Angelman syndrome is a severe genetic disorder that causes permanent 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. Because some of its symptoms such as seizures and poor communication can be life-threatening, the diagnosis of Angelman syndrome must be correct and quick.
Physicians use two distinct methods in the diagnosis of Angelman syndrome: a thorough clinical evaluation and a combination of genetic tests. Because symptoms can be misleading, the physician may look for other causes before attempting to specifically diagnose Angelman syndrome using genetic testing.
The doctor will obtain a detailed account of the patient’s medical history and complete an exhaustive physical examination. Angelman syndrome may be suspected if the patient has physical and mental developmental delays. Specific physical indicators of the disease include issues with movement and balance, small head size (known as microcephaly), flat back of the head (known as brachycephaly), and frequent smiling and laughter.
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 typically need to be used to identify Angelman syndrome because of the various genetic defects that can cause the disorder.
A standard chromosome test is used to look for clear changes in chromosomes, such as very large deletions (or chunks of DNA missing), 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 testing 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 are present in the maternal or paternal copies. If the specific maternal pattern indicates that the UBE3A gene is missing, the patient has Angelman syndrome. Testing positive in the DNA methylation test identifies about 80 percent of patients with Angelman syndrome.
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 — 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.
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