Diagnosis of Angelman Syndrome

Angelman syndrome is a genetic disorder characterized by physical and mental disabilities. It is caused by genetic abnormalities in the gene UBE3A.

Infants with Angelman syndrome do not typically manifest any abnormalities when they are born or within the first few months of life. Usually, developmental delays are first noted at about 6 months of age, though these delays are generally nonspecific. Unique features of Angelman syndrome  usually do not become apparent until age 1 or older.

A diagnosis of Angelman syndrome often is first suspected due to behavioral and developmental abnormalities, most notably the combination of absent speech, movement disorders, and an unusually happy demeanor. While Angelman syndrome can cause physical abnormalities such as a small head (microcephaly), it is uncommon for physical abnormalities to serve as the basis for diagnosis.

Because Angelman syndrome shares many characteristics with more common disorders like autism and cerebral palsy, it can be difficult to diagnose, especially early on. About half of all Angelman syndrome patients are misdiagnosed initially.

A definitive diagnosis of Angelman syndrome is made when genetic testing reveals abnormalities in the UBE3A gene. Other tests may help to identify the condition, or rule out other conditions with similar symptoms.

Genetic testing

Angelman syndrome is caused by a missing or inactive maternal UBE3A gene, which is needed for certain neurologic functions. About three-quarters 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 through abnormalities in a process called genetic imprinting. The rarest cause is a genetic phenomenon known as paternal uniparental disomy, in which the patient inherits two copies of chromosome 15 from the biological father, so no maternal UBE3A gene exists in their cells.

Several tests, usually 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 (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 is sometimes done during pregnancy.

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 with specialized markers. This allows scientists to  identify distinct biochemical patterns on 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% 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 caused by genetic abnormalities in the paternal chromosome, rather than the maternal chromosome.

Ruling out uniparental disomy and imprinting defects

If the DNA methylation test is positive but the FISH test is negative, a physician likely will request a polymerase chain reaction (PCR) assay. This test requires a blood sample from the patient and both biological parents. By comparing the sequences of chromosome 15 in each, 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 also can identify small mutations or deletions in the child’s maternal chromosome 15, called imprinting center defects, which also would 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  the genetic building blocks of the DNA — in the UBE3A gene should be analyzed.

Neurological and imaging tests

A variety of other clinical tests can aid in the diagnosis of Angelman syndrome, and can be useful for differential diagnosis — that is, distinguishing between Angelman syndrome and other conditions that may appear similar.

Electroencephalogram 

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 doctors can use the EEG result to distinguish Angelman syndrome from other diseases.

Magnetic resonance imaging 

Magnetic resonance imaging 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; the amount of myelin is diminished in Angelman syndrome patients.

Positron emission tomography

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

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 often are used early in efforts to diagnose Angelman syndrome. 

 

Last updated: May 5, 2021

 

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