Understanding Angelman Syndrome

Introduction

Understanding Angelman Syndrome is important for the parents of an affected person, but also it’s valuable to spread awareness and knowledge amongst the wider population. Angelman Syndrome (AS) is a rare neurogenetic disorder that affects approximately one in 15,000 people – about 500,000 individuals worldwide. Children and adults with Angelman Syndrome typically have balance issues, motor impairment and debilitating seizures. Some individuals never walk. Most do not speak. Disrupted sleep cycles also can be a serious challenge to the individual and caretaker(s). Individuals with Angelman Syndrome require continuous care and are unable to live independently. They have a normal life expectancy. This is life today for people living with Angelman syndrome, but hope is here.

Scientists believe that Angelman Syndrome has the greatest potential for being cured when compared to other neurogenetic disorders, and FAST (Foundation for Angelman Syndrome Therapeutics) has a plan well underway to achieve just that.

Video Explanation

Types

There are multiple types of the syndrome, some more common the others. And the symptoms vary quite significantly.

Deletion (65-75%)

DNA (deoxyribonucleic acid) is the main component of chromosomes. It contains our unique genetic code. Most individuals with Angelman Syndrome are missing a piece of DNA in region 15q11-13 on the maternal chromosome 15.

Mutation (5-11%)

This occurs when there is a small abnormality in the DNA of the UBE3A gene. A mutation can happen anywhere on the gene.

UPD or Uniparental Disomy (3-7%)

An individual with UPD has two copies of chromosome 15 from their father, instead of one each from the father and mother. UPD usually happens if there is no chromosome 15 in the egg.

ICD or Imprinting Centre Defect (<3%)

The imprinting centre is a small stretch of DNA located in the q11-13 region of the chromosome. In rare cases, the mother’s chromosome 15 is blank, and the centre copies the father’s chromosome 15. This is an imprinting defect.

Characteristics

Typical characteristics of Angelman Syndrome are not usually evident at birth. People with the disorder have feeding difficulties as infants and noticeable delayed development around 6-12 months of age. They need intensive therapies to help develop functional skills. Angelman Syndrome affects every race and both genders. It is often misdiagnosed as autism or cerebral palsy.

Behavioral Traits

People with Angelman syndrome have some distinct behavioural traits, including a happy demeanor, characterised by frequent laughing, smiling and excitability. Many individuals with Angelman Syndrome have a fascination with water and take great pleasure in activities like swimming and bathing.

Causes of Angelman Syndrome

Angelman syndrome is a single-gene disorder caused by a loss of function in the UBE3A gene on the maternal 15th chromosome. People have two sets of chromosomes – one inherited from the mother and one from the father. In a typical person, the maternally inherited UBE3A gene is active, while the copy of the gene inherited from the father is silenced in the neurons in our brains – a phenomenon known as imprinting. For people with Angelman Syndrome, this maternal gene is not doing its job, and that impacts their Messenger RNA (mRNA).

What is mRNA?

mRNA is the FedEx of the body. Our DNA uses mRNA as a delivery service to send blueprints to the protein-assembly factories of our cells. People with Angelman Syndrome have a mutation, deletion or other defect in their UBE3A gene that interrupts this delivery service. As a result, their neurons do not make any functional UBE3A protein, and that’s what triggers the symptoms of Angelman Syndrome. This protein is what helps us walk, talk and perform other everyday tasks.

Is it Genetic?

In most cases, Angelman Syndrome isn’t inherited – particularly those caused by a deletion or UPD. Instead, these genetic changes occur as random events during the formation of reproductive cells or in early embryonic development.

Testing

Suspicion of Angelman Syndrome; Chromosomal microarray or FISH; Methylation test; Abnormal; Normal; Maternal; Paternal; Prader-Willi deletion; DNA markers for UPD; UBE3A mutation analysis; AS deletion positive; AS from UPD; AS from ID; UBE3A PCR; Whole genome sequencing; AS UBE3A mutation; AS deletion positive
FAST US

Medical Diagnosis Criteria

Findings typically present in affected individuals:

  • Normal prenatal and birth history, normal head circumference at birth, no major birth defects.
  • Normal metabolic, hematologic, and chemical laboratory profiles.
  • Structurally normal brain by magnetic resonance imaging (MRI) or computed tomography, although mild cortical atrophy or dysmyelination may be observed.
  • Delayed attainment of developmental milestones without loss of skills.
  • Evidence of developmental delay by age 6 to 12 months, eventually classified as severe.
  • Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills.
  • Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs.
  • Behavioural uniqueness, including any combination of frequent laughter/smiling; apparent happy demeanor; excitability, often with hand-flapping movements; hypermotoric behavior; short attention span.

Findings in more than 80% of affected individuals:

  • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age 2 years.
  • Seizures, usually starting before age 3 years.
  • Abnormal electroencephalogram (EEG), with a characteristic pattern of large-amplitude slow-spike waves.

Findings in fewer than 80% of affected individuals:

  • Flat occiput.
  • Occipital groove.
  • Protruding tongue.
  • Tongue thrusting; suck/swallowing disorders.
  • Feeding problems and/or muscle hypotonia during infancy.
  • Prognathia.
  • Wide mouth, wide-spaced teeth.
  • Frequent drooling.
  • Excessive chewing/mouthing behaviours.
  • Strabismus.
  • Hypopigmented skin, light hair and eye color (compared with family); seen only in those with a deletion.
  • Hyperactive lower-extremity deep-tendon reflexes.
  • Uplifted, flexed arm position especially during ambulation.
  • Wide-based gait with out-going (i.e., pronated or valgus-positioned) ankles.
  • Increased sensitivity to heat.
  • Abnormal sleep-wake cycles and diminished need for sleep.
  • Attraction to/fascination with water; fascination with crinkly items such as certain papers and plastics.
  • Abnormal food-related behaviours.
  • Obesity (in the older child; more common in those who do not have a deletion).
  • Scoliosis.
  • Constipation.

Source: “Genetics in Medicine: Clinical and genetic aspects of Angelman syndrome.” Charles A. Williams, M.D., Daniel J. Driscoll, Ph.D., M.D. and Aditi I. Dagli, M.D. May 2010 © 2010 Lippincott Williams & Wilkins