ANGELMAN SYNDROME

Disease

Brief Summary

Angelman syndrome is a genetic condition that induces abnormal growth, speech and balance problems, cognitive impairment, and occasional seizures. Individuals who suffer from Angelman Syndrome frequently laugh, smile, and have exciting personalities. The disease is normally caused by complications in a gene called the ubiquitin-protein ligase E3A (UBE3A) gene which is situated in chromosome 15. Albeit, there's no current remedy available, affected individuals almost have an average life expectancy.

Source

Image:

Person affected by Angelman Syndrome

Frequency

It affects an estimated 1 in 12,000 to 20,000 people

The registry of the Section of Clinical Genetics and Department of Pediatrics of the Philippine General Hospital listed three confirmed cases by FISH and ten clinically diagnose individuals of AS.

Inheritance

Angelman syndrome results from a lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion in most cases or from uniparental disomy in rare cases. Most families are therefore associated with a low recurrence risk. Although Angelman syndrome is not typically mendelian, familial occurrence has been reported.

Brief Summary

History of Disease

The first reports of the disease appeared in the early 1980s from North America, but it was in 1965 when Dr. Harry Angelman, an English physician, first identified three children with features now known as Angelman syndrome. He observed that everyone had a tense, jerky gait, absent voice, excessive laughing, and seizures. After working with the children, he was encouraged to write an article called "A Boy with a Puppet" after seeing a painting in a museum in Verona, Italy. Because of their cheerful character and static jerky movements, Dr. Angelman described the children as "Happy Puppet Children" in his writing and this phrase was commonly used until the late eighties, but the word 'Happy Puppet' was deemed offensive by two researchers, Charles A. Williams and Dr. Jaime L. Frias, so the name of the condition was changed to 'Angelman syndrome' in 1982. Eventually, several cases were reported, and even at that time the disease was deemed exceedingly rare, and many doctors suspected its existence.

Up to the late eighties, the trigger behind AS remained unexplained. However, it was first noticed in 1987 that about half of the children with AS had a small chromosome 15 missing. Due to extreme mental retardation, seizures, and ataxia-like incoordination, two unrelated females, aged 15 and 5 years respectively, were studied cytogenetically. In both patients, a related deletion of the proximal long arm of chromosome 15 was observed by R E Magenis and colleagues. Their re-evaluation revealed that there is no voracious appetite nor obesity; average hand and foot size, minimal to no hypotonia by history or examination, and facial characteristics not indicative of the Prader-Willi syndrome, but with slight hypertelorism, the girls' facial appearance was comparable with each other. The resemblance between these girls and the dissimilarity between them and Prader-Willi syndrome indicates a separate syndrome, probably the product of the deletion of another 15q segment, but instead, the effects of ataxic-like gestures, regular, unprovoked, and prolonged laughter, and facial appearance bouts are more consistent with the Angelman syndrome diagnosis.

History of Disease

Pathogenesis

Achondroplasia is caused by a mutation in the FGF3 gene in chromosome 4 at 4p 16.3. This mutation causes a decreased production of fibroblast growth factor receptor 3 which is crucial in the conversion of cartilage into bone which is vital in the proper development of a person. This mutation is inherited in an autosomal dominant manner. More than 80 percent of people with achondroplasia have parents with normal characteristics and are born with achondroplasia due to a recent (de novo) gene modification (mutation).

Pathogenesis

Angelman syndrome results from a lack of maternal involvement from chromosome 15q11-q13 resulting in the majority of cases from de novo deletion or in rare cases, from single-parent dysomia. Therefore, most households are associated with a low risk of recidivism. Although Angelman syndrome is not usually Mendelian, it has been confirmed to be a family occurrence, wherein the syndrome is inherited. The mutated gene is a dominant gene situated on one of the n genes in an autosomal dominant disorder nonsex chromosomes (autosomes).

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Mutated chromosome by Angelman Syndrome

Source

Symptoms

developmental delay, functionally severe

speech impairment, no or minimal use of words; receptive and non-verbal communication skills higher than verbal ones

movement or balance disorder, usually ataxia of gait and/or tremulous movement of limbs

behavioral characteristics of the following types: any combination of atypical frequent laughter/smiling; atypically happy demeanor; easily excitable personality, often with hand flapping movements; hypermotoric behavior; short attention span

delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2

seizures, onset usually less than 3 years of age

abnormal EEG, characteristic pattern with large amplitude slow-spike waves

tongue thrusting; suck/swallowing disorders

Social Concerns

With age, people with Angelman syndrome become less excitable, and sleeping problems tend to improve. However, affected individuals continue to have intellectual disability, severe speech impairment, and seizures throughout their lives.

Clinical Trials

Treatment

No cure is currently available. The use of one or more types of anticonvulsant drugs can control epilepsy. However because people with AS often have multiple types of seizures, there are difficulties in determining the levels and types of anticonvulsant medications needed to establish control. In a disorder that often impacts sleep patterns, many families use melatonin to promote sleep. Most people with Angelman syndrome sleep at any time for a maximum of five hours at any one time. Mild laxatives are also frequently used to promote regular bowel movements. Early physiotherapy intervention is sometimes used to promote joint mobility and prevent joint stiffening. Speech and Language Therapy is commonly used to help people with Angelman syndrome and their problems with communication.

Those with the syndrome are generally happy and contented people who like human contact and play. People with AS exhibit a profound desire for personal interaction with others. Communication can be difficult at first, but as a child with AS develops, there is a definite character and ability to make themselves understood. People with AS tend to develop strong non-verbal skills to compensate for their limited use of speech. It is widely accepted that their understanding of communication directed to them is much larger than their ability to return conversation. Most affected people will not develop more than 5–10 words if any at all.

Source

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Treatment for Angelman Syndrome

Expert Directory

Clinical Trials

Title:

A Dose-escalation Tolerability Study of Levodopa/Carbidopa in Angelman Syndrome

Intervention:

Dosages are based on drug levodopa/Carbidopa (4:1)

Phase:

Phase 1

Procedure:

Each cohort of 3 subjects will be placed on an increasing dose of levodopa (2, 5, 10, and 15 mg/kg/day) for 1 week, provided subjects in the preceding cohort tolerated the lower dose. Levodopa/Carbidopa is a combined formulation that will be dispensed as capsules. It should be taken 3 times a day.

Goal:

This study is designed to determine the highest dose of levodopa/carbidopa that can be tolerated without any serious side effects by children with Angelman syndrome.

Further details at:

https://clinicaltrials.gov/ct2/show/study/NCT00829439?cond=Angelman+Syndrome&draw=3&rank=15