Angelman syndrome is a rare genetic and neurological disorder characterised by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioural pattern characterised by a happy nature and unprovoked episodes of laughter and smiling as reult it is also known as “happy puppet syndrome”
The characteristic findings of Angelman syndrome are not usually apparent at birth and diagnosis of the disorder is usually made between 1 and 4 years of age.
It affects males and females in equal numbers and is usually only recognised when the child is six to 12 months old.
Cause
Deletion or abnormal expression of the UBE3A gene (involve absence of the gene, changes in the structure of the gene, or changes in the function or expression of the gene)
UBE3A gene is unique in that only the mother’s contribution is active in the brain; the fathers are not. As such, if the maternal gene is missing or damaged, there will be no working copy of the UBE3A gene in the brain. If this happens, Angelman syndrome will invariably occur.
The gene is located in chromosome region 15 (15q11-q13).
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 15q11-q13” refers to bands 11-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Most cases of Angelman syndrome, these genetic changes appear to occur randomly (sporadically) but in about 3-5% they can be inherited.
In approximately 70-75 percent of cases there is a microdeletion of region 15q11-13 of the maternally-derived chromosome 15 that includes deletion of the UBE3A gene.
This deletion usually occurs sporadically (de novo) and is not inherited.
The risk of recurrence for the deletion in a family is estimated to be 1-2 percent or less.
In about 1 percent of cases, a deletion of this chromosomal region may occur due to a complex chromosomal rearrangement, in which a segment of chromosome 15 breaks off and moves to another chromosomal location.
Those with this type of mechanism for the deletion are at a greater risk for recurrence.
A unique genetic phenomenon associated with Angelman syndrome is “imprinting.” Everyone has two copies of every gene (except for genes on the Y chromosome): one received from the father and the other from the mother. In most cases both genes are turned on and are thus active. However, in some cases, one gene is preferentially silenced or turned off depending upon which parent that gene came from.
Some individuals with Angelman syndrome (approximately 3-5 percent) have a defect in genetic imprinting caused by errors in DNA methylation (see above for imprinting definition). In approximately 20 percent of cases (of the 3-5%) this is caused by a deletion of DNA within the Imprinting Center; the remaining 80 percent of cases are caused by as yet unknown or unidentified defects in genetic imprinting. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to imprinting defects that have DNA deletions.
Approximately 2-5 percent of Angelman syndrome cases are caused by uniparental disomy, an abnormality in which a person receives both copies of a chromosome from one parent instead of receiving one from each parent. In Angelman syndrome, both copies of chromosome 15 can be received from the father (paternal uniparental disomy). As a result, there are only paternally-expressed genes in this region and UBE3A is thus not expressed at all in the brain since it is normally only expressed on the maternal-derived chromosome.
The risk of recurrence of uniparental disomy is less than 1 percent.
Abnormal changes (mutations) within UBE3A have been detected in 10-20 percent of individuals with Angelman syndrome. Loss of function of this gene causes all the cardinal clinical features of Angelman syndrome. UBE3A contains instructions for creating (encoding) the ubiquitin ligase protein. This protein marks other proteins so that the body is able to degrade targeted proteins, a process known as ubiquitination.
There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to a mutation of the UBE3A gene.
Some individuals with the symptoms of Angelman syndrome have no identifiable abnormality of chromosome 15. Some individuals in this group may have a disorder different from Angelman syndrome, but others may have an undetected mutation of the UBE3A gene or a mutation in another, yet-to-be-identified gene that can also cause or mimic Angelman syndrome.
This process of “parent-of-origin” inactivation is an example of “genomic imprinting”. Genomic imprinting is controlled by molecular switches, and some of these switches act through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Imprinted genes tend to be found clustered or grouped together.
Several imprinted genes are found in region 15q11-13 of chromosome 15.
This region also contains an area known as the Imprinting Center, and this area regulates the imprinted genes in this region.
As many as 10 percent of cases have no known cause.
(Symptoms can vary and is usually only recognised when the child is six to 12 months old)
(symptoms are noticed between one or two years old)
Small head (microcephaly)?
Flat back of the head (Brachycephaly)?
Deep set eyes?
Wide-set eyes (ocular hypertelorism)?
Bilateral epicanthal folds (prominent skin folds on the upper and lower eyelids)?
Squinting eyes causing one of the eyes to turn inwards, outwards or upwards, while other eye looks forward and/or tilting head to one side and/or one eye is closed regularly when focusing (Strabismus – crossed eyes)?
Wide mouth (Macrostomia)?
Widely spaced teeth?
Prominent chin?
Fingers become smaller and thinner toward the ends (tapered fingers) with broad thumbs?
Smooth palms with abnormal creases?
Pale skin [lack of normal colour of the (hypo-pigmentation) of the skin) eyes and hair due to lack of certain melanin pigments]?
Bone and joint movement problems and/or difficulty using arms and/or body and/or legs and/or lack of stamina and/or walking difficulties and/or crawling difficulties and/or rolling over difficulties?
Decreased clarity of vision (visual acuity)- blurred vision?
Bulging eyes?
Bilateral epicanthic folds (prominent skin folds on the upper and lower eyelids)?
Abnormal enlargement of the jaw?
Excessive drooling?
Tongue thrusting or a protruding tongue?
Excessive chewing or mouth motions?
Absence or near absence of speech?
Difficulty in concentration and memory problems?
Speaking difficulties/delays?
Behavioural feature in which the affected adult or child will laugh and smile frequently while maintaining a heightened state of cheer and excitability (often typified by hand-flapping or waving movements)?
Hyperactive, difficulty in getting to sleep and/or lack of sleep?
Fascination with water, love music, and be attracted to shiny objects?
Gastroesophageal reflux disease (GERD) – long term Heartburn (which then can lead to: pneumonitis – asthma symptoms and /or cracking sound in lungs and/or tiredness and/or finger clubbing)
Sleep disorders (waking up early, disrupted or abnormal sleep/wake cycles)
Christianson syndrome – X-linked disorder can mimic Angelman syndrome and involves mutations in the SLC9A6 gene.
Clinical features include apparently happy disposition, severe cognitive delays, ataxia, microcephaly and a seizure disorder. Some may have cerebellar and brain stem atrophy. Individuals with SLC9A6 disorder may have thinner body appearance and may lose ambulation beyond 10 years of age.
Microdeletions of the 2q23.1 region may result in severe speech delay, seizures, behavioural disorders and microcephaly.
Some individuals present with an Angelman syndrome-like phenotype. Other microdeletion disorders, especially newer ones detected by comparative genomic hybridization (chromosomal microarray analysis) may be associated with some features of Angelman syndrome.
As chromosome microarray analysis and whole exome sequencing become more frequent in the testing of individuals who have nonspecific intellectual disability, additional conditions have been identified that mimic Angelman syndrome, and surely these conditions will increase over time.
Some of these conditions include: KANSL1 haploinsufficiency syndrome (Koolen-de Vries syndrome); Kleefstra syndrome and variants; HERC2 deficiency syndrome; male MECP2 duplications; MEF2C syndrome and WAC-related intellectual disability.
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Detailed Information
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