Angelman Syndrome

Etiology

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.[4]

AS is typically caused by a sporadic de novo mutation on the maternal gene UBE3A (part of the ubiquitin pathway) at chromosome 15q11-13. Around 70 to 75% of cases arise from maternal deletion within chromosome 15q11-q13, containing this gene. Approximately 2% to 3% can be due to paternal uniparental disomy (UPD), imprinting center defect (3% to 5%), or single gene point mutation in the maternal UBE3A allele (5 to 10%).[5]

Inherited causes of AS are mostly either due to UBE3A mutation (mainly in the mother's paternally inherited allele), which is inherited by the baby and a subtype of imprinting defects called submicroscopic deletion of imprinting center.[6][7]

Epidemiology

The incidence of Angelman syndrome (AS) varies from 1 in 20,000 to 1 in 12,000 live birth. There is no gender preference, and AS affects males and females equally.[8] However, many cases may go undiagnosed due to the underreporting of cases and misdiagnosis.[9]

Pathophysiology

The findings of Angelman syndrome (AS) are mostly limited to the nervous system because physiologically paternal UBE3A is only imprinted in the brain. So if there is a pathologic loss of function mutation of maternal UBE3A, mainly the brain is affected.[10]

UBE3A codes for a ubiquitin ligase called E6-associated protein (E6-AP).[11] E6-AP is critical for the functioning of the ubiquitin-proteasome pathway, which is essential for the normal functioning of neurons and synaptic plasticity. Loss of function mutation of E6-AP causes impaired ubiquitin-proteasome degradation of many proteins. Many targets of E6-AP that have been identified are p53, p27, Arc, and ephexin5. P53 and p27 are crucial for the regulation of cell survival in the nervous system. Elevation of Arc levels increases the internalization of surface AMPA receptors causing impairment of post-synaptic excitatory transmission. Increased expression of ephexin5, which regulates synapse formation, caused decreased synapse formation. Together with increased levels of Arc and ephexin5 cause decreased experience-dependent synapse remodeling. This gives rise to neurologic deficits.[12][13][14][15][16]

Mouse models of AS with UBE3A knockout of the maternal gene have shown ataxia, seizures, decreased size of the brain, motor abnormalities. These models have also demonstrated deficits in hippocampal long term potentiation (LTP), which explains deficits in memory and learning in AS patients.[17] Also, several of these experiments have shown abnormal dendritic morphology and decreased spine density. This might also explain the motor and cognitive deficits in AS.[18]

There are mainly four mechanisms that cause loss of function of UBE3A. These are deletion, mutation, imprinting, and uniparental disomy.

The most severe symptoms are seen in the deletion subtype, out of which class 1 has the worst clinical phenotype. These include global developmental delay, microcephaly, and seizures, no speech, and oculocutaneous hypopigmentation. Increased susceptibility to seizures is seen since some of the GABA genes are deleted in deletion mutations. The deletion of OCA1 genes in combination with the regulatory effect of UBE3A on MC1R might explain oculocutaneous hypopigmentation.[19][20]

History and Physical

The major hallmark of presentation of Angelman syndrome (AS) is characterized by movement and balance disorder (ataxia), speech deficits (absent or minimal), psychomotor delay, 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.[21] 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.[22]

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.[23][24] 

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 [2]

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.[7]

Evaluation

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 diagnose 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 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.

EEG can show a characteristic pattern of AS and also an epileptic activity, which can help in the diagnosis of AS.

Polysomnography (Sleep Study) to diagnose any sleep disorders.[25]

Treatment / Management

 The management of Angelman syndrome (AS) is mainly symptomatic as there is no curative treatment till now.

Therapeutic and Management Guidelines for Treating AS[26]

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 checkup of weight and BMI. Also, regular exercise is advised.
• Diet -The ketogenic diet is helpful and is effective.[27]
(B3)

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.[9] 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.[28](B3)

Antisense oligonucleotides(ASO) are also very promising. They function via RNA interference against SNHG14, causing its degradation.[29](B3)

Differential Diagnosis

 It is essential to rule out other neurodevelopmental disorders that can resemble Angelman syndrome (AS), including:

Microdeletion Syndromes[30][31]

• Phelan–McDermid syndrome (22q13.3 deletion)
• MBD5 haploinsuffi­ciency syndrome (2q23.1 deletion) 
• KANSL1 haplo­insufficiency syndrome (17q21.31 deletion)

 Single Gene Disorders[31]

• Pitt–Hopkins syndrome(TCF4 haploinsufficiency)
• Christianson syndrome(SLC9A6 mutation)
• Mowat–Wilson syndrome( ZEB2 haploinsufficiency)
• Rett syndrome(MECP2 mutations)
• Kleefstra syndrome (EHMT1)

Prognosis

All the individuals with Angelman syndrome (AS) will have some form of developmental delay, speech, and motor deficits. However, there are many variations in the severity of these symptoms. This depends on the genetic cause of AS (big deletions have the worse prognosis), time of diagnosis, and intervention. Some patients can achieve a higher degree of ambulation, speech, and independence in tasks of daily living. 

Most individuals with AS will have a normal life span. They do not show any developmental regression, and they might become better with some self-help skills with supportive care. Most of the patients remain dependent and need constant care and attention as they have perilous behavior. Prognosis improves remarkably with early diagnosis and interventions like speech, physical, and occupational therapies.

Symptoms of AS vary with age. Most patients have decreased frequency of seizures, hyperactivity, and improved sleep as they age. However, they may become obese as they age, which can cause scoliosis and reduce mobility. Puberty seems unaffected with normal sexual development.[2]

Complications

The main complications arising in Angelman syndrome (AS) individuals are due to their comorbidities. Due to the seizure and ataxia, the patient can have injuries during these episodes. The combination of hyperactivity, exploratory behavior, and intellectual disability in patients with AS leads to an increased risk of accidents.[26] This contributes majorly to the morbidity and mortality of AS individuals.

Between 20 to 80% can present with feeding difficulties requiring nutrition evaluation or even surgical intervention, nasogastric tube placement, depending on the severity of the malnutrition. Developmental delay is commonly seen in different ranges, but the majority of the patient will not be able to care for themselves.