What is Angelman syndrome?
Angelman Syndrome (AS) is a rare neuro-genetic disorder named after an English paediatrician, Dr. Harry Angelman, who first described the syndrome in 1965. A syndrome is number of features which occur together as a group and indicate a particular condition. AS is characterised by severe intellectual disability, speech impediment, sleep disturbance, unstable jerky gait, seizures and usually a happy demeanour.
Is it difficult to diagnose?
Yes, but with increasing public awareness of the condition and more accurate diagnostic tests, more children are being diagnosed. It is estimated that Angelman Syndrome occurs about one in 20,000 births. Assessing the physical and behavioural features of AS helps in a more accurate diagnosis.
Always Seen/Consistent (100%)
- Severe intellectual disability and developmental delay (failure to match developmental milestones of other children), eg. delays in sitting and walking, delay in fine motor skills development and delay in toilet training;
- Profound speech impairment: no speech or minimal use of words; receptive and non-verbal communication skills higher than verbal ones;
- Movement for balance disorder (tremulous movement of limbs, stiffness and jerkiness in limbs) and ataxia of gait (lack of muscular co-ordination when walking);
- Behavioural uniqueness: any combination of frequent laughter/smiling; Happy demeanour; easily excitable personality, often with hand flapping movements; short attention span and hyperactivity.
Usually Seen/Frequent (More than 80%)
- Small head size - often by age two years; *Seizures - onset usually before three years of age; *Abnormal EEG (brain wave pattern irregularity).
Sometimes Seen/Associated (20% to 80%)
- Flat occiput (flattened back of head);
- Protruding tongue;
- Tongue thrusting; suck/swallowing disorders;
- Feeding problems during infancy;
- Wide mouth, widely spaced teeth;
- Frequent drooling;
- Excessive chewing/mouthing behaviours;
- Scoliosis (curvature of the spine);
- Strabismus (crossed eye);
- Hypo pigmented skin, light hair and eye colour (compared to family), a feature in deletion cases;
- Wide based gait (feet far apart with flat, out turned feet);
- Tendency to hold arms up and flexed while walking;
- Increased sensitivity to heat;
- Sleep disturbance;
- Attraction to/fascination with water.
Not all features may be present. A diagnosis of Angelman Syndrome is based on a combination of the clinical features as above, together with genetic diagnostic tests.
For several decades the chromosome study of AS individuals revealed no abnormalities but with the development of improved methods a very small deleted area was found in chromosome 15. Newer chromosome testing methods such as FISH (fluorescence in situ hybridization) now demonstrate a deletion in about 70% of individuals with AS. The deleted area, although extremely small, is actually quite large when viewed at the molecular level. It is believed to be about 4 million base pairs in length, enough to contain many genes.
The deleted region on chromosome 15 is known to contain genes that are activated or inactivated depending upon the chromosome’s parent of origin (i.e., a gene may be turned on on the chromosome 15 inherited from the mother but off on the chromosome 15 inherited from the father). This parent-specific gene activation is referred to as genetic imprinting. Because the deletions seen in AS only occur on the chromosome 15 inherited from the mother, the gene(s) responsible for AS were predicted to be active only on the maternal chromosome 15. Disruption of genes that are active on the paternally-derived chromosome 15 is now known to cause another developmental disorder termed the Prader-Willi syndrome (PWS). The PWS gene(s) are actually located close to the AS gene, but they are different.
In 1997, a gene within the AS chromosome deletion region, called UBE3A, was discovered. 11, 12 Abnormalities of only this gene now appear to be the fundamental cause of AS. All mechanisms known to cause AS either disrupt, inactivate or lead to absence of this gene. UBE3A encodes an enzymatic protein called a ubiquitin protein ligase and it is a component of a complex protein degradation system termed the ubiquitin-proteasome pathway. This pathway is located in the cytoplasm of all cells and it enables a small protein molecule, ubiquitin, to be attached to certain proteins, thereby causing them to be degraded. 13 In the normal brain, the copy of UBE3A inherited from the father is almost completely inactive, so the maternal copy performs most of the UBE3A function in the brain. Inheritance of a UBE3A mutation from the mother causes AS; inheritance of a UBE3A mutation from the father has no detectable effect on the child. In some families, AS caused by a UBE3A mutation can recur in more than one family member.
Another cause of AS (2-3% of cases) is paternal uniparental disomy (UPD), where the child inherits both copies of chromosome 15 from the father, with no copy inherited from the mother. In this case, there is no deletion or mutation, but the child is still missing the active UBE3A gene because the paternal-derived chromosomes only have brain-inactivated UBE3A genes.
A fourth class of AS individuals (3-5% of cases) have inherited chromosome 15 copies from both mother and father, but the copy inherited from the mother functions in the same way that a paternal chromosome 15 should function. This is referred to as an “imprinting defect”. A small percentage of AS individuals with imprinting defects have very small DNA deletions in a region called the Imprinting Center (IC) 14-17 but all AS individuals with IC defects have abnormal DNA methylation changes in this region. The IC is located some distance from the UBE3A gene but it is still able to regulate UBE3A by a complex mechanism that is the subject of intense research. In some cases, AS caused by imprinting defects can recur in more than one member of a family. It has recently been discovered that assisted reproductive technologies (ART), such as in vitro fertilization (IVF) or intra-cytoplasmic sperm injection (ICSI), are associated with a few cases of AS due to the non-deletion type of IC defect. 18-20
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