Back To Search Results

Angelman Syndrome

Editor: Magda D. Mendez Updated: 8/8/2023 1:40:40 AM

Introduction

In 1965 Harry Angelman, a British pediatrician, described the "Puppet Children," later being renamed Angelman syndrome (AS). Angelman described three children who had similar symptoms of learning disability, minimal or absent speech, ataxic and jerky movements, and a happy social disposition.[1]

Angelman syndrome is a rare neurogenic disorder. It is a classic example of genomic imprinting, where the expression of a genomic region differs depending on the chromosome's parent of origin. AS is a neurodevelopmental disorder affecting mostly the nervous system that manifests with intellectual and developmental disabilities, a puppet-like ataxic movement and phenotype, as well as sleep disorders, and hyperactivity.[2]

One of the causes of AS was found in 1987 through high-resolution chromosome banding technique, which revealed de novo microdeletions in the long arm of chromosome 15 in the region 11-13 (15q11-13). Later it was shown that there are multiple mechanisms other than deletions that can cause AS involving the region 15q11-13. We know now that the primary cause of Angelman syndrome is a selective loss of function of ubiquitin-ligase E3A(UBE3A) in the brain, which is usually expressed maternally.[3][4]

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology

Angelman syndrome (AS) is caused by a pathologic lack of expression of the UBE3A gene on the maternal chromosome in combination with physiologic genomic imprinting or silencing on the paternal chromosome in neurons. UBE3A gene is an example of an imprinted gene because it is expressed in a parent of origin-specific manner. The paternal UBE3A gene is imprinted mainly in the neurons and has some level of expression in the rest of the body.[4]

AS is typically caused by a sporadic de novo mutation on the maternal gene UBE3A (part of the ubiquitin pathway) at chromosome 15q11-13. Around 70 to 75% of cases arise from maternal deletion within chromosome 15q11-q13, containing this gene. Approximately 2% to 3% can be due to paternal uniparental disomy (UPD), imprinting center defect (3% to 5%), or single gene point mutation in the maternal UBE3A allele (5 to 10%).[5]

Inherited causes of AS are mostly either due to UBE3A mutation (mainly in the mother's paternally inherited allele), which is inherited by the baby and a subtype of imprinting defects called submicroscopic deletion of imprinting center.[6][7]

Epidemiology

The incidence of Angelman syndrome (AS) varies from 1 in 20,000 to 1 in 12,000 live birth. There is no gender preference, and AS affects males and females equally.[8] However, many cases may go undiagnosed due to the underreporting of cases and misdiagnosis.[9]

Pathophysiology

The findings of Angelman syndrome (AS) are mostly limited to the nervous system because physiologically paternal UBE3A is only imprinted in the brain. So if there is a pathologic loss of function mutation of maternal UBE3A, mainly the brain is affected.[10]

UBE3A codes for a ubiquitin ligase called E6-associated protein (E6-AP).[11] E6-AP is critical for the functioning of the ubiquitin-proteasome pathway, which is essential for the normal functioning of neurons and synaptic plasticity. Loss of function mutation of E6-AP causes impaired ubiquitin-proteasome degradation of many proteins. Many targets of E6-AP that have been identified are p53, p27, Arc, and ephexin5. P53 and p27 are crucial for the regulation of cell survival in the nervous system. Elevation of Arc levels increases the internalization of surface AMPA receptors causing impairment of post-synaptic excitatory transmission. Increased expression of ephexin5, which regulates synapse formation, caused decreased synapse formation. Together with increased levels of Arc and ephexin5 cause decreased experience-dependent synapse remodeling. This gives rise to neurologic deficits.[12][13][14][15][16]

Mouse models of AS with UBE3A knockout of the maternal gene have shown ataxia, seizures, decreased size of the brain, motor abnormalities. These models have also demonstrated deficits in hippocampal long term potentiation (LTP), which explains deficits in memory and learning in AS patients.[17] Also, several of these experiments have shown abnormal dendritic morphology and decreased spine density. This might also explain the motor and cognitive deficits in AS.[18]

There are mainly four mechanisms that cause loss of function of UBE3A. These are deletion, mutation, imprinting, and uniparental disomy.

The most severe symptoms are seen in the deletion subtype, out of which class 1 has the worst clinical phenotype. These include global developmental delay, microcephaly, and seizures, no speech, and oculocutaneous hypopigmentation. Increased susceptibility to seizures is seen since some of the GABA genes are deleted in deletion mutations. The deletion of OCA1 genes in combination with the regulatory effect of UBE3A on MC1R might explain oculocutaneous hypopigmentation.[19][20]

History and Physical

The major hallmark of presentation of Angelman syndrome (AS) is characterized by movement and balance disorder (ataxia), speech deficits (absent or minimal), psychomotor delay, inappropriate paroxysms of laughter with hand flapping (happy puppet), and seizures.

Psychomotor Delay

Developmental delay can be seen by six months of age. Microcephaly presents before three years of age; however, it is not present in all cases. It is more common in the deletion subtype of AS.[21] Most children with Angelman syndrome are not able to achieve ambulation until three years of age, and some never walk and remain wheelchair-bound. The gait is ataxic, with toe-walking and jerky arm movements. Some of them even have uplifted arms that are flexed at the elbows.

Characteristic Behavior

AS patients have a unique behavioral phenotype. They have a happy demeanor with inappropriate and excessive laughter, often showing tremulous movements of limbs with hand flapping. They are easily distracted as they have a short attention span, and this leads to poor concentration. They also are easily excitable.[22]

Seizures

When they are three years of age, 80% of the patients have seizures, with abnormal EEGs, with spike even when there is no seizure activity (akinetic seizure). Seizures are described to improve during puberty but recur in adulthood.[23][24] 

Sleep Problems

AS patients may also have sleep problems. Total sleep time may be decreased with nighttime awakenings.  

Other Findings 

  • Protruding tongue
  • Tongue thrusting; suck/swallowing disorders
  • Feeding problems during infancy
  • Truncal hypotonia
  • Prognathism 
  • Wide mouth, widely spaced teeth
  • Frequent drooling
  • Excessive chewing/mouthing behaviors
  • Strabismus
  • Hypopigmented—light skin, hair, and eye color
  • compared with the family (seen only in the deletion cases)
  • Hyperactive lower extremity deep tendon reflexes
  • Wide-based gait with pronated or valgus-positioned ankles
  • Uplifted, flexed arm position especially during walking
  • Increased sensitivity to heat
  • Sleep disturbances
  • Attraction to/fascination with water
  • Abnormal food-related behaviors
  • Obesity (in childhood)
  • Scoliosis [2]

With aging in Individuals with Angelman syndrome, hyperactivity decreases due to increased muscle rigidity, sleep becomes better, and concentration improves. Some AS patients develop obesity in adulthood.[7]

Evaluation

The first evaluation for Angelman syndrome (AS) can be started in the prenatal stage when evaluating a fetus with growth restrictions. Current studies have shown noninvasive prenatal testing (NIPS) technique is highly accurate in the diagnose of AS prenatally.

After birth, when AS suspicion arises, workup should start with methylation studies.

Methylation Studies - Normally, the SNRPN exon 1 region/promoter is differentially methylated, that is, the paternal allele is unmethylated, and the maternal allele is methylated. In 80% of patients with AS (consisting deletion, imprinting center defect, and parental disomy) that maternal methylated allele cannot be found.

FISH - FISH is done after methylation studies. It detects any deletions in the maternal chromosome 15. If negative, imprinting defects or paternal disomy must be considered. Paternal disomy is confirmed via DNA marker analysis. If negative, imprinting center defects must be considered and can be confirmed by molecular studies.

DNA Sequencing - if the patient has a negative methylation study, but the suspicion for AS is high, DNA sequencing can be done. It rules out any mutation in UBE3A, which can be missed in methylation studies. If it is negative other alternative diagnoses must be considered.

EEG can show a characteristic pattern of AS and also an epileptic activity, which can help in the diagnosis of AS.

Polysomnography (Sleep Study) to diagnose any sleep disorders.[25]

Treatment / Management

 The management of Angelman syndrome (AS) is mainly symptomatic as there is no curative treatment till now.

Therapeutic and Management Guidelines for Treating AS[26]

Feeding Problems

  • Feeding Difficulties - Sucking might be ineffective, so breastfeeding is not possible sometimes. The use of special nipples is advised, monitoring weight gain and referral to specialized teams for advice and training on feeding.
  • Gastroesophageal Reflux - Administration of magnesium carbonate and aluminum hydroxide in upright positioning.
  • Constipation - Increased fluid intake. Jelly can be used as an alternative. A diet rich in fiber and laxatives can also be used.
  • Obesity - Regular checkup of weight and BMI. Also, regular exercise is advised.
  • Diet -The ketogenic diet is helpful and is effective.[27]
  • (B3)

Developmental Delay

  • General Developmental Delay - Organization of an early, individualized, and active intervention program. Bayle scales should be used to assess development.
  • Gross and Fine Motor Delay - Physiotherapy, orthotics, and occupational therapy are required for developing motor skills, posture management, and managing contractures.
  • Poor Active Communication - Speech and language therapy. This can be done using verbal and nonverbal methods of communication. Computers can help massively with this.

Seizures

The most effective drugs are sodium valproate, clonazepam, and phenobarbital.[9] Drugs such as carbamazepine and vigabatrin are ineffective and may cause worsening of seizures.

Sleep Problems

Proper sleep hygiene and melatonin are effective.

Vision Problems 

Visual assessment for ocular problems is done to increase interaction and decrease autistic tendencies. Refer to an ophthalmologist if strabismus is suspected.

Novel Therapeutic Approaches

Since all patients with AS have one functional but silenced copy of paternal UBE3A, many attempts have been made to unsilenced the paternal UBE3A allele. The paternal UBE3A allele is silenced due to the SNHG14 transcript, which caused transcriptional interference. Then, one of the ways to activate the paternal allele would be to prevent the formation of the SNHG14 transcript. This has been successful in mice with topotecan, which is a topoisomerase inhibitor.[28](B3)

Antisense oligonucleotides(ASO) are also very promising. They function via RNA interference against SNHG14, causing its degradation.[29](B3)

Differential Diagnosis

 It is essential to rule out other neurodevelopmental disorders that can resemble Angelman syndrome (AS), including:

Microdeletion Syndromes[30][31]

  • Phelan–McDermid syndrome (22q13.3 deletion)
  • MBD5 haploinsuffi­ciency syndrome (2q23.1 deletion) 
  • KANSL1 haplo­insufficiency syndrome (17q21.31 deletion)

 Single Gene Disorders[31]

  • Pitt–Hopkins syndrome(TCF4 haploinsufficiency)
  • Christianson syndrome(SLC9A6 mutation)
  • Mowat–Wilson syndrome( ZEB2 haploinsufficiency)
  • Rett syndrome(MECP2 mutations)
  • Kleefstra syndrome (EHMT1)

Prognosis

All the individuals with Angelman syndrome (AS) will have some form of developmental delay, speech, and motor deficits. However, there are many variations in the severity of these symptoms. This depends on the genetic cause of AS (big deletions have the worse prognosis), time of diagnosis, and intervention. Some patients can achieve a higher degree of ambulation, speech, and independence in tasks of daily living. 

Most individuals with AS will have a normal life span. They do not show any developmental regression, and they might become better with some self-help skills with supportive care. Most of the patients remain dependent and need constant care and attention as they have perilous behavior. Prognosis improves remarkably with early diagnosis and interventions like speech, physical, and occupational therapies.

Symptoms of AS vary with age. Most patients have decreased frequency of seizures, hyperactivity, and improved sleep as they age. However, they may become obese as they age, which can cause scoliosis and reduce mobility. Puberty seems unaffected with normal sexual development.[2]

Complications

The main complications arising in Angelman syndrome (AS) individuals are due to their comorbidities. Due to the seizure and ataxia, the patient can have injuries during these episodes. The combination of hyperactivity, exploratory behavior, and intellectual disability in patients with AS leads to an increased risk of accidents.[26] This contributes majorly to the morbidity and mortality of AS individuals.

Between 20 to 80% can present with feeding difficulties requiring nutrition evaluation or even surgical intervention, nasogastric tube placement, depending on the severity of the malnutrition. Developmental delay is commonly seen in different ranges, but the majority of the patient will not be able to care for themselves.

Deterrence and Patient Education

There is no cure for Angelman syndrome (AS), but only the management of the symptoms which requires a multidisciplinary team. Early diagnosis and early, consistent treatment using speech, physical, and occupational therapy has shown improvement in prognosis.

Parents must be educated on the requirement of constant care and support for their child and the need for early and regular therapy. Genetic counseling can be offered to parents of AS patients. Even though most cases of AS are sporadic, some are familial.  Genetic counseling can help determine recurrence risk and plan future pregnancies.[26]

Enhancing Healthcare Team Outcomes

Angelman syndrome (AS) is a challenging disorder with complex management. Due to no definitive cure, the management aims to control symptoms and improve the quality of life.

Once AS is suspected, the patient should be evaluated by an interprofessional team. Neonatal nurses should be tuned to the physical features of AS, and a full neurologic exam should be carried out. They should also provide support to the parents. Early diagnosis and treatment improve the prognosis of individuals with AS.[26]

Pediatricians need to have a high degree of suspicion when a patient presents with symptoms of AS. When AS is suspected, methylation studies and FISH must be done to confirm the diagnosis. Once the diagnosis is critical to incorporate a multidisciplinary team consisting of a neurologist, developmental specialist, speech therapist, and a geneticist. Genetic counseling can help calculate future recurrence risk of AS and plan subsequent pregnancies.

Early intervention, developmental evaluation, and therapies should be started since infancy, to improve and reach the maximum developmental capacity of the patient. A family meeting and follow-ups will help the parent to be actively involved in the management of the patient. Other commodities should be evaluated and treated by every subspecialty to prevent any further possible complications. [Level5]

References


[1]

Hart H. 'Puppet' children. A report on three cases (1965). Developmental medicine and child neurology. 2008 Aug:50(8):564. doi: 10.1111/j.1469-8749.2008.03035.x. Epub     [PubMed PMID: 18754889]

Level 3 (low-level) evidence

[2]

Clayton-Smith J, Laan L. Angelman syndrome: a review of the clinical and genetic aspects. Journal of medical genetics. 2003 Feb:40(2):87-95     [PubMed PMID: 12566516]


[3]

Magenis RE, Brown MG, Lacy DA, Budden S, LaFranchi S. Is Angelman syndrome an alternate result of del(15)(q11q13)? American journal of medical genetics. 1987 Dec:28(4):829-38     [PubMed PMID: 3688021]

Level 3 (low-level) evidence

[4]

Vu TH,Hoffman AR, Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nature genetics. 1997 Sep;     [PubMed PMID: 9288087]

Level 3 (low-level) evidence

[5]

Jana NR. Understanding the pathogenesis of Angelman syndrome through animal models. Neural plasticity. 2012:2012():710943. doi: 10.1155/2012/710943. Epub 2012 Jul 8     [PubMed PMID: 22830052]

Level 3 (low-level) evidence

[6]

Buiting K, Saitoh S, Gross S, Dittrich B, Schwartz S, Nicholls RD, Horsthemke B. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nature genetics. 1995 Apr:9(4):395-400     [PubMed PMID: 7795645]


[7]

Van Buggenhout G, Fryns JP. Angelman syndrome (AS, MIM 105830). European journal of human genetics : EJHG. 2009 Nov:17(11):1367-73. doi: 10.1038/ejhg.2009.67. Epub 2009 May 20     [PubMed PMID: 19455185]


[8]

Buiting K, Clayton-Smith J, Driscoll DJ, Gillessen-Kaesbach G, Kanber D, Schwinger E, Williams C, Horsthemke B. Clinical utility gene card for: Angelman Syndrome. European journal of human genetics : EJHG. 2015 Feb:23(2):. doi: 10.1038/ejhg.2014.93. Epub 2014 Jun 4     [PubMed PMID: 24896151]


[9]

Fiumara A, Pittalà A, Cocuzza M, Sorge G. Epilepsy in patients with Angelman syndrome. Italian journal of pediatrics. 2010 Apr 16:36():31. doi: 10.1186/1824-7288-36-31. Epub 2010 Apr 16     [PubMed PMID: 20398390]


[10]

Mabb AM, Judson MC, Zylka MJ, Philpot BD. Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends in neurosciences. 2011 Jun:34(6):293-303. doi: 10.1016/j.tins.2011.04.001. Epub 2011 May 17     [PubMed PMID: 21592595]

Level 3 (low-level) evidence

[11]

Dagli A,Buiting K,Williams CA, Molecular and Clinical Aspects of Angelman Syndrome. Molecular syndromology. 2012 Apr;     [PubMed PMID: 22670133]


[12]

Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. The EMBO journal. 1991 Dec:10(13):4129-35     [PubMed PMID: 1661671]

Level 3 (low-level) evidence

[13]

Mishra A, Godavarthi SK, Jana NR. UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27. Neurobiology of disease. 2009 Oct:36(1):26-34. doi: 10.1016/j.nbd.2009.06.010. Epub 2009 Jul 8     [PubMed PMID: 19591933]

Level 3 (low-level) evidence

[14]

Greer PL, Hanayama R, Bloodgood BL, Mardinly AR, Lipton DM, Flavell SW, Kim TK, Griffith EC, Waldon Z, Maehr R, Ploegh HL, Chowdhury S, Worley PF, Steen J, Greenberg ME. The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc. Cell. 2010 Mar 5:140(5):704-16. doi: 10.1016/j.cell.2010.01.026. Epub     [PubMed PMID: 20211139]

Level 3 (low-level) evidence

[15]

Margolis SS,Salogiannis J,Lipton DM,Mandel-Brehm C,Wills ZP,Mardinly AR,Hu L,Greer PL,Bikoff JB,Ho HY,Soskis MJ,Sahin M,Greenberg ME, EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation. Cell. 2010 Oct 29;     [PubMed PMID: 21029865]

Level 3 (low-level) evidence

[16]

Sato M, Stryker MP. Genomic imprinting of experience-dependent cortical plasticity by the ubiquitin ligase gene Ube3a. Proceedings of the National Academy of Sciences of the United States of America. 2010 Mar 23:107(12):5611-6. doi: 10.1073/pnas.1001281107. Epub 2010 Mar 8     [PubMed PMID: 20212164]

Level 3 (low-level) evidence

[17]

Kaphzan H, Hernandez P, Jung JI, Cowansage KK, Deinhardt K, Chao MV, Abel T, Klann E. Reversal of impaired hippocampal long-term potentiation and contextual fear memory deficits in Angelman syndrome model mice by ErbB inhibitors. Biological psychiatry. 2012 Aug 1:72(3):182-90. doi: 10.1016/j.biopsych.2012.01.021. Epub 2012 Mar 3     [PubMed PMID: 22381732]

Level 3 (low-level) evidence

[18]

Kühnle S, Mothes B, Matentzoglu K, Scheffner M. Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. Proceedings of the National Academy of Sciences of the United States of America. 2013 May 28:110(22):8888-93. doi: 10.1073/pnas.1302792110. Epub 2013 May 13     [PubMed PMID: 23671107]


[19]

Gentile JK,Tan WH,Horowitz LT,Bacino CA,Skinner SA,Barbieri-Welge R,Bauer-Carlin A,Beaudet AL,Bichell TJ,Lee HS,Sahoo T,Waisbren SE,Bird LM,Peters SU, A neurodevelopmental survey of Angelman syndrome with genotype-phenotype correlations. Journal of developmental and behavioral pediatrics : JDBP. 2010 Sep;     [PubMed PMID: 20729760]

Level 3 (low-level) evidence

[20]

Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, Hutson A, Nicholls RD, Zori RT, Williams CA, Driscoll DJ. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. Journal of medical genetics. 2001 Dec:38(12):834-45     [PubMed PMID: 11748306]


[21]

Tan WH, Bacino CA, Skinner SA, Anselm I, Barbieri-Welge R, Bauer-Carlin A, Beaudet AL, Bichell TJ, Gentile JK, Glaze DG, Horowitz LT, Kothare SV, Lee HS, Nespeca MP, Peters SU, Sahoo T, Sarco D, Waisbren SE, Bird LM. Angelman syndrome: Mutations influence features in early childhood. American journal of medical genetics. Part A. 2011 Jan:155A(1):81-90. doi: 10.1002/ajmg.a.33775. Epub     [PubMed PMID: 21204213]


[22]

Williams CA. The behavioral phenotype of the Angelman syndrome. American journal of medical genetics. Part C, Seminars in medical genetics. 2010 Nov 15:154C(4):432-7. doi: 10.1002/ajmg.c.30278. Epub     [PubMed PMID: 20981772]


[23]

Pelc K,Boyd SG,Cheron G,Dan B, Epilepsy in Angelman syndrome. Seizure. 2008 Apr;     [PubMed PMID: 17904873]


[24]

Thibert RL, Conant KD, Braun EK, Bruno P, Said RR, Nespeca MP, Thiele EA. Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia. 2009 Nov:50(11):2369-76. doi: 10.1111/j.1528-1167.2009.02108.x. Epub 2009 May 12     [PubMed PMID: 19453717]


[25]

Ramsden SC, Clayton-Smith J, Birch R, Buiting K. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC medical genetics. 2010 May 11:11():70. doi: 10.1186/1471-2350-11-70. Epub 2010 May 11     [PubMed PMID: 20459762]

Level 1 (high-level) evidence

[26]

Bonello D, Camilleri F, Calleja-Agius J. Angelman Syndrome: Identification and Management. Neonatal network : NN. 2017 May 1:36(3):142-151. doi: 10.1891/0730-0832.36.3.142. Epub     [PubMed PMID: 28494826]


[27]

Evangeliou A,Doulioglou V,Haidopoulou K,Aptouramani M,Spilioti M,Varlamis G, Ketogenic diet in a patient with Angelman syndrome. Pediatrics international : official journal of the Japan Pediatric Society. 2010 Oct;     [PubMed PMID: 20880305]

Level 3 (low-level) evidence

[28]

Powell WT, Coulson RL, Gonzales ML, Crary FK, Wong SS, Adams S, Ach RA, Tsang P, Yamada NA, Yasui DH, Chédin F, LaSalle JM. R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation. Proceedings of the National Academy of Sciences of the United States of America. 2013 Aug 20:110(34):13938-43. doi: 10.1073/pnas.1305426110. Epub 2013 Aug 5     [PubMed PMID: 23918391]

Level 3 (low-level) evidence

[29]

Meng L, Ward AJ, Chun S, Bennett CF, Beaudet AL, Rigo F. Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Nature. 2015 Feb 19:518(7539):409-12. doi: 10.1038/nature13975. Epub 2014 Dec 1     [PubMed PMID: 25470045]

Level 3 (low-level) evidence

[30]

Williams CA, Lossie A, Driscoll D, R.C. Phillips Unit. Angelman syndrome: mimicking conditions and phenotypes. American journal of medical genetics. 2001 Jun 1:101(1):59-64     [PubMed PMID: 11343340]


[31]

Tan WH,Bird LM,Thibert RL,Williams CA, If not Angelman, what is it? A review of Angelman-like syndromes. American journal of medical genetics. Part A. 2014 Apr;     [PubMed PMID: 24779060]