Angelman syndrome is a rare genetic disorder characterized by severe intellectual and developmental disability, sleep disorder, frequent and sometimes inappropriate laughter, seizures, jerky movements and ataxia. It is named after the British pediatrician, Dr. Harry Angelman, who first described it in 1965.
Patients diagnosed with Angelman syndrome will commonly present with the following signs and symptoms:
Entire Body System
Jaw & Teeth
Most patients of this age group show at least 8 of the major characteristics (bursts of laughter, happy disposition, hyperactive behaviour, microcephaly, brachycephaly, macrostomia, tongue protrusion, mandibular prognathism, widely spaced teeth, stiff [ncbi.nlm.nih.gov]
Generally from 1 year of age, the typical features of AS develop: severe intellectual deficit, absent speech, outbursts of laughter with hand flapping, microcephaly, macrostomia, maxillary hypoplasia, prognathia and neurological problems with a puppet-like [orpha.net]
[…] age, absent speech (or speech limited to less than six words), jerky movements with an ataxic gait if the patient is walking, paroxysm of inappropriate laughing, dysmorphic craniofacial features (brachycephaly, mid-facial hypoplasia, deep set eyes, macrostomia [pesquisa.bvsalud.org]
[…] head), ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia (floppiness), hyperactivity, seizures, absence of speech, frequent smiling and outbursts of laughter, and an unusual facies (facial appearance) characterized by macrostomia [bibliomed.org]
Cerebellar ataxia, muscle hypotonia and tremor, though constant in childhood, tend to be attenuated in adulthood. [ncbi.nlm.nih.gov]
A dictionary of medical eponyms Related people Harry Angelman A chromosome 15 disorder comprising microcephaly with mental and motor retardation, epilepsy, ataxic gait or complete inability to walk, muscle hypotonia, EEG abnormalities, and peculiar [whonamedit.com]
HYPOTONIA ; and a peculiar facies. [hon.ch]
Face, Head & Neck
Large Anterior Fontanels
anterior fontanelle, severe psychomotor retardation, and seizures due to monosomy 1p36. [ncbi.nlm.nih.gov]
PTHS is characterized by severe mental retardation, a wide mouth plus other distinctive facial features (fleshy lips, beaked nose, broad nasal bridge) and breathing abnormalities. [ncbi.nlm.nih.gov]
Children with Angelman syndrome may be easily excited, hypermotoric and hyperactive. They are active explorers and often may appear to be constantly in motion. [web.archive.org]
Behavioral uniqueness - any combination of frequent laughter/smiling, apparent happy demeanor, easily excitable personality, often with hand flapping movements. [achievementcenteroftexas.org]
excitable personality, often with hand flapping movements; hypermotoric behaviour; short attention span Frequent (more than 80%) Delayed, disproportionate growth in head circumference, usually resulting in microcephaly (absolute or relative) by age 2 [angelmanuk.org]
Features seen consistently include: Severe problems with developmental delay Balance or movement problems (unsteady walking, tremor) Behaviorally, the child may have frequent laughing or smiling with a happy sociable demeanor and be easily excitable More [epilepsy.com]
Angelman syndrome is characterized by mental retardation, seizures, ataxia, inappropriate laughter, lack of speech, a particular facial appearance, and generally a chromosome 15q11-q13 deletion. [ncbi.nlm.nih.gov]
Excessive and inappropriate laughter is a telltale sign. The actual number of cases of Angelman syndrome is unknown. Some estimates are 1 in 15,000 babies have Angelman syndrome. Others estimate 1 in 30,000. [mentalhelp.net]
Angelman syndrome is a rare genetic disorder characterized by severe intellectual and developmental disability, sleep disorder, frequent and sometimes inappropriate laughter, seizures, jerky movements and ataxia. [symptoma.com]
7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation. [ncbi.nlm.nih.gov]
Majority of patients with Angelman syndrome will have microcephaly and recurrent bouts of seizures that starts beyond the age of two years old. [symptoma.com]
Abnormal Sleep-Wake Cycles
Sleep disorders are also common, often characterized by abnormal sleep-wake cycles. Movement disorders are nearly universal in Angelman syndrome, most frequently presenting with ataxia and tremor. [ncbi.nlm.nih.gov]
Patients may also exhibit wide mouths with unusual tongue/mouthing behaviors, hypopigmentation, and abnormal sleep-wake cycles. Older patients may experience obesity. [dnatesting.uchicago.edu]
Sleep disturbances such as a decreased need for sleep and disrupted or abnormal sleep/wake cycles (e.g., awaking at night or rising earlier than normal) are frequent findings in children with Angelman syndrome. [web.archive.org]
Diminished muscle tone (hypotonia) of the trunk, increased muscle tone (hypertonia) of the arms and legs, and abnormally exaggerated or brisk reflex responses (hyperreflexia) may also occur. [web.archive.org]
Over time, increased muscle tone in the arms and legs coupled with decreased muscle tone in the trunk will lead to hyperreflexia (exaggerated or repeating reflex responses). Another characteristic neurological symptom is seizures. [verywellhealth.com]
In addition, there was improvement in the myoclonic jerks, sleep pattern, and developmental progress. Corticosteroids appeared to have a broad benefit on the epileptic encephalopathy. [ncbi.nlm.nih.gov]
The types of seizures include myoclonic (‘jerks’), atonic or astatic (‘drops’) prolonged blank episodes ('atypical absences') and tonic (‘stiffening’) seizures. Generalised tonic-clonic seizures and focal onset (partial) seizures are less common. [epilepsy.org.uk]
Recently Elia [ 26 ] by polygraphic studies, documented that myoclonic jerks are not correlated with EEG paroxysmal abnormalities. [ijponline.biomedcentral.com]
Two intellectually disabled adults with Angelman Syndrome are reported who developed intermittent episodes of a severe resting tremor, cogwheel rigidity and bradykinesia in their late teens. [ncbi.nlm.nih.gov]
Children with Angelman syndrome will typically present clinically with obvious developmental delays, microcephaly, movement disorders, impaired balance, and seizure disorders. This constellation of signs and symptoms is very suggestive of the syndrome clinically. The following tests may be used to confirm the diagnosis of Angelman syndrome:
- Chromosome analysis or karyotyping: This is the direct microscopic examination of the chromosomes to determine and identify any defects in the morphology and size of the sampled chromosomes.
- Fluorescence in situ hybridization (FISH): This fluorescence assay will demonstrate the defective long arm of chromosome 15 in Angelman syndrome.
- DNA methylation test: This test reveals any gene imprinting defects by the use of methylation techniques. Angelman syndrome will show the absence of the maternal gene copy and expression within the brain tissues.
- UBE3A gene sequencing: This a specific test that demonstrates the presence of gene mutation within the maternal copy of the gene found in a chromosome subset.
The gene defect in Angelman syndrome is irreparable; thus, there is no known cure for this rare syndrome. Treatment will only focus on the management of the medical and developmental problems of the affected child. Because of the complexity of the problems involved in Angelman syndrome, a multidisciplinary approach is often times imperative in the management of the disease. The following treatment modalities are available for Angelman syndrome:
- Anti-convulsant medications: This therapy is given to control the seizure disorders associated with Angelman syndrome.
- Physical therapy: Patients with Angelman syndrome may learn to walk promptly and balance with the help of physical therapy and rehabilitation.
- Speech therapy: Speech therapy among patients with the syndrome may hasten communication problems. Patients may be taught sign language if verbal communication is not achieved .
- Behavioral therapy: This will help children with Angelman syndrome to control hyperactivity and hasten developmental delays.
The majority of patients with Angelman syndrome will have progressive developmental delay, speech dysfunctions, and motor difficulties till adulthood. However, these patients will have a normal lifespan without any developmental regression as they chronologically age. The prompt diagnosis of Angelman syndrome coupled with a customized interventional therapy and support improves the prognosis among patients. Female patients with Angelman syndrome have been observed to be prone to obesity and worsening of scoliosis .
Angelman syndrome results from the maternal gene deletion of the locus UBE3A located at the long arm of chromosome 15 (15q11-13) . Studies have demonstrated that Angelman syndrome is closely associated with the intracytoplasmic sperm injection (ICSI) procedures with in vitro fertilization (IVF) techniques used for male infertility . The genetic etiology in Angelman syndrome is brought about by the imprinting defects during the DNA gene expression of the maternal chromosome subset.
The international incidence of Angelman syndrome as a molecular gene defect is approximately 1 case per 300,000 genetic diseases. The syndrome is further evident with an overall incidence rate of 1 case per 12,000 to 20,000 population. Mothers undergoing assistive IVF hormonal steroid therapy have an increased risk of giving birth to an infant afflicted with Angelman syndrome to more than 12.5 times compared to normal unassisted births .
The main pathophysiology of Angelman syndrome stems out from the absence of the maternal gene contribution in the long arm of the chromosome 15 . Other possible genetic causes of the syndrome include genetic translocation, uniparental disomy, and single gene mutation within the chromosome. The subsequent deletion of the gene within the long arm of chromosome 15 will result in the non-expression of the UBE3A gene needed in the DNA methylation during the ubiquitin pathway.
Recent studies have postulated that the absence of the UBE3A gene will lead to the impairment of the hippocampus memory and cognitive functioning that assists in the learning process, and the synaptic plasticity that controls movements and balance. One of the pathognomonic signs of Angelman syndrome is the characteristic electroencephalogram changes in the prefrontal leads suggesting that the pathogenesis of the syndrome could possibly be associated with some abnormalities in the neurophysiology of the brain .
In few cases of Angelman syndrome, there has been an observable genetic transmission pattern noted. Genetic counselling may be needed to prevent the recurrence of the disease in the family lineage.
Angelman syndrome is an uncommon genetic disorder presenting with developmental delays and neurologic impairments. Patients with Angelman syndrome are observably happy and excitable people with frequent outburst of laughter . Developmental delays with this syndrome are observable between the first 6 to 12 months of life while seizure ensues around 2 to 3 years of age. Majority of patients with Angelman syndrome will have microcephaly and recurrent bouts of seizures that starts beyond the age of two years old.
Despite their coarse anatomic features and severe neurologic impairments, patients suffering from Angelman syndrome have a comparatively similar life expectancy compared to the normal population. The goal in the management of Angelman syndrome focuses on the patient’s neurological dysfunctions and developmental delays.
Angelman syndrome results from the maternal gene deletion of the locus UBE3A located at the long arm of chromosome 15 (15q11-13). Some less common genetic causes include genetic translocation, uniparental disomy, and single gene mutation.
Patients will physically present with microcephaly, with observable speech, developmental, and movement impairments.
Clinical history, physical examination and neurologic examinations may clinch the diagnosis of Angelman syndrome. Confirmatory test like karyotyping, FISH, DNA methylation tests, and gene sequencing may also be implored.
Treatment and follow-up
Patients are treated with anti-convulsant therapy, physical and speech therapy, and behavioral therapy.
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