Angelman Syndrome

What causes Angelman syndrome

We inherit two copies of most genes, one from each parent, and both usually work. In certain brain cells, however, only the mother's copy of the UBE3A gene is active, because the father's copy is switched off (a process called genomic imprinting). When the maternal UBE3A gene is missing or not working, those nerve cells lack the UBE3A protein, which is needed for normal brain development.

There are several genetic mechanisms:

Most cases happen by chance. A UBE3A mutation or imprinting defect can be inherited, so genetic counseling is important to estimate the risk for future children.

The same chromosome region is involved in Prader-Willi syndrome, but that condition results from loss of the father's genes and has very different features.

Symptoms

Babies usually appear normal at birth. Signs develop over the first year.

Development and communication

• severe developmental delay, noticeable by 6 to 12 months
• intellectual disability, usually severe
• little or no speech. Most people use fewer than a few words, but understanding is better than expression, and many communicate well with gestures, signs or devices

Movement

• unsteady, jerky movements and a wide-based, stiff-legged walk with arms held up
• tremor of the limbs
• some children walk late or not at all

Behavior

• frequent laughter and smiling, and an easily excitable personality
• hand-flapping when excited
• short attention span and hyperactivity
• fascination with water, mirrors and crinkly objects

Other features

• Epilepsy: seizures affect most people with Angelman syndrome, usually starting before age 3, and can be hard to control
• sleep problems: reduced need for sleep and frequent night waking
• small head size (microcephaly) by age 2 in many children
• feeding problems and reflux in infancy, later excessive chewing or mouthing
• strabismus (crossed eyes)
• fair skin and light hair in children with the deletion type
• scoliosis in adolescence and adulthood

Diagnosis

Angelman syndrome is suspected from the combination of severe delay, absent speech, movement problems and happy behavior. Testing proceeds in steps:

1. DNA methylation analysis of chromosome 15: detects about 80% of cases (deletions, uniparental disomy and imprinting defects).
2. Chromosomal microarray or FISH to identify a deletion.
3. UBE3A gene sequencing if methylation is normal.
4. EEG often shows a characteristic pattern, even without obvious seizures.

Conditions that can look similar include Rett syndrome, Pitt-Hopkins syndrome, cerebral palsy and autism.

Treatment and care

There is no approved cure, but a team approach helps:

• Seizure control: anti-seizure medicines chosen by a neurologist. Some medicines can worsen certain seizure types in Angelman syndrome, so specialist input matters. Dietary therapies such as the ketogenic diet help some children.
• Sleep: consistent routines, a safe sleep space and, if needed, melatonin or other medicines.
• Communication therapy: early use of signs, picture systems and speech-generating devices.
• Physical and occupational therapy: balance, walking, fine motor skills and daily living.
• Behavior support for hyperactivity and difficult behavior.
• Monitoring for scoliosis, eye problems, reflux, constipation and weight.

Clinical trials of treatments that switch on the father's silenced copy of UBE3A, such as antisense oligonucleotides, are underway.

Outlook

People with Angelman syndrome have a near-normal life expectancy. Seizures often become easier to control in adulthood, and hyperactivity and sleep problems tend to improve with age. Most adults need lifelong support with daily living. Many are sociable and affectionate, and enjoy music, water and social contact.

Frequently asked questions

What causes Angelman syndrome?

It is caused by loss of function of the UBE3A gene on the chromosome 15 inherited from the mother. Most often a small piece of the mother's chromosome 15 is missing. Other causes are a UBE3A mutation, two copies of chromosome 15 from the father, or an imprinting defect.

What are the main symptoms of Angelman syndrome?

The main features are severe developmental delay, little or no speech, unsteady jerky movements, seizures, sleep problems and a happy, excitable demeanor with frequent laughter and hand-flapping. Many children also have a small head size and feeding problems as babies.

What is the life expectancy with Angelman syndrome?

Life expectancy is close to normal. Most people with Angelman syndrome live into adulthood and older age. Good seizure control, prevention of injuries and aspiration, and attention to scoliosis and general health support long-term wellbeing.

Is Angelman syndrome inherited?

Usually not. Most cases arise by chance, and the chance of it happening again in the same family is under 1%. When it is caused by a UBE3A mutation or certain imprinting defects in the mother, the recurrence risk can be as high as 50%, so genetic counseling is recommended.

What is the difference between Angelman and Prader-Willi syndrome?

Both involve the same region of chromosome 15. Angelman syndrome results from loss of the mother's genes and causes severe delay, absent speech, seizures and a happy demeanor. Prader-Willi results from loss of the father's genes and causes low muscle tone, constant hunger and obesity risk.