS; 176270) is a clinically distinct disorder resulting from paternal deletion of the same 15q11-q13 region. In addition, the chromosome 15q11-q13 duplication syndrome (608636) shows overlapping clinical features. Clayton-Smith and Pembrey (1992) provided a review of Angelman syndrome. Cassidy and Schwartz (1998) reviewed the molecular and clinical aspects of both Prader-Willi syndrome and Angelman syndrome. Horsthemke and Wagstaff (2008) provided a detailed review of the mechanisms of imprinting of the Prader-Willi/Angelman syndrome region. Van Buggenhout and Fryns (2009) provided a review of Angelman syndrome and discussed genetic counseling of the disorder, which can show a recurrence risk of up to 50%, depending on the underlying genetic mechanism.  http://www.omim.org/entry/105830
From GHR
Angelman syndrome is a complex genetic disorder that primarily affects the nervous system. Characteristic features of this condition include delayed development, intellectual disability, severe speech impairment, and problems with movement and balance (ataxia). Most affected children also have recurrent seizures (epilepsy) and a small head size (microcephaly). Delayed development becomes noticeable by the age of 6 to 12 months, and other common signs and symptoms usually appear in early childhood.Children with Angelman syndrome typically have a happy, excitable demeanor with frequent smiling, laughter, and hand-flapping movements. Hyperactivity, a short attention span, and a fascination with water are common. Most affected children also have difficulty sleeping and need less sleep than usual.With age, people with Angelman syndrome become less excitable, and the sleeping problems tend to improve. However, affected individuals continue to have intellectual disability, severe speech impairment, and seizures throughout their lives. Adults with Angelman syndrome have distinctive facial features that may be described as "coarse." Other common features include unusually fair skin with light-colored hair and an abnormal side-to-side curvature of the spine (scoliosis). The life expectancy of people with this condition appears to be nearly normal.  https://ghr.nlm.nih.gov/condition/angelman-syndrome

Clinical features

Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of FECES. These symptoms are associated with a variety of causes, including low DIETARY FIBER intake, emotional or nervous disturbances, systemic and structural disorders, drug-induced aggravation, and infections.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Excessive production of saliva.
Exotropia
MedGen UID:
4613
Concept ID:
C0015310
Disease or Syndrome
A form of ocular misalignment where the visual axes diverge inappropriately. For example, medial rectus muscle weakness may produce this condition as the affected eye will deviate laterally upon attempted forward gaze. An exotropia occurs due to the relatively unopposed force exerted on the eye by the lateral rectus muscle, which pulls the eye in an outward direction.
Macroglossia
MedGen UID:
44236
Concept ID:
C0024421
Disease or Syndrome
A finding indicating enlargement of the tongue.
Wide mouth
MedGen UID:
44238
Concept ID:
C0024433
Congenital Abnormality
Distance between the oral commissures more than 2 SD above the mean. Alternatively, an apparently increased width of the oral aperture (subjective).
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Myopia
MedGen UID:
44558
Concept ID:
C0027092
Disease or Syndrome
A refractive error in which rays of light entering the EYE parallel to the optic axis are brought to a focus in front of the RETINA when accommodation (ACCOMMODATION, OCULAR) is relaxed. This results from an overly curved CORNEA or from the eyeball being too long from front to back. It is also called nearsightedness.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Obesity
MedGen UID:
18127
Concept ID:
C0028754
Disease or Syndrome
A status with BODY WEIGHT that is grossly above the acceptable or desirable weight, usually due to accumulation of excess FATS in the body. The standards may vary with age, sex, genetic or cultural background. In the BODY MASS INDEX, a BMI greater than 30.0 kg/m2 is considered obese, and a BMI greater than 40.0 kg/m2 is considered morbidly obese (MORBID OBESITY).
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
Misalignment of the visual axes of the eyes. In comitant strabismus the degree of ocular misalignment does not vary with the direction of gaze. In noncomitant strabismus the degree of misalignment varies depending on direction of gaze or which eye is fixating on the target. (Miller, Walsh & Hoyt's Clinical Neuro-Ophthalmology, 4th ed, p641)
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Autonomic nervous system overreaction to stimuli, most commonly after spinal cord injury at a T-5 level and above.
Hypopigmentation of the skin
MedGen UID:
102477
Concept ID:
C0162835
Disease or Syndrome
A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Limb tremor
MedGen UID:
115980
Concept ID:
C0235081
Sign or Symptom
Brain atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Hypoplasia of the maxilla
MedGen UID:
66804
Concept ID:
C0240310
Congenital Abnormality
Abnormally small dimension of the Maxilla. Usually creating a malocclusion or malalignment between the upper and lower teeth or resulting in a deficient amount of projection of the base of the nose and lower midface region.
Protruding tongue
MedGen UID:
66831
Concept ID:
C0241442
Finding
Tongue extending beyond the alveolar ridges or teeth at rest.
Mandibular prognathia
MedGen UID:
98316
Concept ID:
C0399526
Finding
Abnormal prominence of the chin related to increased length of the mandible.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Excessive movement of muscles of the body as a whole, which may be associated with organic or psychological disorders.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Blue irides
MedGen UID:
108297
Concept ID:
C0578626
Finding
A markedly blue coloration of the iris.
Scoliosis
MedGen UID:
195976
Concept ID:
C0700208
Finding
The presence of an abnormal lateral curvature of the spine.
Sleep-wake cycle disturbance
MedGen UID:
371548
Concept ID:
C1833362
Finding
Flat occiput
MedGen UID:
332439
Concept ID:
C1837402
Finding
Reduced convexity of the occiput (posterior part of skull).
Paroxysmal bursts of laughter
MedGen UID:
374299
Concept ID:
C1839749
Finding
Progressive gait ataxia
MedGen UID:
375309
Concept ID:
C1843885
Finding
A type of gait ataxia displaying progression of clinical severity.
Widely spaced teeth
MedGen UID:
337093
Concept ID:
C1844813
Finding
Increased spaces (diastemata) between most of the teeth in the same dental arch.
Intellectual disability, progressive
MedGen UID:
337397
Concept ID:
C1846149
Finding
The term progressive intellectual disability should be used if intelligence decreases/deteriorates over time.
Postnatal microcephaly
MedGen UID:
339779
Concept ID:
C1847514
Finding
Microcephaly (HP:0000252) with onset in the postnatal period, that is, the head circumference is in the normal range at birth but falls behind normal values later in development.
Fair hair
MedGen UID:
336542
Concept ID:
C1849221
Finding
A lesser degree of hair pigmentation than would otherwise be expected.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.

Professional guidelines

PubMed

Gregg AR, Skotko BG, Benkendorf JL, Monaghan KG, Bajaj K, Best RG, Klugman S, Watson MS
Genet Med 2016 Oct;18(10):1056-65. Epub 2016 Jul 28 doi: 10.1038/gim.2016.97. PMID: 27467454
Dondorp W, de Wert G, Bombard Y, Bianchi DW, Bergmann C, Borry P, Chitty LS, Fellmann F, Forzano F, Hall A, Henneman L, Howard HC, Lucassen A, Ormond K, Peterlin B, Radojkovic D, Rogowski W, Soller M, Tibben A, Tranebjærg L, van El CG, Cornel MC; European Society of Human Genetics.; American Society of Human Genetics.
Eur J Hum Genet 2015 Nov;23(11):1438-50. Epub 2015 Mar 18 doi: 10.1038/ejhg.2015.57. PMID: 25782669Free PMC Article
Schaefer GB, Mendelsohn NJ; Professional Practice and Guidelines Committee.
Genet Med 2013 May;15(5):399-407. Epub 2013 Mar 21 doi: 10.1038/gim.2013.32. PMID: 23519317
Shaffer LG, Agan N, Goldberg JD, Ledbetter DH, Longshore JW, Cassidy SB
Genet Med 2001 May-Jun;3(3):206-11. doi: 10.109700125817-200105000-00011. PMID: 11388763Free PMC Article

External

Eurogentest, 2008

Recent clinical studies

Etiology

Glassman LW, Grocott OR, Kunz PA, Larson AM, Zella G, Ganguli K, Thibert RL
Am J Med Genet A 2017 Oct;173(10):2703-2709. Epub 2017 Aug 16 doi: 10.1002/ajmg.a.38401. PMID: 28816003
Grocott OR, Herrington KS, Pfeifer HH, Thiele EA, Thibert RL
Epilepsy Behav 2017 Mar;68:45-50. Epub 2017 Jan 19 doi: 10.1016/j.yebeh.2016.12.018. PMID: 28109989
Wagner C, Niemczyk J, Equit M, Curfs L, von Gontard A
Eur J Pediatr 2017 Feb;176(2):225-232. Epub 2016 Dec 20 doi: 10.1007/s00431-016-2828-1. PMID: 28000035
Erickson CA, Wink LK, Baindu B, Ray B, Schaefer TL, Pedapati EV, Lahiri DK
Am J Med Genet A 2016 Sep;170(9):2334-7. Epub 2016 Jun 21 doi: 10.1002/ajmg.a.37811. PMID: 27327493
Shaaya EA, Grocott OR, Laing O, Thibert RL
Epilepsy Behav 2016 Jul;60:138-141. Epub 2016 May 18 doi: 10.1016/j.yebeh.2016.04.030. PMID: 27206232

Diagnosis

Aguilera C, Viñas-Jornet M, Baena N, Gabau E, Fernández C, Capdevila N, Cirkovic S, Sarajlija A, Miskovic M, Radivojevic D, Ruiz A, Guitart M
BMC Med Genet 2017 Nov 21;18(1):137. doi: 10.1186/s12881-017-0500-x. PMID: 29162042Free PMC Article
Erickson CA, Wink LK, Baindu B, Ray B, Schaefer TL, Pedapati EV, Lahiri DK
Am J Med Genet A 2016 Sep;170(9):2334-7. Epub 2016 Jun 21 doi: 10.1002/ajmg.a.37811. PMID: 27327493
Shaaya EA, Grocott OR, Laing O, Thibert RL
Epilepsy Behav 2016 Jul;60:138-141. Epub 2016 May 18 doi: 10.1016/j.yebeh.2016.04.030. PMID: 27206232
Fernandes ML, do Carmo Santos M, Gomez RS
Braz J Anesthesiol 2016 Mar-Apr;66(2):212-4. Epub 2014 Mar 31 doi: 10.1016/j.bjane.2013.06.020. PMID: 26952234
Ranasinghe JC, Chandradasa D, Fernando S, Kodithuwakku U, Mandawala DE, Dissanayake VH
J Med Case Rep 2015 Jun 16;9:142. doi: 10.1186/s13256-015-0622-8. PMID: 26077608Free PMC Article

Therapy

Tan WH, Bird LM
Am J Med Genet C Semin Med Genet 2016 Dec;172(4):384-401. Epub 2016 Nov 8 doi: 10.1002/ajmg.c.31536. PMID: 27860204
Shaaya EA, Grocott OR, Laing O, Thibert RL
Epilepsy Behav 2016 Jul;60:138-141. Epub 2016 May 18 doi: 10.1016/j.yebeh.2016.04.030. PMID: 27206232
Fernandes ML, do Carmo Santos M, Gomez RS
Braz J Anesthesiol 2016 Mar-Apr;66(2):212-4. Epub 2014 Mar 31 doi: 10.1016/j.bjane.2013.06.020. PMID: 26952234
Sewell MD, Wallace C, Gibson A, Noordeen H, Tucker S, Molloy S, Lehovsky J
Dev Neurorehabil 2016 Oct;19(5):315-20. Epub 2014 Dec 30 doi: 10.3109/17518423.2014.980524. PMID: 25549057
Thibert RL, Pfeifer HH, Larson AM, Raby AR, Reynolds AA, Morgan AK, Thiele EA
Epilepsia 2012 Sep;53(9):1498-502. Epub 2012 Jul 10 doi: 10.1111/j.1528-1167.2012.03537.x. PMID: 22779920

Prognosis

Ververi A, Islam L, Bewes B, Busby L, Sullivan C, Canham N
Cytogenet Genome Res 2017;152(3):132-136. Epub 2017 Sep 13 doi: 10.1159/000480030. PMID: 28898887
Glassman LW, Grocott OR, Kunz PA, Larson AM, Zella G, Ganguli K, Thibert RL
Am J Med Genet A 2017 Oct;173(10):2703-2709. Epub 2017 Aug 16 doi: 10.1002/ajmg.a.38401. PMID: 28816003
Bonello D, Camilleri F, Calleja-Agius J
Neonatal Netw 2017 May 1;36(3):142-151. doi: 10.1891/0730-0832.36.3.142. PMID: 28494826
Le Fevre A, Beygo J, Silveira C, Kamien B, Clayton-Smith J, Colley A, Buiting K, Dudding-Byth T
Am J Med Genet A 2017 Mar;173(3):753-757. doi: 10.1002/ajmg.a.38072. PMID: 28211971
Wagner C, Niemczyk J, Equit M, Curfs L, von Gontard A
Eur J Pediatr 2017 Feb;176(2):225-232. Epub 2016 Dec 20 doi: 10.1007/s00431-016-2828-1. PMID: 28000035

Clinical prediction guides

Wagner C, Niemczyk J, Equit M, Curfs L, von Gontard A
Eur J Pediatr 2017 Feb;176(2):225-232. Epub 2016 Dec 20 doi: 10.1007/s00431-016-2828-1. PMID: 28000035
Fernandes ML, do Carmo Santos M, Gomez RS
Braz J Anesthesiol 2016 Mar-Apr;66(2):212-4. Epub 2014 Mar 31 doi: 10.1016/j.bjane.2013.06.020. PMID: 26952234
Sewell MD, Wallace C, Gibson A, Noordeen H, Tucker S, Molloy S, Lehovsky J
Dev Neurorehabil 2016 Oct;19(5):315-20. Epub 2014 Dec 30 doi: 10.3109/17518423.2014.980524. PMID: 25549057
Mertz LG, Christensen R, Vogel I, Hertz JM, Østergaard JR
Res Dev Disabil 2014 Nov;35(11):2681-90. Epub 2014 Jul 26 doi: 10.1016/j.ridd.2014.07.025. PMID: 25064682
Thibert RL, Pfeifer HH, Larson AM, Raby AR, Reynolds AA, Morgan AK, Thiele EA
Epilepsia 2012 Sep;53(9):1498-502. Epub 2012 Jul 10 doi: 10.1111/j.1528-1167.2012.03537.x. PMID: 22779920

Recent systematic reviews

Bi X, Sun J, Ji AX, Baudry M
Expert Opin Ther Targets 2016;20(5):601-13. Epub 2015 Nov 26 doi: 10.1517/14728222.2016.1115837. PMID: 26558806Free PMC Article
Leung HT, Ring H
J Intellect Disabil Res 2013 Jan;57(1):3-20. Epub 2011 Dec 6 doi: 10.1111/j.1365-2788.2011.01505.x. PMID: 22142420
Kitsiou-Tzeli S, Tzetis M, Sofocleous C, Vrettou C, Xaidara A, Giannikou K, Pampanos A, Mavrou A, Kanavakis E
Am J Med Genet A 2010 Aug;152A(8):1925-32. doi: 10.1002/ajmg.a.33447. PMID: 20575009
Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J
Am J Med Genet A 2006 Mar 1;140(5):413-8. doi: 10.1002/ajmg.a.31074. PMID: 16470747
Valente KD, Koiffmann CP, Fridman C, Varella M, Kok F, Andrade JQ, Grossmann RM, Marques-Dias MJ
Arch Neurol 2006 Jan;63(1):122-8. doi: 10.1001/archneur.63.1.122. PMID: 16401744

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