Angelman syndrome (AS) is a rare neuro-genetic disorder named after a British pediatrician, Dr. Harry Angelman, who first described the syndrome in 1965.^[1] AS is characterised by intellectual and developmental delay, speech impediment, sleep disturbance, unstable jerky gait, seizures, hand flapping movements, frequent laughter/smiling and usually a happy demeanour. AS is a classic example of genetic imprinting caused by deletion or inactivation of critical genes on the maternally inherited chromosome 15. The sister syndrome is called Prader-Willi syndrome, and is caused by loss of paternal genes. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) is a coding of diseases and signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or diseases, as classified by the World Health Organization (WHO). ... // Q00-Q99 - Congenital malformations, deformations and chromosomal abnormalities (Q00-Q07) Congenital malformations of the nervous system (Q00) Anencephaly and similar malformations (Q01) Encephalocele (Q02) Microcephaly (Q03) Congenital hydrocephalus (Q04) Other congenital malformations of brain (Q05) Spina bifida (Q06) Other congenital malformations of spinal cord (Q07) Other congenital malformations of nervous... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... A genetic disorder is a condition caused by abnormalities in genes or chromosomes. ... Pediatrics (also spelled paediatrics or pædiatrics) is the branch of medicine that deals with the medical care of infants and children. ... In medicine, the term syndrome is the association of several clinically recognizable features, signs, symptoms, phenomena or characteristics which often occur together, so that the presence of one feature alerts the physician to the presence of the others. ... Mental retardation (abbreviated as MR), is a term for a pattern of persistently slow learning of basic motor and language skills (milestones) during childhood, and a significantly below-normal intellectual capacity as an adult. ... This article is about the medical condition. ... Genomic imprinting is the phenomenon whereby a small subset of all the genes in the genome are expressed according to their parent of origin. ... Chromosome 15 is one of the 23 pairs of chromosomes in humans. ... Prader-Willi syndrome (abbreviated PWS) is a genetic disorder, in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion) on the paternal chromosome. ...

An older, alternative term for AS, happy puppet syndrome, is generally considered pejorative and stigmatizing so it is no longer used, though it remains useful as a diagnostic heuristic. For other uses, see Heuristic (disambiguation). ...

History

Dr. Angelman stated this painting led him to write his seminal paper in 1965 - "I happened to see an oil painting...called... "a Boy with a Puppet". The boy's laughing face and the fact that my patients exhibited jerky movements gave me the idea of writing an article about the three children with a title of Puppet Children."^[1]

Dr. Harry Angelman, a pediatrician working in Warrington (then in Lancashire) first reported three children with this condition in 1965.^[1] It was initially incorrectly presumed to be rare. Image File history File links No higher resolution available. ... Image File history File links No higher resolution available. ... This article is about the Borough in the north-west of England. ... Lancashire is a non-metropolitan county of historic origin in the North West of England, bounded to the west by the Irish Sea. ...

In 1987, it was first noted that around half of the children with Angelman syndrome have a small piece of chromosome 15 missing (chromosome 15q partial deletion). Chromosome 15 is one of the 23 pairs of chromosomes in humans. ...

Prevalence

Though the prevalance of Angelman syndrome is not precisely known, there are some estimates. The best data available is from studies of school age children, ages 6-13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8 year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/12,000^[2] and the Danish study showed a minimum AS prevalence of about 1/10,000.^[3] Note that it is desirable to use the term prevalence, since estimates of AS diagnosis have been made in relatively small cohorts of children over various periods of time. In epidemiology, the prevalence of a disease in a statistical population is defined as the total number of cases of the disease in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population. ... A cohort was a sub-division of the Roman infantry, originally of a Roman legion, consisting of 480 men, itself divided in 6 centurias commanded each by a centurion. ...

Pathophysiology

Angelman syndrome is caused by the loss of the normal maternal contribution to a region of chromosome 15, most commonly by deletion of a segment of that chromosome. Other causes include uniparental disomy, translocation, or single gene mutation in that region. A healthy person receives two copies of chromosome 15, one from mother, the other from father. However, in the region of the chromosome that is critical for Angelman syndrome, the maternal and paternal contribution express certain genes very differently. This is due to sex-related epigenetic imprinting; the biochemical mechanism is DNA methylation. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (When the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.) Image File history File links Angelman. ... Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. ... Chromosomal translocation of the 4th and 20th chromosome. ... Genomic imprinting is the phenomenon whereby a small subset of all the genes in the genome are expressed according to their parent of origin. ... DNA methylation is a type of chemical modification of DNA that can be inherited without changing the DNA sequence. ... Prader-Willi syndrome (abbreviated PWS) is a genetic disorder, in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion) on the paternal chromosome. ...

Angelman syndrome can also be the result of mutation of a single gene. This gene (Ube3a,^[4] part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (Imprinting). The paternal silencing of the Ube3a gene occurs in a brain region-specific manner; the maternal allele is active almost exclusively in the hippocampus and cerebellum. The most common genetic defect leading to Angelman syndrome is an ~4Mb (mega base) maternal deletion in chromosomal region 15q11-13 causing an absence of Ube3a expression in the maternally imprinted brain regions. Ube3a codes for an E6-AP ubiquitin ligase, which chooses its substrates very selectively and the four identified E6-AP substrates have shed little light on the possible molecular mechanisms underlying the human Angelman syndrome mental retardation state. UBE3A is a human gene that provides instructions for making the enzyme ubiquitin protein ligase E3A. This enzyme is involved in targeting other proteins to be broken down (degraded) within cells. ... Ubiquitin is a very conserved small regulatory protein that is ubiquitous in eukaryotes. ... Methylation is a term used in the chemical sciences to denote the attachment or substitution of a methyl group on various substrates. ... Genomic imprinting is the phenomenon whereby a small subset of all the genes in the genome are expressed according to their parent of origin. ... For other uses, see Hippocampus (disambiguation). ... The cerebellum (Latin: little brain) is a region of the brain that plays an important role in the integration of sensory perception and motor output. ... A Ubiquitin ligase is a protein which covalently attaches ubiquitin to a lysine residue on a target protein. ...

Initial studies of mice that do not express maternal Ube3a show severe impairments in hippocampal memory formation. Most notably, there is a deficit in a learning paradigm that involves hippocampus-dependent contextual fear conditioning. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a^-/- mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vitro, and the molecular pathology of Angelman syndrome. Fear conditioning is the method by which organisms learn to fear new stimuli. ... In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength. ... In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength. ...

Features

• Feeding problems during infancy (poor suck and poor weight gain) in 75%
• Delay in sitting and walking
• Absent or little speech (not in all cases - some children have a vocabulary of up to 50 words)
• Receptive and non-verbal communication skills higher than verbal ones
• Poor attention span and hyperactivity
• Severe learning disabilities
• Epilepsy (80%) and an abnormal EEG
• Unusual movements (fine tremors, hand flapping, jerking movements)
• Affectionate nature and frequent laughter
• Wide-based stiff-legged gait, with tendency to hold arms up and flexed while walking.
• Below average head size, often with flattening at the back
• Subtle, but sometimes characteristic facial features (wide mouth, widely spaced teeth, prominent chin, tendency to tongue thrust)
• Poor sleeping pattern
• Strabismus (Squint - crossed eye/s) in 40%
• Scoliosis (abnormal curvature of the spine) in 10%
• Increased sensitivity to heat
• Attraction to/fascination with water

Hyperactivity can be described as a state in which a person is abnormally easily excitable and exuberant. ... Strabismus (from Greek: στραβισμός strabismos, from στραβίζειν strabizein to squint, from στραβός strabos squinting, squint-eyed[1]) is a condition in which the eyes are not properly aligned with each other. ...

Diagnosis

The diagnosis of Angelman syndrome is based on:

• A history of delayed motor milestones and then later a delay in general development, especially of speech
• Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-legged gait.
• Characteristic facial appearance (but not in all cases).
• A history of epilepsy and an abnormal EEG tracing.
• A happy disposition with frequent laughter
• A deletion on chromosome 15

The Angelman Syndrome Foundation defined criteria for diagnosis in 1995,^[5], and updated these criteria in 2005.^[6] EEG can mean: Electroencephalography - the method and science of recording and interpreting traces of brain electrical activity as recorded from the skull surface or the device used to record such traces Emperor Entertainment Group - A Hong Kong entertainment company. ...

Treatment

Because Angelman Syndrome is not an illness, but a genetic condition, there is no currently available cure for AS. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because AS is usually associated with having multiple varieties of seizures, rather than just the one as is normal cases of epilepsy. Many families use melatonin to promote sleep in a condition which often affects sleep patterns. Many individuals with Angelman Syndrome sleep for a maximum of 5 hours at any one time. Mild laxatives are also used frequently to encourage regular bowel movements and early intervention with physiotherapy is important to encourage joint mobility and prevent stiffening of the joints. Occupational therapy, speech therapy, hydrotherapy and music therapy are also used in the management of this condition. Occupational therapy refers to the use of meaningful occupation to assist people who have difficulty in achieving healthy and balanced life; and to enable an inclusive society so that all people can participate to their potential in daily occupations of life. ... It has been suggested that Speech-Language Pathology, Speech pathology, Phoniatrics be merged into this article or section. ... For hydrotherapy in dogs, see Canine hydrotherapy. ... Music therapy is the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship by a qualified professional who has completed an approved music therapy program. ...

Living with Angelman syndrome

Although a diagnosis of AS is life changing, it needn't be life destroying. Individuals with Angelman Syndrome are generally happy and contented individuals, who like human contact and play. AS individuals exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as an AS child develops, there is a definite character and ability to make themselves understood. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most afflicted individuals will not develop more than 5-10 words, if at all.^[7]

Prognosis

Note that the severity of the symptoms associated with AS varies significantly across the population of affected persons. Some speech and a greater degree of self-care are possible among the least profoundly affected. Unfortunately, walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to improve significantly the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected. UBE3A is a human gene that provides instructions for making the enzyme ubiquitin protein ligase E3A. This enzyme is involved in targeting other proteins to be broken down (degraded) within cells. ... For other uses, see Gene (disambiguation). ...

The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile in order to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent AS girls but do not seem to affect long-term health.

The facial features remain recognizable but many adults with AS look remarkably youthful for their age.

Puberty and menstruation begin at around the normal time. Sexual development is thought to be normal, as evidenced by a single reported case of a woman with Angelman syndrome conceiving a female child who also had Angelman syndrome. ^[8] Puberty refers to the process of physical changes by which a childs body becomes an adult body capable of reproduction. ... Not to be confused with Mensuration. ... Human sexuality is the expression of sexual feelings. ...

The majority of those with AS achieve continence by day and some by night. Continence is the opposite of incontinence, and can mean: sexual continence urinary continence This is a disambiguation page — a navigational aid which lists pages that might otherwise share the same title. ...

Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults are able to eat with a knife or spoon and fork and can learn to perform simple household tasks. General health is fairly good and life-span near normal. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis^[9] if it is present. The affectionate nature which is also a positive aspect in the younger children may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable.

See also

• Epigenetics

Epigenetics is a term in biology used today to refer to features such as chromatin and DNA modifications that are stable over rounds of cell division but do not involve changes in the underlying DNA sequence of the organism. ...

References

Who Named It is a Norwegian database of several thousand eponymous medical signs and the doctors associated with their identification. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ...

External links

• Angelman syndrome at the Open Directory Project
• Angelman Syndrome at NIH/UW GeneTests

The Open Directory Project (ODP), also known as dmoz (from , its original domain name), is a multilingual open content directory of World Wide Web links owned by Netscape that is constructed and maintained by a community of volunteer editors. ... National Institutes of Health Building 50 at NIH Clinical Center - Building 10 The National Institutes of Health (NIH) is an agency of the United States Department of Health and Human Services and is the primary agency of the United States government responsible for biomedical research. ... The University of Washington, founded in 1861, is a public research university in Seattle, Washington. ...