Angelman syndrome
Angelman syndrome | |
---|---|
Other names | Angelman's syndrome Supportive care[7] |
Prognosis | Nearly normal life expectancy[6] |
Frequency | 1 in 12,000 to 20,000 people[6] |
Angelman syndrome or Angelman's syndrome
Angelman syndrome is due to a lack of function of part of
No cure is available.
AS affects 1 in 12,000 to 20,000 people.
Signs and symptoms
Signs and symptoms of Angelman syndrome and their relative frequency in affected individuals are:[12]
Consistent (100%)
- 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
Frequent (more than 80%)
- 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
Associated (20–80%)
- Strabismus
- Hypopigmented skin and eyes
- Tongue thrusting; suck/swallowing disorders
- Hyperactive tendon reflexes
- Feeding problems during infancy
- Uplifted, flexed arms during walking
- Prominent mandible
- Increased sensitivity to heat
- Wide mouth, wide-spaced teeth
- Sleep disturbance
- Frequent drooling, protruding tongue
- Attraction to/fascination with water
- Excessive chewing/mouthing behaviors
- Flat back of head
- Smooth palms
- Gastroesophageal reflux disease (GERD)[13]
- Constipation[13]
Cause
Angelman syndrome is caused by the lack of expression of a gene known as
Typically, a fetus inherits a maternal copy of UBE3A and a paternal copy of UBE3A. In certain areas of the developing brain, the paternal copy of UBE3A is inactivated through a process known as imprinting and the fetus relies on the functioning maternal copy of UBE3A in order to develop normally. In an individual with AS, however, the maternal UBE3A gene is absent or not functioning normally. This can be due to genetic errors such as the deletion or mutation of a segment of chromosome 15, uniparental disomy, or translocation. While Angelman syndrome can be caused by a single mutation in the UBE3A gene, the most common genetic defect leading to Angelman syndrome is a 5- to 7-Mb (megabase) maternal deletion in chromosomal region 15q11.2-q13.[16]
Specifically, the paternal copy of UBE3A is known to be imprinted within the hippocampus, cortex, thalamus, olfactory bulb, and cerebellum. Therefore, in these areas of the brain, a functioning maternal copy of UBE3A is essential for proper development.[17]
Region 15q11-13 is implicated in both Angelman syndrome and Prader–Willi syndrome (PWS). While AS results from mutation, loss or abnormal imprinting involving the UBE3A gene within this region on the maternal chromosome,[16] loss of a different cluster of genes within the same region on the paternal chromosome causes PWS.[18]
The methylation test that is performed for Angelman syndrome looks for methylation on the gene's neighbor
Neurophysiology
The
EEG anomalies may be used as a quantitative biomarkers to "chart progression of AS and as clinical outcome measures".[23] Slow delta activity (~3 Hz) is greatly increased in AS relative to typically developing children, yet more pronounced in children with partial 15q deletions as opposed to those with etiologies principally affecting UBE3A.[24] Theta activity (~5 Hz) is much greater in children with partial 15q deletions.[24] Thus, delta activity appears to be chiefly reflective of UBE3A dysfunction with some modulation from other 15q genes, whereas theta activity may be an electrophysiological readout of genes beyond UBE3A such as GABRA5, GABRB3, and GABRG3.[24]
Diagnosis
The diagnosis of Angelman syndrome is based on:[citation needed]
- A history of delayed motor milestones and then later a delay in general development, especially of speech
- Unusual movements including fine tremors, jerky limb movements, hand flapping and a wide-based, stiff-legged gait.
- Characteristic facial appearance (but not in all cases).
- A history of epilepsy and an abnormal EEG tracing.
- A happy disposition with frequent laughter
- A deletion or inactivity on chromosome 15 by array comparative genomic hybridization(aCGH) or by BACs-on-Beads technology.
Diagnostic criteria for the disorder were initially established in 1995 in collaboration with the Angelman syndrome Foundation (US);[25] these criteria underwent revision in 2005.[26]
Seizures are a consequence, as is excessive laughter,[27] which is a major hindrance to early diagnosis.
Differential diagnosis
Other conditions that can appear similar include:[7][8]
- Autism spectrum
- Cerebral palsy
- Rett syndrome
- Mowat–Wilson syndrome
- Adenylosuccinate lyase deficiency
- Pitt–Hopkins syndrome
- Phelan–McDermid syndrome
- Prader–Willi syndrome
Treatment
There is currently no cure available. The epilepsy can be controlled by the use of one or more types of anticonvulsant medications. However, there are difficulties in ascertaining the levels and types of anticonvulsant medications needed to establish control, because people with AS often have multiple types of seizures.[28] Many families use melatonin[13] to promote sleep in a condition which often affects sleep patterns. Mild laxatives are also used frequently to encourage regular bowel movements. Additionally, among a cohort of 163 individuals with AS, ranitidine was shown to be the most frequently prescribed medication for treating gastroesophageal reflux disease (GERD).[13] Early intervention with physiotherapy is sometimes used to encourage joint mobility and prevent stiffening of the joints.[citation needed]
Occupational therapists can contribute to the development and augmentation of non-verbal communication skills by addressing the foundational skills such as finger isolation, motor planning, hand-eye coordination, spatial awareness, and refining gestures.[29] This is important because individuals with Angelman Syndrome who already possess some form of non-verbal communication have a much harder time adapting to changes in a new or existing AAC device because they can communicate their needs much faster nonverbally.[29]
Occupational therapists can assist individuals with Angelman syndrome with many other skills as well.[30] Many individuals with Angelman syndrome also have difficulty processing sensory information and responding appropriately to sensory stimuli.[31] Occupational therapists can work together with these individuals to improve their visual perceptual skills and increase their sensory awareness.[31]
Expressive verbal communication is limited by AS, but many people with the disorder are able to learn non-verbal communication skills to express their needs. Deictic gesturing (i.e, pointing to an object) is the most commonly used form of non-symbolic communication in AS, followed by physically manipulating others (such as moving a caregiver's hand to a specific object or guiding a person to a new location) and non-speech vocalizations.[30] Some are able to use symbolic communication such as signing, though the prevalence of this ability is related to both genetic etiology and epilepsy status, with non-deletion etiologies without epilepsy showing the highest prevalence of symbolic communication skills.[32] People with AS tend to have much higher receptive language abilities than expressive; recent studies have shown that patients with AS have typical auditory brain region responses to speech but atypical memory responses, suggesting that word meaning recall is delayed or processed differently in AS.[33] This may be caused by the altered cortical morphology seen in AS [34] in the precuneus, a region of the brain involved in self-reflection and memory. Similarly, both adults and children with AS show a delay in processing speed in speech processing,[35] and this should be accounted for during communication.
Prognosis
The severity of the symptoms associated with Angelman syndrome varies significantly across the population of those affected. Some speech and a greater degree of self-care are possible among the least profoundly affected. Walking and the use of simple sign language may be beyond the reach of the more profoundly affected. Early and continued participation in physical, occupational (related to the development of fine-motor control skills), and communication (speech) therapies are believed to significantly improve the prognosis (in the areas of cognition and communication) of individuals affected by AS. Further, the specific genetic mechanism underlying the condition is thought to correlate to the general prognosis of the affected person. On one end of the spectrum, a mutation to the UBE3A gene is thought to correlate to the least affected, whereas larger deletions on chromosome 15 are thought to correspond to the most affected.[citation needed]
The clinical features of Angelman syndrome alter with age. As adulthood approaches, hyperactivity and poor sleep patterns improve. The seizures decrease in frequency and often cease altogether and the EEG abnormalities are less obvious. Medication is typically advisable to those with seizure disorders. Often overlooked is the contribution of the poor sleep patterns to the frequency and/or severity of the seizures. Medication may be worthwhile to help deal with this issue and improve the prognosis with respect to seizures and sleep. Also noteworthy are the reports that the frequency and severity of seizures temporarily escalate in pubescent Angelman syndrome girls, but do not seem to affect long-term health.[citation needed]The facial features remain recognizable with age, but many adults with AS look remarkably youthful for their age.[citation needed]
The majority of those with AS achieve continence by day and some by night. Angelman syndrome is not a degenerative syndrome, and thus people with AS may improve their living skills with support.[citation needed]
Dressing skills are variable and usually limited to items of clothing without buttons or zippers. Most adults can eat with a knife or spoon and fork, and can learn to perform simple household tasks. Particular problems which have arisen in adults are a tendency to obesity (more in females), and worsening of scoliosis[37] if it is present. The affectionate nature may also persist into adult life where it can pose a problem socially, but this problem is not insurmountable. People with Angelman syndrome appear to have a reduced but near-normal life expectancy, dying on average 10 to 15 years earlier than the general population.[38]
Epidemiology
Though the prevalence of Angelman syndrome is not precisely known, there are some estimates. The best data available are from studies of school age children, ages 6–13 years, living in Sweden and from Denmark where the diagnosis of AS children in medical clinics was compared to an 8-year period of about 45,000 births. The Swedish study showed an AS prevalence of about 1/20,000[39] and the Danish study showed a minimum AS prevalence of about 1/10,000.[40]
History
Harry Angelman, a pediatrician working in Warrington, England, first reported three children with this condition in 1965.[9] Angelman later described his choice of the title "Puppet Children" to describe these cases as being related to an oil painting he had seen while vacationing in Italy:
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. [sic], 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 quoted by Charles Williams[42]
Case reports from the United States first began appearing in the medical literature in the early 1980s.
Society and culture
Many poems in Richard Price's poetry collections Hand Held (1997), Lucky Day (2005), and Small World (2012) reflect on the disability of the poet's daughter, who has Angelman syndrome. In the 2011 Philippine drama series Budoy, the titular character and main protagonist Budoy Maniego (played by Filipino actor Gerald Anderson) is diagnosed with Angelman syndrome.[citation needed]
See also
- List of syndromes
- Characteristics of syndromic ASD conditions
References
- ^ a b c "Angelman syndrome". Oxford English Dictionary. Archived from the original on June 17, 2020 – via Lexico.com.
- ^ a b c d "Angelman syndrome". Merriam-Webster Medical Dictionary. Merriam-Webster. Retrieved April 15, 2022 – via Merriam-Webster.com.
- The McGraw-Hill Companies, Inc. 2003. Retrieved April 15, 2022 – via thefreedictionary.com.
- ^ Houghton Mifflin Company. 2004. Retrieved April 15, 2022 – via thefreedictionary.com.
- ISBN 9780128063415. Retrieved April 15, 2022 – via Google Books.
- ^ a b c d e f g h i j k l m n o "Angelman syndrome". ghr.nlm.nih.gov. Genetics Home Reference, US National Institutes of Health. May 2015. Archived from the original on 27 August 2016. Retrieved 28 April 2017.
- ^ a b c d e f g h i j k "Angelman Syndrome". rarediseases.org. National Organization for Rare Disorders (NORD). 2015. Archived from the original on 13 November 2016. Retrieved 28 April 2017.
- ^ a b "Common Misdiagnoses". Foundation For Angelman Syndrome Therapeutics. 2 August 2019. Retrieved 10 March 2024.
- ^ S2CID 53730099.
- ISBN 9780521776738. Archivedfrom the original on 2017-11-05.
- ISBN 978-1437717815. Archivedfrom the original on 2017-11-05. Retrieved 2022-04-15 – via Google Books.
- ^ "Facts about Angelman syndrome" (PDF). US: Angelman Syndrome Foundation. Archived from the original (PDF) on 2013-05-27. Retrieved 2012-09-29.
- ^ PMID 31090212.
- PMID 14993414.
- PMID 29263404.
- ^ PMID 20301323. Retrieved 28 August 2022.
- PMID 21592595.
- S2CID 20832857.
- PMID 16574761.
- ^ a b c Williams C (2005) "Neurological aspects of the Angelman syndrome" Brain & Development 27: 88–94
- S2CID 5912.
- ^ Dan, B., Angelman syndrome: Current understanding and research prospects. Epilepsia, 2009. 50(11): p. 2331–2339.
- PMID 28503211.
- ^ a b c Frohlich, Joel, Meghan Miller, Lynne M. Bird, Pilar Garces, Hannah Purtell, Marius C. Hoener, Benjamin D. Philpot et al. "Electrophysiological phenotype in Angelman syndrome differs between genotypes." Biological Psychiatry (2019).
- PMID 7625452.
- S2CID 2449346.
- PMID 7625442.
- PMID 22142420.
- ^ S2CID 149445749.
- ^ PMID 16915878.
- ^ S2CID 209329797.
- hdl:2066/77094.
- PMID 36502770.
- PMID 36788499.
- PMID 36244082.
- PMID 11258627.
- PMID 9072912.
- PMID 23949824.
- PMID 8703225.
- PMID 7573182.
- PMID 27380555.
- ^ Williams C. "Harry Angelman and the History of AS". Stay informed. US: Angelman Syndrome Foundation. Archived from the original on 2011-02-06. Retrieved 2011-07-01.
- PMID 7246489.
- PMID 7091188.
- PMID 3688021.