Pediatrics

Angelman syndrome

OVERVIEW: What every practitioner needs to know

What is Angelman syndrome?

Angelman syndrome is a neurogenetic disorder characterized by developmental delay leading to intellectual disability, minimal or no speech development, seizures, and a stereotypic ataxic gait that suggests the appearance of a marionette. Children with Angelman syndrome often have spontaneous laughter and appear happy. The latter two findings led to the use of the older descriptive term, "happy puppet syndrome," which is no longer used because it is considered demeaning and nonclinical.

The disorder is caused by lack of expression of the maternally inherited copy of the UBE3A gene located on the long arm of chromosome 15, at 15q11-q13. Although this chromosomal region is also involved in the pathogenesis of Prader-Willi syndrome, Angelman syndrome and Prader-Willi syndrome are distinct conditions.

Are you sure your patient has Angelman syndrome? What are the typical findings for this disease?

The major clinical diagnostic criteria for Angelman syndrome follow:

  • Functionally severe developmental delay

  • Severe speech impairment (especially expressive language; no words or minimal words used, although may use gestures or communication boards)

  • Movement or balance disorder, usually gait ataxia or tremulousness of limbs

  • Characteristic personality and behavioral profile (frequent/easily provoked laughter or smiling, often unassociated with environmental cues or stimuli; apparently happy demeanor; easily excitable personality, often with uplifted hand-flapping or waving movements; hypermotoric/hyperactive behavior)

These four features are found in virtually 100% of individuals with Angelman syndrome. Absence of one of these features in a child old enough to manifest the feature should cast serious doubt on the diagnosis. Comprehensive genetic testing can identify about 90% of patients with Angelman syndrome; in the other approximately 10% of cases, clinical criteria are the sole determinant of the diagnosis. Many of these clinically diagnosed individuals are now being recognized as having another disorder with overlapping features.

The next most common symptoms (each seen in >80%):

  • Seizures—usually by 3 years of age

  • Abnormal electroencephalogram (EEG) (even in the absence of seizures—usually by 2 years of age)

  • Microcephaly or delayed head growth—by 2 years of age

What types of seizures are typically seen in Angelman syndrome?

Atypicalabsence, atonic, generalized tonic-clonic, complex partial, andmyoclonic seizures are relatively common seizure types in Angelmansyndrome. Other seizure types may also be seen, and convulsive andnonconvulsive status epilepticus may occur. Multiple seizure types oftenoccur in the same patient. Infantile spasms are uncommon. The seizuresmay be difficult to control.

What features are seen in 20%-80% of individuals with Angelman syndrome?

Dysmorphic Features:

Flat occiput, occipital groove, protruding tongue, prognathia, wide mouth, widely spaced teeth

Neurologic features:

Wide-basedgait with ankles in the pronated or valgus position, uplifted, flexedarm position (particularly during ambulation), tongue-thrusting, truncalhypotonia during infancy, excessive chewing/mouthing behaviors,frequent drooling, hyperactive lower extremity deep tendon reflexes

Behavioral Features:

Attractionto or fascination with water, fascination with crinkly items (e.g.,certain papers or plastics), abnormal sleep-wake cycles and diminishedneed for sleep

Feeding and Gastrointestinal Issues:

Feedingproblems during infancy, suck/swallowing disorders, abnormalfood-related behaviors, obesity (in the older child and adult,especially with certain genetic mechanisms), constipation

Other Issues:

Strabismus,refractive errors, scoliosis, increased sensitivity to heat, lighterskin, hair, and eye color than expected for family (in gene deletioncases only)

What are other typical features?

  • Normal prenatal and birth history, normal head circumference at birth, no major birth defects

  • Normal metabolic, hematologic, and chemical laboratory profiles

  • Structurallynormal brain by magnetic resonance imaging (MRI) or computed tomography(CT) (mild cortical atrophy or dysmyelination may be seen)

  • Delayed attainment of milestones, with evidence of developmental delay by age 6-12 months, but no regression

Are there exceptional cases?

Rarely,irritability and hyperactivity are more prominent than the "happy"personality traits. Occasionally, obesity occurs in older children andis fairly common in adults. Mosaicism for the imprinting center defect(one uncommon genetic mechanism) may result in milder speechimpairment.

What other disease/condition shares some of these symptoms?

During infancy, feeding problems, hypotonia, and developmental delay predominate, which overlap nonspecifically with a large number of conditions, including a variety of chromosomal rearrangements and microdeletion syndromes (including deletion 22q13.3, deletion 2q23.1, and others), Rett syndrome due to mutation in the MECP2 gene (in girls), Prader-Willi syndrome, and many others.

In older childhood, the absence of speech, cognitive impairment, and typical appearance and behavior may overlap or have similarities to atypical Rett syndrome caused by MECP2 mutations (or in some boys, duplication), congenital disorders of glycosylation (especially with ataxia), and the microdeletion syndromes noted above.

Seizure disorders (epilepsy) and intellectual disability are often found together, and several single-gene conditions have been suggested to clinically overlap with Angelman syndrome. Christianson syndrome, an X-linked disorder caused by a mutation in the SLC9A6 gene, can have a similar neurologic and behavioral phenotype, although the facial characteristics may help to distinguish it from Angelman syndrome.

The Pitt-Hopkins syndrome, caused by mutations in the TCF4 gene, presents with seizures, hypotonia, intellectual disability, and often constipation. Brain malformations may be seen, which are not typical of Angelman syndrome.

A similar cluster of problems is seen in Mowat-Wilson syndrome (MWS), caused by mutations in ZEB2, with some children having a "happy" personality; severe constipation and often Hirschsprung disease are characteristic of MWS.

α-Thalassemia/mental retardation (the X-linked form, caused by mutations in ATRX, more than the form caused by a contiguous gene deletion on chromosome 16p) also has significant overlap with Angelman syndrome, although, again, the facial appearance can help distinguish the two conditions.

A recently described disorder, intellectual disability, autosomal dominant, type 40, or CHAMP1-related disorder, also shares many features with Angelman syndrome, such as severe speech delay, microcephaly, and gait ataxia.

Several inborn errors of metabolism associated with hypotonia and seizures have rarely been confused with Angelman syndrome, including adenylosuccinate lyase deficiency (a deficiency of purine synthesis) and methylene tetrahydrofolate reductase (MTHFR) deficiency (a defect in homocysteine remethylation that interferes with multiple aspects of one-carbon metabolism).

Many nonspecific seizure disorders have also been confused with Angelman syndrome. When testing for Angelman syndrome produces normal results in a child with seizures, the clinical diagnosis should be reserved for only those with all of the typical findings Even in these cases, consideration would be given to genetic or metabolic testing for disorders with similar presentations.

What caused this disease to develop at this time?

The genetic defect in Angelman syndrome is present from the time of conception. Angelman syndrome usually has one of four genetic causes (in ~10% of cases, the genetic cause cannot be found). All of these genetic mechanisms share loss of activity of the maternally inherited copy of the UBE3A (ubiquitin protein ligase E3A) gene, which is normally the predominant copy expressed in the brain. The four genetic causes follow:

  • Deletion (loss) of a large segment (typically 5-7 Mb) of the long arm of the chromosome 15 inherited from the mother (specifically at 15q11-q13). Other genes may be included in the deleted segment; thus individuals with this mechanism may be more severely affected and may have additional symptoms, such as hypopigmentation at least partially due to loss of the P gene (OCA2). This mechanism accounts for 70%-75% of cases. Rarely (<1% of cases), the deletion is due to a chromosomal rearrangement more complex than the common microdeletion.

  • Paternal uniparental disomy (UPD) of chromosome 15. This accounts for 3%-7% of cases.

  • A defect of the imprinting process (such as a deletion or epigenetic mutation at the imprinting center) that causes the maternally inherited UBE3A gene to be inactive. This accounts for 2%-3% of cases. The imprinting defect can be inherited by the mother, in which case the recurrence risk may be as high as 50%.

  • A mutation within the maternally inherited UBE3A gene. This accounts for approximately 10% of cases.

Genetic testing is available for each of these causes (see below).

Although it is not fully understood why certain features of Angelman syndrome emerge when they do, lack of UBE3A gene expression in the brain during certain critical periods of development may play a role. The UBE3A gene appears to be critical for synapse formation and neural plasticity. The extent to which the neurodevelopmental defects are established from the time of birth, versus the extent to which they may develop later and be potentially amenable to treatment, is unknown.

Symptoms typically emerge as follows:

  • Developmental delay—apparent by 6-12 months of age

  • Seizures, when present—before 3 years of age

  • Electroencephalographic abnormalities, when present—before 2 years of age (rarely, may even be seen before 6 months of age)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

DNA methylation analysis (SNRPN locus) is the first step in the laboratory evaluation of Angelman syndrome and detects approximately 80% of cases. This test is typically performed by methylation-sensitive polymerase chain reaction (PCR) but can also be performed by Southern blotting.

If DNA methylation is abnormal, chromosome analysis and fluorescence in situ hybridization (FISH) evaluation of 15q11.2-q13 will distinguish between a chromosomal rearrangement (typically a deletion) of this region and other causes of abnormal methylation.

Some experts have begun to use array comparative genomic hybridization (CGH; sometimes referred to as a microarray) instead of karyotype and FISH because it can provide additional information on other chromosomal rearrangements. Many specialists evaluate the chromosomes simultaneously with the methylation test because that is an important step in the evaluation of the child with suspected Angelman syndrome, whether or not the methylation is abnormal.

Although the typical deletion causing Angelman syndrome occurs de novo, some experts recommend obtaining a maternal karyotype if the child has a deletion to rule out balanced rearrangements predisposing to the deletion in the child. Although extremely rare, if found, there are significant genetic counseling implications.

If no deletion is found, UPD studies using DNA polymorphisms on chromosome 15 are indicated to detect paternal UPD. This study is most informative using DNA from the affected child and both parents but if necessary can be performed using only one parent's DNA.

Single nucleotide polymorphism (SNP) array can be used to investigate the chromosomes in evaluation of 15q11.2-q13, which may also identify some cases of paternal UPD. However, the SNP array only identifies UPD when the same paternal chromosome is duplicated (isodisomy). It cannot detect heterodisomy, in which the child has inherited one copy of each of the father's two chromosome 15s.

If UPD of chromosome 15 is not found, but the methylation analysis indicates Angelman syndrome, the diagnosis of an imprinting defect is confirmed. In this situation, the chromosome 15 inherited from the mother carries the methylation pattern of a male because the mother's body is unable to complete the reprogramming required before passing on the chromosome 15 she (the mother) inherited from her father.

Evaluation for the specific cause of the imprinting defect includes searching for small deletions of the imprinting center to detect the small proportion of imprinting defects caused by this mechanism (<20%). DNA tests to further investigate imprinting defects not caused by a microdeletion are available on a research basis only and detect epigenetic mutations at the imprinting center.

If DNA methylation is normal, sequencing of the UBE3A gene to detect mutations is indicated. Rarely, deletion/duplication analysis of the UBE3A gene will be needed to detect a deletion of all or part of the UBE3A gene (not routinely performed but clinically available).

The methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test can be used to combine methylation information with dosage testing (the next step when methylation is abnormal).

Although a positive methylation test result confirms the diagnosis of Angelman syndrome approximately 80% of the time, completing the additional testing to identify the specific cause is critical to provide accurate recurrence information to the parents and extended family.

Following this order of testing will reveal the cause of Angelman syndrome in approximately 90% of cases. If comprehensive testing produces normal results, the diagnosis may be established by the clinical criteria given above, but consideration should be given to testing for other genetic disorders with overlapping features. A medical geneticist or genetic counselor can assist in interpreting the results of testing and determining the implications of each type of abnormal result, both for the affected person and for relatives who may be at risk of having a child with Angelman syndrome.

Would imaging studies be helpful? If so, which ones?

MRI of the brain (noncontrast) is recommended as a baseline in individuals with Angelman syndrome, and it may be helpful in ruling out other potential diagnoses. In Angelman syndrome, MRI of the brain is typically normal, although mild atrophy or delayed myelination may be seen. Although somewhat costly, MRI entails no radiation exposure and provides a more detailed and comprehensive view of the brain compared with CT.

Electroencephalography can also be a very useful adjunct when Angelman syndrome is suspected. A baseline EEG is recommended in confirmed cases of Angelman syndrome. One of three abnormal electroencephalographic patterns is seen in more than 80% of individuals with Angelman syndrome, although a normal EEG does not preclude a diagnosis of Angelman syndrome.

Confirming the diagnosis

Once a child is identified as having clinical features consistent with Angelman syndrome (see above), the genetic testing algorithm described above should be used. The clinical criteria for Angelman syndrome were established by consensus of a group of scientists and clinicians with experience in Angelman syndrome. Scientific publications were used to support the group's decisions. The consensus criteria, originally written in 1995, were last revised in 2005 and published the following year.

Because molecular testing can identify the specific cause of Angelman syndrome in the majority of cases, the clinical criteria should be used to help identify appropriate cases for further testing. When testing is unrevealing, the clinical criteria can be used as a diagnostic tool. If the child with negative molecular testing results does not have the full Angelman syndrome phenotype, efforts to investigate other disorders in the differential diagnosis should be undertaken.

The genetic testing strategy follows from these consensus criteria and agrees with the practice guidelines written by Simon C. Ramsden, Ph.D. et al in 2010, which were informed by review of 5 years of external quality assessment returns submitted to the European Molecular Genetics Quality Network and the United Kingdom External Quality Assessment Scheme.

When you have confirmed that the patient has Angelman syndrome, what treatment should be initiated?

When the diagnosis of Angelman syndrome is made, the family should receive information about the diagnosis and its expected neurodevelopmental implications. Genetic counseling should also be provided to parents of the affected child, and possibly to other relatives (depending on the specific genetic mechanism) at risk for having a child with Angelman syndrome.

Long-term management consists of the following:

Seizures:

A baseline EEG should be obtained. Suspected or confirmed seizures should be evaluated and managed by a neurologist/pediatric neurologist or epileptologist. Antiepileptic medication is typically required when seizures are present. Certain antiepileptic drugs (AEDs) have been found by some to be more effective than others in patients with Angelman syndrome. These more effective AEDs include valproic acid, clonazepam, phenobarbital, topiramate, lamotrigine, and ethosuximide. Other AEDs, including carbamazepine, oxcarbazepine, vigabatrin, tigabine, and possibly gabapentin may aggravate seizures in Angelman syndrome. The ketogenic diet has shown promise in a prospective study.

The deficiency of UBE3A protein in Angelman syndrome, as well as the 15q11-q13 deletion seen in many of these patients, may impair GABAergic transmission by the mechanisms outlined below. Care should be taken in the use of valproic acid if the diagnosis is suspected but has not been confirmed by molecular testing, because of the small but serious possibility that there may be an underlying mitochondrial disorder (e.g., POLG1-related disorder) that would predispose to acute hepatic failure when initiating therapy.

Intellectual Disability/ Neurobehavioral Manifestations:

An individualized education plan (IEP) with specific classroom interventions is recommended at school entry. Physical and occupational therapy may be beneficial, depending on the specific motor impairments. Speech/language therapy is critical and should emphasize signing and other nonverbal communication strategies.

GI Manifestations:

Constipation and gastroesophageal reflux disease (GERD) typically respond to standard treatments.

Scoliosis and Orthopedic Complications:

These conditions may require bracing or surgical management.

Strabismus:

Surgical treatment may be required.

Sleep Disruption:

Melatonin may improve sleep in individuals with Angelman Syndrome.

What are the adverse effects associated with each treatment option?

All AEDS have side effects, which vary from person to person. Some AEDs may increase the chance of seizures or encourage other seizure types to develop. They may also trigger nonconvulsive status epilepticus. These drugs include those described above as potentially aggravating.

What are the possible outcomes of Angelman syndrome?

Adults with Angelman syndrome have severe intellectual disability and are not able to live independently. They may live at home or in a group home. Of note, these children and adults generally are curious and socially interactive. They continue to learn in adulthood.

Seizures often improve (or even resolve) in late childhood but then reappear or worsen again in adulthood. Adolescents and adults may have periods of tremor, some of which may represent cortical myoclonus. Chronic problems such as constipation and GERD may persist, and new complications may develop, such as scoliosis. Sleep dysfunction is common and overweight and obesity are seen in about one-third.

Puberty and fertility appear to be normal. Lifespan data are beginning to emerge. Lifespan is generally normal or near normal for individuals with Angelman syndrome who are in generally good general health. Several of the manifestations of the disorder, especially seizures and intellectual disability, are associated with modestly increased morbidity and mortality, with death occurring prematurely secondary to drowning, choking, respiratory infection, or in the context of a seizure.

Although all antiepileptic drugs have side effects, if seizures are persistent, treatment is usually recommended to reduce the risk of mortality from uncontrolled epilepsy.

What causes this disease and how frequent is it?

Angelman syndrome occurs in approximately 1 in 12,000 to 1 in 24,000 individuals, affecting an equal number of females and males.

A variety of molecular mechanisms have been identified; however, the central problem in Angelman syndrome is lack of UBE3A gene expression in the brain, in which the maternally inherited copy of this gene is predominantly expressed in certain cells.

As described above in the discussion of testing strategy, absence of the maternally contributed chromosome 15 can occur by a number of mechanisms, including maternal deletion, paternal UPD, or defects in switching the methylation pattern when the mother passes on the copy of chromosome 15 she inherited from her father. Several references in the bibliography have extensive discussions of these mechanisms.

Microdeletions in this region involving the chromosome 15 inherited from the mother cause Angelman syndrome, but those involving the chromosome 15 inherited from the father cause Prader-Willi syndrome, which is caused by lack of expression of other genes in this region and is not related to UBE3A expression. Microdeletions arise at a high rate in this region of chromosome 15 because it is flanked by long stretches of DNA that became duplicated during evolution, leading to the increased potential for misalignment during meiosis, leading to microdeletion and microduplication.

UPD in Angelman syndrome most likely results from fertilization of an ovum that is lacking chromosome 15 (nullisomy). The resulting embryo will not survive unless there is a second error, in this case a mitotic duplication of the paternally inherited chromosome 15. When this occurs in a totipotent cell soon after fertilization, "rescue" from the monosomy 15 results in the entire embryo deriving from the daughters of the cell that underwent the corrective action.

How do these pathogens/genes/exposures cause the disease?

The UBE3A gene produces the protein UBE3A, also called E6AP. This ligase attaches ubiquitin to selected brain proteins to mark them for degradation by the proteosome. This system of protein degradation and replacement is critical for multiple aspects of cellular functioning. Decreased UBE3A protein appears to lead to impaired regulation of synaptic plasticity and dendrite growth. It does this via multiple interactions and mechanisms.

The mechanisms by which deficiency of UBE3A causes the features of Angelman syndrome are beginning to be elucidated:

One of the proteins that UBE3A helps mark for degradation is a synaptic protein called Arc. In animal models, when Arc is not degraded, AMPA receptors are internalized by the synaptic membrane, and fewer AMPA receptors are available for glutaminergic synaptic transmission. This would be expected to impair cognition.

The relationship between GABAA receptor dysregulation and epilepsy and its treatment in Angelman syndrome is an active area of investigation. Individuals with Angelman syndrome caused by a deletion of 15q11-q13 may have a deletion of genes encoding 3 subunits of the GABAA receptor complex, altering GABAergic neurotransmission.

UBE3A appears to have other roles as well. These mechanisms, as well as other potential contributors to the features of Angelman syndrome, are an active area of research.

Other clinical manifestations that might help with diagnosis and management

Two specific clinical findings are highly suggestive of Angelman syndrome in the appropriate clinical setting. The first is an excessive and almost compulsive pleasure in playing with water. Parents may spontaneously describe the child learning to turn on the bathtub faucet or playing in the toilet bowl.

The second is a fairly specific laughing response, induced by striking a tuning fork that is held out of sight but within hearing range of the child with Angelman syndrome. Clinical studies have demonstrated that both of these phenomena are accurate predictors of Angelman syndrome, although neither has been suggested to have the sensitivity or specificity to replace molecular testing.

What complications might you expect from the disease or treatment of the disease?

Individuals with Angelman syndrome caused by UPD or imprinting defects may become obese, especially if inactive, whereas those with chromosomal deletion have a tendency to be underweight.

All AEDs have side effects, which vary from person to person. Because the EEG may be persistently abnormal even when seizures are well controlled, and abnormal movements can resemble seizures, individuals with Angelman syndrome are at risk for excessive treatment with AEDs.

Other complications include scoliosis (especially after puberty), other orthopedic problems, strabismus, GERD, constipation, disrupted nighttime sleep and hyperactivity.

Are additional laboratory studies available; even some that are not widely available?

Testing is available on a research basis to detect epigenetic mutations at the imprinting center. This is indicated only when methylation testing is abnormal but no other cause of abnormal methylation has been found. Refer to the genetic testing algorithm above.

How can Angelman syndrome be prevented?

Genetic counseling should be made available to individuals at risk of having a child with Angelman syndrome. The recurrence risk to siblings of an affected child depends on the genetic mechanism involved and ranges from less than 1% (several genetic mechanisms) to approaching 100% (paternal UPD15 with 15;15 robertsonian translocation, an unusual cause).

In cases in which the genetic defect is demonstrated to have occurred de novo in the affected person, the risk of recurrence is less than 1% but not zero because of the possibility of germ cell mosaicism. The common 15q11-q13 deletion usually occurs de novo in affected individuals.

In cases caused by maternal UBE3A mutations or imprinting defects, which have a recurrence risk up to 50%, other maternal relatives may be at risk of having a child with Angelman syndrome.

Of note, girls with Prader-Willi syndrome caused by a deletion of 15q11-q13 are at risk of having a child with Angelman syndrome if they reproduce. Girls with Angelman syndrome may be at risk of having a child with Angelman syndrome depending on the genetic mechanism of their Angelman syndrome. A male with Angelman syndrome caused by a deletion would be predicted to have a 50% chance of having a child with Prader-Willi syndrome (due to paternally inherited deletion of chromosome 15), although male fertility has not been described to date.

Prenatal testing with amniocentesis is available when the underlying genetic defect in the proband is known. Chorionic villus sampling (CVS) does not provide the preferred cells for methylation testing, although other genetic testing described above may be performed. Preimplantation genetic diagnosis is available in cases of known imprinting center deletions or UBE3A mutations in a family.

What is the evidence?

Bird, L. "Angelman syndrome: review of clinical and molecular aspects". Appl Clin Genet. vol. 7. 2014. pp. 93-104.

(An updated comprehensive review of both the clinical and pathophysiologic aspects of Angelman syndrome.)

Boyd, SG, Harden, A, Patton, MA. "The EEG in early diagnosis of Angelman syndrome". Eur J Pediatr . vol. 147. 1988. pp. 508-13.

(The original description of EEG abnormalities in Angelman syndrome; 19 children studied.)

Braam, W. "Melatonin for chronic insomnia in Angelman syndrome: a randomized placebo-controlled trial". J Child Neurol. . vol. 23. 2008. pp. 649-54.

(Evidence and author's dosing recommendations for melatonin for insomnia in Angelman syndrome.)

Dagli, A, Buiting, K, Williams, CA. "Molecular and clinical aspects of Angelman syndrome". Mol Syndromol. vol. 2. 2012 Apr. pp. 100-112.

Another comprehensive review, includes detailed discussions of natural history and lifespan, and of differential diagnosis

Dagli, AI, Mueller, J, Williams, CA, Pagon, RA, Bird, TD, Dolan, CR. "GeneReviews [Internet]". University of Washington, Seattle. 1993-. Updated May 14, 2015. http://www.ncbi.nlm.nih.gov/books/NBK1144/.

(A comprehensive review of Angelman syndrome, including the authors' recommended diagnostic algorithm.)

Galvan-Manso, M, Campistol, J, Conill, J. "Analysis of the characteristics of epilepsy in 37 patients with the molecular diagnosis of Angelman syndrome". Epileptic Disord . vol. 7. 2005. pp. 19-25.

(The medical histories of 37 patients with molecularly confirmed Angelman syndrome (all with abnormal methylation) were reviewed, regarding the features and course of epilepsy, response to treatment, and electroencephalographic findings.)

Goto, M. " Episodic tremors representing cortical myoclonus are characteristic in Angelman syndrome due to UBE3A mutations". Brain Dev. 2014; May 2.

(A study of tremor in Angelman syndrome and a discussion of its pathophysiology.)

Greer, PL, Hanayama, R, Bloodgood, BL. "The Angelman-syndrome associated ubiquitin ligase UBE3A regulates synapse development by ubiquinating Arc". Cell . vol. 140. 2010. pp. 704-16.

(A report of mouse model findings regarding the mechanisms by which deficient UBE3A expression leads to decreased AMPA receptor quantity at synapses.)

Hall, BD. "Adjunct diagnostic test for Angelman syndrome: the tuning fork response". Am J Med Genet . vol. 109. 2002. pp. 238-40.

(A report of 6 children and adults with molecularly confirmed Angelman syndrome (deletion mechanism), comparing their responses to a vibrating tuning fork held up to the ear with the responses of individuals with other neurodevelopmental disorders.)

Harting, I, Seitz, A, Rating, D. "Abnormal myelination in Angelman syndrome". Eur J Paediatr Neurol . vol. 13. 2009. pp. 271-6.

(A report of MRI findings in 9 patients with Angelman syndrome imaged between 7.5 months and 5 years of age.)

Hempel, M, Cremer, K, Ockeloen, CW. "De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment". Am J Hum Genet . vol. 97. 2015. pp. 493-500.

(The first publication describing a series of patients with CHAMP1-related disorder, which has similar features to those of Angelman syndrome. This is an example of why clinicians should consider additional genetic testing for individuals whose clinical diagnosis of Angelman syndrome cannot be molecularly confirmed.)

Huang, H-S. "Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons". Nature . vol. 481. 2011. pp. 185-9.

(Drugs to allow expression of the silenced paternal copy of the UBE3A gene have been suggested as an avenue to a disease-specific treatment.)

Laan, LEM, Vein, AA. "Angelman syndrome: is there a characteristic EEG?". Brain Dev . vol. 27. 2005. pp. 80-7.

(A review of the encephalographic findings in Angelman syndrome, commenting on the utility of electroencephalography in the diagnosis of Angelman syndrome.)

Larson, AM, Shinnick, JE, Shaaya, EA, Thiele, EA, Thibert, RL. "Angelman syndrome in adulthood". Am J Med Genet A. vol. 167A. 2015. pp. 331-44.

(Describes the clinical picture of Angelman syndrome in adulthood based on interviews with the caregivers of 110 adolescents and adults with Angelman syndrome.)

Lossie, AC, Whitney, MM, Amidon, D. "Distinct phenotypes distinguish the molecular classes of Angelman syndrome". J Med Genet. vol. 38. 2001. pp. 834-45.

(A study of natural history and genotype-phenotype correlation in 104 individuals with Angelman syndrome from 93 families. Subjects represented all four molecular classes of Angelman syndrome, as well as those with a clinical diagnosis of Angelman syndrome of unknown etiology.)

Margolis, S. "EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation". Cell. . vol. 143. 2010. pp. 442-55.

(The role of Ephexin 5 in the pathophysiology of Angelman syndrome.)

Meng, L, Ward, AJ2, Chun, S2. "Towards a therapy for Angelman syndrome by targeting a long non-coding RNA". Nature. vol. 518. 2015 Feb 19. pp. 409-12.

(Discusses the potential use of antisense oligonucleotides targeted at the the non-coding RNA that silences the paternal copy of UBE3A in an attempt express the paternal copy.)

Nazlican, H, Zeschnigk, M, Claussen, U. "Somatic mosaicism in patients with Angelman syndrome and an imprinting defect". Hum Mol Genet . vol. 13. 2004. pp. 2547-55.

(Analysis of somatic mosaicism in patients with Angelman syndrome due to imprinting center defects without deletion of the imprinting center; clinical data presented for 19 patients.)

Pelc, K, Boyd, SG, Cheron, G. " Epilepsy in Angelman syndrome". Seizure . vol. 17. 2008. pp. 211-7.

(A review of epilepsy in Angelman syndrome, including a discussion of natural history and treatment options based on review of the literature.)

Ramsden, SC, Clayton-Smith, J, Birch, R. "Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes". BMC Med Genet. vol. 11. 2010. pp. 70.

(Practice guidelines for Angelman syndrome diagnostic testing, approved by the UK Clinical Molecular Genetics Society and European Molecular Genetics Quality Network. The guidelines were informed by review of 5 years of external quality assessment returns submitted to the European Molecular Genetics Quality Network and United Kingdom External Quality Assessment Scheme.)

Roden, WH, Peugh, LD, Jansen, LA. "Altered GABA(A) receptor subunit expression and pharmacology in human Angelman syndrome cortex". Neurosci Lett. vol. 483. 2010 Oct 15. pp. 167-72.

(Evidence for the role of GABA(A) receptor dysregulation in Angelman syndrome, and potential relevance for seizures and their treatment.)

Tan, W-H, Bacino, CA, Skinner, SA. "Angelman syndrome: mutations influence features in early childhood". Am J Med Genet A . vol. 155A. 2011. pp. 81-90.

(A presentation of the baseline data from the Angelman Syndrome Natural History Study, a 5-year multicenter longitudinal study, including information about the prevalence of dysmorphic features in Angelman syndrome.)

Tan, W-H, Bird, LM, Thibert, RL, Williams, CA. "If not Angelman, what is it? A review of Angelman-like syndromes". Am J Med Genet Part A . vol. 164A. 2014. pp. 975-992.

(A thorough discussion of differential diagnosis.)

Thibert, RL, Conant, KD, Braun, EK. "Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options". Epilepsia . vol. 50. 2009. pp. 2369-76.

(A study of epilepsy natural history and treatment response using a detailed electronic survey conducted through the Angelman Syndrome Foundation. Responses were obtained from 461 family members of individuals with Angelman syndrome, 86% of whom had epilepsy, constituting the largest study to date of epilepsy in Angelman syndrome.)

Thibert, RL, Pfeifer, HH, Larson, AM. "Low glycemic index treatment for seizures in Angelman syndrome". Epilepsia. vol. 53. 2012 Sep. pp. 1498-502.

(A prospective study of the ketogenic diet in Angelman syndrome. The diet was generally very effective in controlling seizures in this small cohort, actually showing better efficacy than in the general population of individuals with epilepsy.)

Williams, CA, Beaudet, AL, Clayton-Smith, J. " Angelman syndrome 2005: updated consensus for diagnostic criteria". Am J Med Genet . vol. 140A. 2006. pp. 413-8.

(This publication revises the 1995 consensus criteria for the diagnosis of Angelman syndrome. There is no scoring system, but these features can guide diagnosis.)

Williams, CA. "The behavioral phenotype of Angelman syndrome". Am J Med Genet C Semin Med Genet . vol. 154C. 2010. pp. 432-7.

(A review of typical and atypical behavioral features in Angelman syndrome.)

Williams, CA, Lossie, A, Driscoll, D. "R.C. Philips Unit. Angelman syndrome: mimicking conditions and phenotypes". Am J Med Genet . vol. 101. 2001. pp. 59-64.

(A discussion of mimicking conditions encountered at a large referral center for Angelman syndrome, as well as those reported in the literature.)

Valente, KD, Koiffman, CP, Fridman, C. "Epilepsy in patients with Angelman syndrome caused by deletion of the chromosome 15q11-13". Arch Neurol . vol. 63. 2006. pp. 122-8.

(A study of epilepsy severity, epilepsy evolution, and response to antiepileptic drug treatment based on parent and caregiver interview and medical record review in 19 patients with this deletion.)
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