| Angelman Syndrome Classification and external resources |
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| ICD-10 | Q93.5 |
|---|---|
| ICD-9 | 759.89 |
| OMIM | 105830 |
| DiseasesDB | 712 |
| MeSH | D017204 |
Angelman syndrome (AS) is a neuro-genetic disorder named after a British pediatrician, Dr. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings Q00-Q89 - Congenital malformations and deformations (Q00-Q07 Nervous system ( Anencephaly and similar malformations The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases 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 The Diseases Database 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 A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired Pediatrics (also spelled paediatrics) is the branch of Medicine that deals with the medical care of Infants Children and Adolescents Harry Angelman, who first described the syndrome in 1965. In Medicine and Psychology, the term syndrome refers to the association of several clinically recognizable features signs (observed by a physician [1] AS is characterized by intellectual and developmental delay, speech impediment, sleep disturbance, unstable jerky gait, seizures, hand flapping movements, frequent laughter/smiling and usually a happy demeanour. Developmental disability is a term used to describe life-long disabilities attributable to mental and/or physical or combination of mental and physical impairments An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting AS is a classic example of genetic imprinting caused by deletion or inactivation of critical genes on the maternally inherited chromosome 15. Genomic imprinting is a genetic phenomenon by which certain Genes are expressed in a Parent -of-origin-specific manner Chromosome 15 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome The sister syndrome is called Prader-Willi syndrome, and is caused by loss of paternal imprinting pattern on paternally-inherited alleles. Prader-Willi syndrome (abbreviated PWS) is a very rare Genetic disorder, in which seven genes (or some subset thereof on chromosome 15 are missing or unexpressed Usually this is determined by maternal genes.
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. heuristic (hyu̇-ˈris-tik is a method to help solve a problem commonly an informal method
Contents |
History
Dr. Harry Angelman, a pediatrician working in Warrington (then in Lancashire) first reported three children with this condition in 1965. Warrington is a large town borough and Unitary authority area in Cheshire, England. Lancashire is a non-metropolitan county of historic origin in the North West of England, bounded to the west by the Irish Sea [1] He titled the paper "Puppet Children" and later explained that this was because of an oil paiting he had seen:
- "I happened to see an oil painting. . . called. . . "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]
The condition was initially incorrectly presumed to be rare.
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 People normally have two copies of this chromosome
Prevalence
Though the prevalence 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 1/20,000[2] and the Danish study showed a minimum AS prevalence of about 1/10,000. 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 [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.
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. 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 In Genetics, a chromosome translocation is a Chromosome abnormality caused by rearrangement of parts between nonhomologous Chromosomes. A healthy person receives two copies of chromosome 15, one from the mother, the other from the 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. Genomic imprinting is a genetic phenomenon by which certain Genes are expressed in a Parent -of-origin-specific manner DNA methylation is a type of chemical modification of DNA that can be inherited and subsequently removed without changing the original DNA sequence In a normal individual, the maternal allele is expressed and the paternal allele is silenced. 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. Prader-Willi syndrome (abbreviated PWS) is a very rare Genetic disorder, in which seven genes (or some subset thereof on chromosome 15 are missing or unexpressed ) Please note that the methylation test that is performed for Angelman syndrome (a defect in UBE3A) is actually looking for the gene's neighbour SNRPN (which has the opposite pattern of methylation). Small nuclear ribonucleoprotein polypeptide N, also known as SNRPN, is a human Gene. [4]
Angelman syndrome can also be the result of mutation of a single gene. This gene (UBE3A,[5] part of the ubiquitin pathway) is present on both the maternal and paternal chromosomes, but differs in the pattern of methylation (Imprinting). UBE3A is a Human Gene that provides instructions for making the Enzyme Ubiquitin protein ligase E3A. Ubiquitin is a highly-conserved regulatory Protein that is ''ubiquitously'' expressed 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 a genetic phenomenon by which certain Genes are expressed in a Parent -of-origin-specific manner 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 hippocampus is a part of the Forebrain, located in the medial Temporal lobe. The cerebellum ( Latin: "little brain" is a region of the Brain that plays an important role in the integration of sensory perception 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. A ubiquitin ligase (also called an E3 ubiquitin ligase is a Protein that covalently attaches Ubiquitin to a Lysine on a target protein via an Isopeptide
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. Fear conditioning is the method by which organisms learn to fear new stimuli In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a-/- mice. In Neuroscience, synaptic plasticity is the ability of the connection or Synapse, between two Neurons to change in strength. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vitro, and the molecular pathology of Angelman syndrome. 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. Hyperactivity can be described as a physical state in which a person is abnormally and easily excitable or exuberant Epilepsy is a common chronic Neurological disorder that is characterized by recurrent unprovoked seizures.
- 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
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. Strabismus (from Greek: στραβισμός strabismos, from στραβίζειν strabizein "to squint" from στραβός strabos Scoliosis is a medical condition in which a person's spine is curved from side to side and may also be rotated
- 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, which first defined criteria for diagnosis in 1995[6], has been updated in 2005. [7]
Treatment
Because Angelman syndrome is not an illness, but a genetic condition, there is no currently available cure. 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, often abbreviated "OT", is the "use of productive or creative activity in the treatment or rehabilitation of physically cognitively or Speech-language pathology is the study of disorders that affect a person's Speech, Language, cognition voice swallowing ( Dysphagia) and the rehabilitative Hydrotherapy, formerly called hydropathy involves the use of Water for soothing pains and treating diseases Music therapy is an interpersonal process in which the therapist uses music and all of its facets&mdashphysical emotional mental social aesthetic and spiritual&mdashto help clients to improve
Living with Angelman syndrome
Although a diagnosis of AS is life changing, it does not need to 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. [8]
Actor Colin Farrell and professional hockey player Peter McDuffe both have sons with AS.
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. History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance
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. See also "Mensuration" a term sometimes used to describe Measurement, particularly in the context of Forestry. 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. Sexual development is the process by which an immature and sterile organism develops the capacity to reproduce [9]
The majority of those with AS achieve continence by day and some by night.
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[10] if it is present. Scoliosis is a medical condition in which a person's spine is curved from side to side and may also be rotated 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
References
- ^ a b c Angelman's syndrome at Who Named It
- ^ Steffenburg S, Gillberg CL, Steffenburg U, Kyllerman M (1996). In Biology, the term epigenetics refers to changes in Gene expression caused by mechanisms other than changes in the underlying DNA sequence Prader-Willi syndrome (abbreviated PWS) is a very rare Genetic disorder, in which seven genes (or some subset thereof on chromosome 15 are missing or unexpressed Who Named It? is an English-language dictionary of medical eponyms and the People associated with their identification "Autism in Angelman syndrome: a population-based study". Pediatr. Neurol. 14 (2): 131-6. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 8703225.
- ^ Petersen MB, Brøndum-Nielsen K, Hansen LK, Wulff K (1995). "Clinical, cytogenetic, and molecular diagnosis of Angelman syndrome: estimated prevalence rate in a Danish county; the disorder predominantly affects Anglo-Saxons. ". Am. J. Med. Genet. 60 (3): 261-2. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 7573182.
- ^ White HE, Durston VJ, Harvey JF, Cross NC (2006). "Quantitative analysis of SNRPN(correction of SRNPN) gene methylation by pyrosequencing as a diagnostic test for Prader-Willi syndrome and Angelman syndrome". Clin. Chem. 52 (6): 1005-13. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16574761.
- ^ Weeber E, Levenson J, Sweatt J (2002). "Molecular genetics of human cognition. ". Mol Interv 2 (6): 376-91, 339. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14993414.
- ^ Williams CA, Angelman H, Clayton-Smith J, et al (1995). "Angelman syndrome: consensus for diagnostic criteria. Angelman Syndrome Foundation". Am. J. Med. Genet. 56 (2): 237-8. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 7625452.
- ^ Williams CA, Beaudet AL, Clayton-Smith J, et al (2006). "Angelman syndrome 2005: updated consensus for diagnostic criteria". Am. J. Med. Genet. A 140 (5): 413-8. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16470747.
- ^ Andersen WH, Rasmussen RK, Strømme P (2001). "Levels of cognitive and linguistic development in Angelman syndrome: a study of 20 children". Logopedics, phoniatrics, vocology 26 (1): 2-9. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 11432411.
- ^ Lossie A, Driscoll D. "Transmission of Angelman syndrome by an affected mother. ". Genet Med 1 (6): 262-6. PMID 11258627.
- ^ Laan LA, den Boer AT, Hennekam RC, Renier WO, Brouwer OF (1996). "Angelman syndrome in adulthood". Am. J. Med. Genet. 66 (3): 356-60. doi:. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 9072912.
External links
- Angelman syndrome at the Open Directory Project
- Angelman Syndrome at NIH/UW GeneTests
- Angelman Syndrome Foundation USA
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