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Editor—Angelman syndrome (AS) is a genetic disorder characterised by severe mental retardation, no speech, a wide based gait with arms flexed at the elbows, resembling a newly walking toddler, paroxysms of laughter, characteristic facial features, epileptic seizures, and typical EEG abnormalities.1-3 The clinical diagnosis can be confirmed by chromosomal studies or molecular analysis in about 80% of patients, in most of whom a maternally inherited deletion of chromosome 15q11-13 is found. Rarely, other abnormalities are found, such as an abnormal methylation pattern of the 15q11-13 region of the maternal chromosome, paternal uniparental disomy (UPD), or imprinting centre mutations. In the remaining 20% no abnormality can be identified. Recently, two groups described mutations in the E6-AP ubiquitin protein ligase gene (UBE3A), located within the 15q11-13 region,4 5 suggesting that deficiency of theUBE3A locus could cause AS.
We previously described AS patients without a detectable deletion or UPD who had been diagnosed with AS on the basis of clinical signs and symptoms as well as EEG findings.6 The DNA samples available to the Department of Clinical Genetics in Rotterdam (n=7) were analysed for mutations in the UBE3Agene. The clinical signs and symptoms of the patients are described in table 1. The cases were two brothers aged 14 and 19 years (patients 1 and 2), one female aged 53 years, an apparently sporadic case (patient 3), male monozygotic twins aged 31 years (patients 4 and 5), and two brothers aged 20 and 16 years (patients 6 and 7).6 In addition, we included the 4 year old affected half sister of patients 6 and 7 (patient 8), who has the same mother. All mothers were phenotypically normal. Five patients have had epileptic seizures. Two of them are seizure free (patients 6 and 7, one taking antiepileptic drugs (AEDs) and one without AEDs) and the other three have absence seizures (patients 1 and 2) or a combination of absence seizures and myoclonic seizures (patient 3). Three patients had never had epileptic seizures. EEG studies have been performed in all patients. The specific EEG findings have been previously described.2 3 6 The results are shown in table1.
Mutations were identified by SSCP analysis of genomic DNA, direct sequencing of exons with aberrant patterns, and confirmation by allele specific oligonucleotide hybridisation. When available, parental DNA was included in the analysis. Patients 1 and 2 had a 1 bp insertion in exon 16 (3027insT), which was shown to be of maternal origin. Patient 3 was found to have a 2 bp deletion in exon 9 (946delAG). The monozygotic twins (patients 4 and 5) had a mutation 3076ins4 in exon 16. Patients 6, 7, and 8 had a 7 bp deletion starting at position −12, in intron 11, which was also found in their mother’s DNA. The effect of this deletion is currently being investigated at the RNA level. Hence, we detected mutations in each of four unrelated cases, two of which were clearly familial. Other studies reported detection of a UBE3A mutation in eight of 10 familial cases7 and six of eight familial cases,8 whereas much lower detection rates were reported in isolated cases (around 20%).
Although the spectrum of clinical signs and symptoms of our patients is essentially the same as in AS patients in general, the overall phenotype seems to be milder than in AS patients with a chromosome 15q11-13 deletion. To investigate this further, it will be necessary to compare our clinical observations with future reports on AS patients with UBE3A mutations. The epileptic seizures in our group of patients are also less severe and easier to control with AEDs.6 9 The same UBE3Amutation may lead to different AS phenotypes. The 4 year old patient, a half sister of patients 6 and 7, is moderately retarded, has milder dysmorphic AS features than her half brothers, and has had no epileptic seizures so far. One of the monozygotic twins has a severe thoracic scoliosis and the other a mild one.
Our study shows that the clinical signs and symptoms in AS patients combined with specific EEG patterns may result in a very high detection rate of UBE3A mutations.
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