By Teesta Roychoudhury (Staff Writer)
Introduction:
Angelman Syndrome is a rare genetic disorder that mainly affects the nervous system. It occurs in an estimate 1 in 12,000 to 20,000 people, but sources may vary. It is a neuro-genetic condition associated with distinct behavioral patterns and developmental challenges. Often characterized by jerky movements and a joyful demeanor, AS was initially termed as ‘happy puppet Syndrome’.
Discovery:
An english doctor in 1965 by the name of Dr. Harry Angelman was the first to report upon this Syndrome. He described 3 children with common characteristics such as absent speech, a stiff gait, seizures and excess laughter. A quote from him says
"The history of medicine is full of interesting stories about the discovery of illnesses. The saga of Angelman's Syndrome is one such story. It was purely by chance that nearly thirty years ago (e.g., circa 1964) three handicapped children were admitted at various times to my children's ward in England. They had a variety of disabilities and although at first sight they seemed to be suffering from different conditions I felt that there was a common cause for their illness. The diagnosis was purely a clinical one because in spite of technical investigations which today are more refined I was unable to establish scientific proof that the three children all had the same handicap. In view of this I hesitated to write about them in the medical journals. However, when on holiday in Italy I happened to see an oil painting in the Castelvecchio museum in Verona 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. It was not a name that pleased all parents but it served as a means of combining the three little patients into a single group. Later the name was changed to Angelman Syndrome. This article was published in 1965 and after some initial interest lay almost forgotten until the early eighties."
Causes:
The root cause of AS is deficient gene expression of UBE3A which produces E3 Ubiquitin Protein Lipase in chromosome 15 (15q11 - q13).
Usually, the maternal copy of UBE3A gene is active (or expressed), while the paternal copy is silenced by the antisense transcript (imprinting). E3 Ubiquitin Protein Lipase is the enzyme which controls proteasome mediated protein degradation (which is a cellular process to break down and recycle damaged protein)
In Angelman Syndrome, the maternal gene is malfunctioning, leading to insufficient expression of UBE3A, and in turn E3 Ubiquitin Protein Lipase and proteasome mediated protein degradation as well. This may be due to several causes..
Deletion of UBE3A gene: An estimated 70% of cases are due to the deletion of a portion of chromosome 15 containing the UBE3A gene. This may also explain why people with AS tend to have light hair and pale skin for the most part, as the gene OCA2 which is responsible for melanin production is also located near the UBE3A gene and may get deleted as well.
Mutations in the UBE3A gene: Occurs in about 11% of cases. Mutations can disrupt the gene’s structure, affecting production of E3 Ubiquitin Protein Lipase and causing Angelman Syndrome.
Uniparental Disomy (UPD): In around 1-2% of cases, a child inherits two copies of chromosome 15 from one parent, and none from the other (usually the paternal gene). This would result in the absence of the normally active maternal gene.
Imprinting Defects: This is the cause of AS in about 6% of cases. Defects in the imprinting process can lead to the maternal gene being silenced. Regardless of the maternal UBE3A gene being present, it’s rendered ineffective.
Symptoms:
The Angelman Syndrome foundations segregates symptoms into three categories, those being
Consistent (present 100% of patients, necessary for diagnosis):
Severe developmental delays
Speech impairments, often minimal or no use of words
Ataxia (loss of muscle control)
Behavioral characteristics (atypical frequent laughter/smiling and happy demeanor, excitable personality, short attention span and hypermotoric behavior, movements like flapping hands)
Frequent (present in 80% of patients, common)
Absolute or relative microcephaly (smaller head size)
Seizures (onset of 3 years, severity decreases with age)
Abnormal EEG characteristics (may precede clinical features, may occur in the first two years of life)
Associated (present in 20% of patients, may occur with AS):
Strabismus (misaligned eyes)
Hypopigmented eyes/skin/hair (lack of melanin, malfunctioning OCA2 gene)
Immature swallow (tongue thrust/reverse swallow)
Hyperreflexia (hyperactive reflexes in the tendons)
Feeding problems during infancy
Mandibular prominence (prominent jawbone)
GERD (gastroesophageal reflux disorder)
And more..
Diagnosis:
Angelman Syndrome is diagnosed through blood tests and genetic testing. Results are usually available within a few weeks.
Initially, a blood test for DNA methylation is conducted to identify if the UBE3A gene is functional. If not, then the person has AS. If the test returns normal, DNA sequencing is performed to confirm results.
To determine the cause of AS in case of abnormal DNA methylation test, two further tests may be conducted. First, a FISH 15 (fluorescent in situ hybridization) or CGH (comparative genomic hybridization) test is performed. If positive, then the cause of AS happens to arise from chromosome deletion.
If normal, then DNA marker analysis is conducted. If positive, then AS happens to arise from UPD.
If negative, then AS happens to be caused by imprinting defects. Molecular studies may be used to confirm this.
Treatment:
As there is currently no way to cure chromosomal damage, Angelman Syndrome does not have a cure. Instead, treatment plans focus on addressing symptoms. This may involve dietary chances to reduce gastrointestinal issues, physical therapy to aid in mobility, anticonvulsant/anti epileptic drugs to help control seizures, and behavioral and speech or communicational therapy.
TL;DR:
To conclude, Angelman Syndrome is a rare genetic disorder primarily affecting the nervous system, caused by disruptions to the UBE3A gene on chromosome 15. While there is no cure, understanding the syndrome’s genetic roots allows for more targeted therapies to manage its symptoms. Early diagnosis, combined with a comprehensive treatment plan involving physical, behavioral, and speech therapy, can significantly improve quality of life for those affected by AS.
Sources + extra reading:
Angelman syndrome - Wikipedia (for those interested in the prognosis. I didn't mention it due to a lack of fully credible sources.)
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