Angelman syndrome is a rare genetic and neurological disorder characterized by severe developmental delay and learning disabilities; absence or near absence of speech; inability to coordinate voluntary movements (ataxia); tremulousness with jerky movements of the arms and legs and a distinct behavioral pattern characterized by a happy disposition and unprovoked episodes of laughter and smiling. Although those with the syndrome may be unable to speak, many gradually learn to communicate through other means such as gesturing. In addition, children may have enough receptive language ability to understand simple forms of language communication. Additional symptoms may occur including seizures, sleep disorders, and feeding difficulties. Some children with Angelman syndrome may have distinctive facial features but most facial features reflect the normal parental traits. Angelman syndrome is caused by deletion or abnormal expression of the UBE3A gene.
Angelman syndrome was first described in the medical literature in 1965 by Dr. Harry Angelman, an English physician. The characteristic findings of Angelman syndrome are not usually apparent at birth and diagnosis of the disorder is usually made between 1 and 4 years of age.
Causes
The deficiency of the E3 ubiquitin-protein ligase (UBE3A) gene expression causes Angelman syndrome. The gene is located in chromosome region 15 (15q11-q13).
Angelman syndrome (AS) is caused by a pathologic lack of expression of the UBE3A gene on the maternal chromosome in combination with physiologic genomic imprinting or silencing on the paternal chromosome in neurons. UBE3A gene is an example of an imprinted gene because it is expressed in a parent of origin-specific manner. The paternal UBE3A gene is imprinted mainly in the neurons and has some level of expression in the rest of the body.[rx]
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 15q11-q13” refers to bands 11-13 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The abnormalities of UBE3A that can cause Angelman syndrome involve the absence of the gene, changes in the structure of the gene, or changes in the function or expression of the gene. Genetic mechanisms that can disrupt UBE3A include chromosome deletion, imprinting error, paternal uniparental disomy, and UBE3A mutation (see below). In approximately 10 percent of cases, no cause can be identified. In most cases of Angelman syndrome, these genetic changes appear to occur randomly (sporadically) but in about 3-5% they can be inherited.
In approximately 70-75 percent of cases, there is a microdeletion of region 15q11-13 of the maternally-derived chromosome 15 that includes deletion of the UBE3A gene. This deletion usually occurs sporadically (de novo) and is not inherited. The risk of recurrence for the deletion in a family is estimated to be 1-2 percent or less.
In about 1 percent of cases, deletion of this chromosomal region may occur due to a complex chromosomal rearrangement, in which a segment of chromosome 15 breaks off and moves to another chromosomal location. Those with this type of mechanism for the deletion are at a greater risk for recurrence.
A unique genetic phenomenon associated with Angelman syndrome is “imprinting.” Everyone has two copies of every gene (except for genes on the Y chromosome): one received from the father and the other from the mother. In most cases, both genes are turned on and are thus active. However, in some cases, one gene is preferentially silenced or turned off depending upon which parent that gene came from. This process of “parent-of-origin” inactivation is an example of “genomic imprinting”. Genomic imprinting is controlled by molecular switches, and some of these switches act through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Imprinted genes tend to be found clustered or grouped. Several imprinted genes are found in region 15q11-13 of chromosome 15. This region also contains an area known as the Imprinting Center, and this area regulates the imprinted genes in this region.
Some individuals with Angelman syndrome (approximately 3-5 percent) have a defect in genetic imprinting caused by errors in DNA methylation (see above for imprinting definition). In approximately 20 percent of cases (of the 3-5%), this is caused by a deletion of DNA within the Imprinting Center; the remaining 80 percent of cases are caused by as yet unknown or unidentified defects in genetic imprinting. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to imprinting defects that have DNA deletions.
Approximately 2-5 percent of Angelman syndrome cases are caused by uniparental disomy, an abnormality in which a person receives both copies of a chromosome from one parent instead of receiving one from each parent. In Angelman syndrome, both copies of chromosome 15 can be received from the father (paternal uniparental disomy). As a result, there are only paternally-expressed genes in this region, and UBE3A is thus not expressed at all in the brain since it is normally only expressed on the maternal-derived chromosome. The risk of recurrence of uniparental disomy is less than 1 percent.
Abnormal changes (mutations) within UBE3A have been detected in 10-20 percent of individuals with Angelman syndrome. Loss of function of this gene causes all the cardinal clinical features of Angelman syndrome. UBE3A contains instructions for creating (encoding) the ubiquitin ligase protein. This protein marks other proteins so that the body can degrade targeted proteins, a process known as ubiquitination. There may be as high as a 50 percent risk of recurrence of Angelman syndrome due to a mutation of the UBE3A gene.
Some individuals with the symptoms of Angelman syndrome have no identifiable abnormality of chromosome 15. Some individuals in this group may have a disorder different from Angelman syndrome, but others may have an undetected mutation of the UBE3A gene or a mutation in another, yet-to-be-identified gene that can also cause or mimic Angelman syndrome.
Diagnosis
A diagnosis of Angelman syndrome may be made based on detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. About 80% of cases can be confirmed through a variety of specialized blood tests such as DNA methylation (which detects but does not discriminate between chromosome deletion, imprinting center defect, and paternal uniparental disomy). Fluorescent in situ hybridization (FISH) or, most commonly, microarray chromosome analysis can detect the characteristic deletion (seen in 70% of cases) of chromosome 15q11-q13 in cells of the body. Mutation analysis of the Angelman gene, UBE3A, can detect about 10% of individuals with Angelman syndrome who have negative DNA methylation studies. Mutation analysis of UBE3A can be either ordered specifically as a single test but, more often now, UBE3A mutations are identified by the use of a whole-exome sequencing panel that includes a group of many genes known to cause intellectual deficiency or when one performs a complete whole-exome sequencing test (e.g., a screening test on approximately 20,000 genes).
The major hallmark of presentation of Angelman syndrome (AS) is characterized by movement and balance disorder (ataxia), speech deficits (absent or minimal), psychomotor delay, and inappropriate paroxysms of laughter with hand flapping (happy puppet), and seizures.
- Psychomotor Delay – Developmental delay can be seen by six months of age. Microcephaly presents before three years of age; however, it is not present in all cases. It is more common in the deletion subtype of AS.[rx] Most children with Angelman syndrome are not able to achieve ambulation until three years of age, and some never walk and remain wheelchair-bound. The gait is ataxic, with toe-walking and jerky arm movements. Some of them even have uplifted arms that are flexed at the elbows.
- Characteristic Behavior – AS patients have a unique behavioral phenotype. They have a happy demeanor with inappropriate and excessive laughter, often showing tremulous movements of limbs with hand flapping. They are easily distracted as they have a short attention span, and this leads to poor concentration. They also are easily excitable.[rx]
- Seizures – When they are three years of age, 80% of the patients have seizures, with abnormal EEGs, with spike even when there is no seizure activity (akinetic seizure). Seizures are described to improve during puberty but recur in adulthood.[rx][rx]
- Sleep Problems – AS patients may also have sleep problems. Total sleep time may be decreased with nighttime awakenings.
Other Findings
- Protruding tongue
- Tongue thrusting; suck/swallowing disorders
- Feeding problems during infancy
- Truncal hypotonia
- Prognathism
- Wide mouth, widely spaced teeth
- Frequent drooling
- Excessive chewing/mouthing behaviors
- Strabismus
- Hypopigmented—light skin, hair, and eye color
- compared with the family (seen only in the deletion cases)
- Hyperactive lower extremity deep tendon reflexes
- Wide-based gait with pronated or valgus-positioned ankles
- Uplifted, flexed arm position especially during walking
- Increased sensitivity to heat
- Sleep disturbances
- Attraction to/fascination with water
- Abnormal food-related behaviors
- Obesity (in childhood)
- Scoliosis [rx]
With aging in Individuals with Angelman syndrome, hyperactivity decreases due to increased muscle rigidity, sleep becomes better, and concentration improves. Some AS patients develop obesity in adulthood.[rx]
The first evaluation for Angelman syndrome (AS) can be started in the prenatal stage when evaluating a fetus with growth restrictions. Current studies have shown noninvasive prenatal testing (NIPS) technique is highly accurate in the diagnosis of AS prenatally.
After birth, when AS suspicion arises, workup should start with methylation studies.
- Methylation Studies – Normally, the SNRPN exon 1 region/promoter is differentially methylated, that is, the paternal allele is unmethylated, and the maternal allele is methylated. In 80% of patients with AS (consisting of deletion, imprinting center defect, and parental disomy) that maternal methylated allele cannot be found.
- FISH – FISH is done after methylation studies. It detects any deletions in the maternal chromosome 15. If negative, imprinting defects or paternal disomy must be considered. Paternal disomy is confirmed via DNA marker analysis. If negative, imprinting center defects must be considered and can be confirmed by molecular studies.
- DNA Sequencing – if the patient has a negative methylation study, but the suspicion for AS is high, DNA sequencing can be done. It rules out any mutation in UBE3A, which can be missed in methylation studies. If it is negative other alternative diagnoses must be considered.
- Polysomnography (Sleep Study) to diagnose any sleep disorders.[rx]
- Electroencephalogram (EEG): An EEG measures and records your child’s brain’s electrical signals. During an EEG, a technician places small metal disks (electrodes) on your child’s scalp. The electrodes attach to a machine that gives the healthcare provider information about your child’s brain’s activity. This test can show a characteristic brain activity pattern of Angelman syndrome and any epileptic activity, which can help in the diagnosis.
Treatment
At this time, therapies for Angelman syndrome are symptomatic and supportive. Several clinical trials on Angelman syndrome are ongoing (see below) but there is no genetic therapy or curative medication available. Advances in neuroscience and gene therapy techniques however hold great potential for providing meaningful treatment and/or cure of the syndrome.
The management of Angelman syndrome (AS) is mainly symptomatic as there is no curative treatment till now.
Therapeutic and Management Guidelines for Treating AS [rx]
Feeding Problems
- Feeding Difficulties – Sucking might be ineffective, so breastfeeding is not possible sometimes. The use of special nipples is advised, monitoring weight gain and referral to specialized teams for advice and training on feeding.
- Gastroesophageal Reflux – Administration of magnesium carbonate and aluminum hydroxide in upright positioning.
- Constipation – Increased fluid intake. Jelly can be used as an alternative. A diet rich in fiber and laxatives can also be used.
- Obesity – Regular checkups of weight and BMI. Also, regular exercise is advised.
- Diet -The ketogenic diet is helpful and is effective.[rx]
Developmental Delay
- General Developmental Delay – Organization of an early, individualized, and active intervention program. Bayle scales should be used to assess development.
- Gross and Fine Motor Delay – Physiotherapy, orthotics, and occupational therapy are required for developing motor skills, posture management, and managing contractures.
- Poor Active Communication – Speech and language therapy. This can be done using verbal and nonverbal methods of communication. Computers can help massively with this.
- Seizures – The most effective drugs are sodium valproate, clonazepam, and phenobarbital.[rx] Drugs such as carbamazepine and vigabatrin are ineffective and may cause worsening of seizures.
- Sleep Problems – Proper sleep hygiene and melatonin are effective.
- Vision Problems – Visual assessment for ocular problems is done to increase interaction and decrease autistic tendencies. Refer to an ophthalmologist if strabismus is suspected.
- Novel Therapeutic Approaches – Since all patients with AS have one functional but silenced copy of paternal UBE3A, many attempts have been made to unsilenced the paternal UBE3A allele. The paternal UBE3A allele is silenced due to the SNHG14 transcript, which caused transcriptional interference. Then, one of the ways to activate the paternal allele would be to prevent the formation of the SNHG14 transcript. This has been successful in mice with topotecan, which is a topoisomerase inhibitor.[rx] Antisense oligonucleotides(ASO) are also very promising. They function via RNA interference against SNHG14, causing its degradation.[rx]
- Anti-seizure medications (anticonvulsants) are helpful to those experiencing seizures. Usually, seizures can be adequately controlled with a single medication but in some cases, seizure control may be difficult and multiple medications are needed. No one anticonvulsant drug has been proven to be most effective in all cases. Sleep disorders are common and may require behavioral therapy and adherence to strict bedtime routines. At times, sedating medications can be helpful. Feeding difficulties may be treated by modified breastfeeding methods and by means such as special nipples to assist infants with a poor ability to suck. Gastroesophageal reflux may be treated by upright positioning and drugs that aid the movement of food through the digestive system (motility drugs). Surgical tightening of the valve that connects the esophagus to the stomach (esophageal sphincter) may be required in some cases. Laxatives may be used to treat constipation.
Ankle braces/supports and physical therapy can help in the achievement of walking. Scoliosis can develop in about 10% and may require braces or surgical correction. In some cases, strabismus may require surgical correction. Genetic counseling is recommended for the families of those with Angelman syndrome.
References
