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Angelman Syndrome: Causes, Symptoms, Clinical Diagnosis, and Treatment Options

Information on the causes, symptoms, clinical diagnosis, and treatment options of Angelman Syndrome

Angelman Syndrome is a rare genetic disorder that has received orphan disease designation.
Genetic testing to examine the gene called UBE3A, whether normal or abnormal, reveals that the loss of normal function within nerve cells is the cause.
There is currently no fundamental treatment, and development is ongoing overseas.

Table of Contents

What is Angelman Syndrome?

Angelman Syndrome is a rare genetic disorder observed in approximately one out of every 15,000 individuals. In Japan, it is designated as one of the rare diseases, with over 3,000 confirmed patients, and is considered a lifelong hereditary condition. The onset of this condition is known to be caused by abnormalities in the ubiquitin-protein ligase E3A (UBE3A) gene, such as deletion of the maternally inherited chromosome 15 (q11-q13 deletion), paternal uniparental disomy of chromosome 15, imprinting mutations, or mutations in UBE3A itself. Symptoms include severe impairments in behavior, learning, verbal communication, motor skills, and sleep, associated with increased uptake of GABA and decreased sustained inhibition. Furthermore, there are currently no approved drugs or established treatments specifically for Angelman Syndrome, and management remains symptomatic.

Causes of Angelman Syndrome

The cause of Angelman Syndrome is attributed to the loss of function of the UBE3A gene, which disrupts communication between nerve cells. This disorder manifests various symptoms in behavior and cognition due to the loss of UBE3A function, leading to impaired inhibition of tension. The UBE3A gene is located on chromosome 15 in humans and is known to be expressed from the maternally inherited chromosome through genomic imprinting in neuronal cells. This distinctive expression mechanism involves molecular control of gene transcription by non-coding RNA (ncRNA). In cells other than neuronal cells, this ncRNA is suppressed on the maternal chromosome but expressed on the paternal chromosome. In neuronal cells, UBE3A from the maternally inherited chromosome is expressed, whereas in patterns as described below, the normal UBE3A gene is not expressed, leading to the development of Angelman Syndrome.

  • Deletion of the maternally inherited chromosome's UBE3A (15q11-q13)
  • Paternal uniparental disomy of chromosome 15 (both copies of chromosome 15 are inherited from the father, resulting in the absence of the maternally inherited UBE3A gene expected to be neuron-specifically expressed)
  • Mutation affecting the imprinting mechanism (inhibiting the expression mechanism known as imprinting)
  • Mutation in the UBE3A gene itself

Clinical Symptoms of Angelman Syndrome

Angelman Syndrome is often not symptomatic in newborns, and delayed development is typically first observed around 6 months of age. Clinical signs specific to Angelman Syndrome, as shown below, may not become prominent until after 1 year of age, making it possible not to immediately recognize the condition. Additionally, the symptoms that appear can vary depending on the cause (whether there is a deletion in the UBE3A gene or not), as described earlier.

Common Symptoms of Angelman Syndrome

  • Normal head size at birth and no significant congenital malformations observed during delivery or prenatal period
  • Metabolic function, hematological parameters, and other clinical test results from blood samples are within normal range
  • Imaging diagnosis using CT or MRI shows normal brain structure. Abnormalities in myelin formation in the brain or mild cortical atrophy may sometimes be observed
  • Developmental delay (without regression)
  • Growth delay (manifesting by around 12 months of age and progressing severely
  • Language impairment (minimal use of words or absence of meaningful speech. High receptive language abilities in sensory non-verbal communication, but low expressive language abilities)
  • Motor impairments, balance issues, inability to walk normally, and often observed tremors in limbs
  • Specific behaviors (e.g., frequent laughter, smiling, showing happy behavior, clapping hands, increased hyperactivity, short attention span) indicative of the syndrome

Symptoms observed in over 80% of patients

  • Absolute (or relative) microcephaly is observed by the age of 2 due to delayed growth in head size
  • Seizures, often noticed in many cases before the age of 3
  • Specific abnormal brain waves characteristic of the syndrome, observed as high-amplitude slow waves (delta) complexes

Symptoms observed in less than 80% of patients

  • Flattened occiput, occipital groove
  • Tongue habits (protrusion or manipulation of the tongue) and associated sucking or swallowing difficulties
  • Feeding difficulties observed in infancy, with reduced muscle tone
  • Prominent features of the face such as protruding upper jaw, wide mouth, wide spaces between teeth, and strabismus
  • Excessive drooling, mouthing objects, or excessive chewing behavior
  • Hypopigmentation of the skin (lighter hair and eye color compared to blood relatives; observed only in cases with confirmed deletions)
  • Hyperactive deep tendon reflexes (in the lower limbs)
  • Postures commonly observed during walking (raising and flexing arms)
  • Wide-based gait and outwardly turned ankles (pronation or supination of the ankles)
  • Heightened sensitivity to temperature changes
  • Abnormalities in sleep-wake rhythms, requiring less sleep
  • Strong interest in specific textures like water, vinyl, paper (objects that produce crackling sounds)
  • Abnormal behaviors related to food
  • Obesity in older ages (less common in individuals with gene deletions)
  • Scoliosis
  • Constipation

Clinical Diagnosis and Testing for Angelman Syndrome

The responsible gene for Angelman syndrome is known to be UBE3A. Therefore, clinical diagnosis is made by testing genes in the region containing the UBE3A gene. In Japan, the following are used as diagnostic criteria. However, it is important to note that there may be cases where unknown genes or other factors affect UBE3A, potentially leading to Angelman syndrome without necessarily meeting the conditions listed below.

"A confirmed diagnosis of Angelman syndrome is made if any of the following are observed in the 15q11.2-15q11.3 region of chromosome 15: deletion, uniparental disomy, or abnormal imprinting mechanism, along with mutations in the responsible gene (UBE3A gene, etc.), and the presence of symptoms 3 and 4 listed below."

I. Major Clinical Symptoms

  • 1. Easily provoked laughter
  • 2. Ataxic gait (difficulty in walking)
  • 3. Characteristic facial features of Angelman syndrome (including protruding jaw)
  • 4. Delayed mental development
  • 5. Seizures (epileptic seizures)

Therapeutic Approaches Expected to Benefit Angelman Syndrome

There is currently no medication specifically for Angelman syndrome, and only symptomatic treatments are available for the aforementioned symptoms. However, in recent years, clinical trials have been progressing overseas, and two potential drug candidates have emerged. One is an oral drug called OV101 (gaboxadol), which acts by antagonizing the γ-aminobutyric acid (GABA)A receptor, aiming to reduce the increased uptake of GABA, believed to be a cause of Angelman syndrome symptoms, and decrease sustained inhibition. As of 2020, it has progressed to Phase 3 trials in the United States and is registered in a fast-track program for priority review, potentially paving the way for approval as the first treatment for Angelman syndrome from 2021 onwards. The other candidate is GTX-102, an intrathecal administration drug that inhibits the function of UBE3A, the responsible gene for Angelman syndrome, aiming to prevent its onset. Clinical trials for GTX-102 started in North America and Europe in 2020, suggesting approval may take longer than OV101, but it is also registered in a similar program with expectations for approval.

References