Happy puppet syndrome

Angelman syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, speaking problems, balance and movement problems, seizures, and sleep problems. Children usually have a happy personality and have a particular interest in water. The symptoms generally become noticeable by one year of age.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. Angelman syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, speaking problems, balance and movement problems, seizures, and sleep problems. Children usually have a happy personality and have a particular interest in water. The symptoms generally become noticeable by one year of age. Angelman syndrome is typically due to a new mutation rather than one inherited from a person's parents. Angelman syndrome is due to a lack of function of part of chromosome 15 inherited from a person's mother. Most of the time, it is due to a deletion or mutation of the UBE3A gene on that chromosome. Occasionally, it is due to inheriting two copies of chromosome 15 from a person's father and none from their mother. As the father's versions are inactivated by a process known as genomic imprinting, no functional version of the gene remains. Diagnosis is based on symptoms and possibly genetic testing. No cure is available. Treatment is generally supportive in nature. Anti-seizure medications are used in those with seizures. Physical therapy and bracing may help with walking. Those affected have a nearly normal life expectancy. AS affects 1 in 12,000 to 20,000 people. Males and females are affected with equal frequency. It is named after a British pediatrician, Harry Angelman, who first described the syndrome in 1965. An older term, 'happy puppet syndrome', is generally considered pejorative. Prader–Willi syndrome is a separate condition, caused by a similar loss of the father's chromosome 15. The following text lists signs and symptoms of Angelman syndrome and their relative frequency in affected individuals. 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. 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-specific epigenetic imprinting; the biochemical mechanism is DNA methylation. In a normal individual, the maternal allele of the gene UBE3A, part of the ubiquitin pathway, is expressed and the paternal allele is specifically silenced in the developing brain. In the hippocampus and cerebellum, the maternal allele is almost exclusively the active one. If the maternal contribution is lost or mutated, the result is Angelman syndrome. (Some other genes on chromosome 15 are maternally imprinted, and when the paternal contribution is lost, by similar mechanisms, the result is Prader-Willi syndrome.) The methylation test that is performed for Angelman syndrome (a defect in UBE3A) looks for methylation on the gene's neighbor SNRPN (which is silenced by methylation on the maternal copy of the gene). While Angelman syndrome can be caused by a single mutation in the UBE3A gene, 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 paternally 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 Angelman syndrome in humans. 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. In addition, maintenance of long-term synaptic plasticity in hippocampal area CA1 in vitro is disrupted in Ube3a−/− mice. These results provide links amongst hippocampal synaptic plasticity in vitro, formation of hippocampus-dependent memory in vivo, and the molecular pathology of Angelman syndrome. The electroencephalogram (EEG) in AS is usually abnormal, more so than clinically expected. This EEG facilitates the differential diagnosis of AS, but is not pathognomonic. Three distinct interictal patterns are seen in these patients. The most common pattern is a very large amplitude 2–3 Hz rhythm most prominent in prefrontal leads. Next most common is a symmetrical 4–6 Hz high voltage rhythm. The third pattern, 3–6 Hz activity punctuated by spikes and sharp waves in occipital leads, is associated with eye closure. Paroxysms of laughter have no relation to the EEG, ruling out this feature as a gelastic phenomenon.