Angelman syndrome is a severe genetic disorder characterized by progressive physical and mental disabilities. It shares many characteristics with more common disorders like autism, cerebral palsy and mitochondrial encephalomyopathy, making it difficult to diagnose. About half of all Angelman syndrome patients are initially misdiagnosed.

A correct and early diagnosis is important for many reasons, not least of which is that disease symptoms such as seizures can be life-threatening.

Physicians can use a variety of methods to diagnose Angelman syndrome, and these are summarized below.

Clinical evaluation

The doctor will obtain a detailed account of the patient’s medical history, and complete a comprehensive physical examination. Angelman syndrome may be suspected if the patient has physical and mental developmental delays. Specific physical disease indicators include issues with movement and balance, small head size (known as microcephaly), a flatness to the back of the head (known as brachycephaly), hyperactivity, and frequent smiling and laughing for no obvious reason.

Electroencephalogram (EEG)

An electroencephalogram (EEG) is a test that measures electrical patterns in the brain. Angelman patients have several distinct patterns that are visible using this test, and which doctors can use to distinguish Angelman syndrome from other diseases.

Magnetic resonance imaging (MRI)

Magnetic resonance imaging (MRI) can be used to visualize the brain. People with Angelman syndrome may have a lower-than-usual amount of white matter in the brain (white matter being the long fibers of nerve cells). These nerve fibers are normally surrounded and protected by a protein coat called the myelin sheath — this myelination is diminished in Angelman syndrome patients.

Positron emission tomography (PET) scan

A positron emission tomography (PET) scan is an imaging test that can be used to visualize tissue and organ function. A radioactive tracer is ingested or inhaled by the patient, or injected into the patient’s body, and a machine visualizes the tracer as it moves through the body. In Angelman syndrome, PET scans can be used to measure how well signaling molecule receptors are working in the brain.

Computerized tomography (CT) scan

A computerized tomography (CT) scan uses a number of X-ray images, taken in a series, to build a cross-sectional model of bones and tissues. CT scans are often taken early in efforts to diagnose Angelman syndrome. Distinctive disease features are usually not observed by CT scan of Angelman patients.

Genetic testing

Angelman syndrome is caused by a missing or inactive maternal UBE3A gene, which is needed for certain neurologic functions. About 70 percent of Angelman syndrome cases are caused by a deletion in the region of maternal chromosome 15 where the UBE3A gene resides. In a smaller percentage of cases, the maternal UBE3A gene may be present but inactive.

The rarest cause is a genetic phenomenon known as paternal uniparental disomy, in which the patient inherits two copies of chromosome 15 from the father, so no maternal UBE3A gene exists in their cells.

Several tests, conducted on blood samples, typically are needed to identify Angelman syndrome because of the various genetic defects that can cause the disorder:

Cytogenetics analysis

A standard chromosome test is used to look for clear changes in chromosomes, such as very large deletions (or chunks of missing DNA), rearrangements, or duplications. This test alone is generally not detailed enough to diagnose the disease, but it does allow physicians to rule out other neurologic disorders that may be easily confused with Angelman syndrome. This test is similar to the general prenatal genetic screening test that a pregnant woman may undergo.

Assessing chromosome 15 activity

Chromosome 15 activity can be assessed using the DNA methylation test. For this test, specific parts of both the maternal and paternal chromosome 15 are tagged. This lets scientists identify distinct patterns in the chromosome, and determine whether these patterns are present in the maternal or paternal copies. If the specific maternal pattern indicates that the UBE3A gene is missing, a doctor can conclude that the patient has Angelman syndrome. A positive DNA methylation test can identify about 80 percent of Angelman patients.

Detecting a missing UBE3A gene

A technique called fluorescence in situ hybridization (FISH) or a comparative genomic hybridization (CGH) test can be used to identify whether parts of a chromosome are missing or have been deleted. This test must be completed with an accompanying DNA methylation test in order to rule out Prader-Willi syndrome — a markedly different disorder in which the deletion is on the paternal chromosome.

Ruling out uniparental disomy and imprinting defects

If the DNA methylation test is positive but the FISH test is negative, the physician will likely request a polymerase chain reaction (PCR) assay. This test requires a blood sample from the patient and both parents, so the child’s chromosome 15 inheritance can be determined. If there is no evidence of a maternal copy of chromosome 15 in the child’s DNA, the physician will diagnose the patient with Angelman syndrome, with uniparental disomy as the cause.

A PCR assay can also identify small mutations or deletions in the child’s maternal chromosome 15, called imprinting center defects, which would also cause Angelman syndrome. Sometimes, a misprint in the child’s DNA can be linked back to a similar alteration in the mother’s DNA. This would indicate an unusual case of inherited Angelman syndrome.

Identifying gene mutations

Although rare, Angelman syndrome can be caused by an active UBE3A gene with an error in the DNA sequence. If all other tests are negative, the sequence of nucleotides, or the genetic building blocks of the DNA, in the UBE3A gene will be reviewed. This test is called for in about 20 percent of patients.

 

Last updated: Oct 03, 2019

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Angelman Syndrome News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. 

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Özge has a MSc. in Molecular Genetics from the University of Leicester and a PhD in Developmental Biology from Queen Mary University of London. She worked as a Post-doctoral Research Associate at the University of Leicester for six years in the field of Behavioural Neurology before moving into science communication. She worked as the Research Communication Officer at a London based charity for almost two years.