Clinical Quiz Answer
What is the diagnosis?
What is the diagnosis?
In view of his global developmental delay, aCGH was performed, and it came back negative. As there was concomitant movement disorder, frequent laughter and sleep disturbances, Angelman syndrome was suspected, and DNA methylation study was also performed. Methylation study showed amplification of the unmethylated paternal allele and absence of the methylated maternal allele of SNRPN gene (Figure 2). The molecular diagnosis of Angelman syndrome was thus confirmed.
In order to determine the genetic mechanism behind the diagnosis of Angelman syndrome, DNA of the index patient and his parents was taken for uniparental disomy studies. The pattern of the short tandem repeat (STR) markers from chromosome 15 suggested that the index patient had a pair of identical chromosome 15 of paternal origin (Figure 3) in view of previous normal aCGH result. This was confirmatory of paternal uniparental disomy (UPD) 15.
What is Angelman syndrome?
Angelman syndrome is a neurodevelopmental disorder with reported incidence of one in 10,000 to one in 40,000.1 It was first described by British paediatrician Harry Angelman in 1965, who referred to three children as 'puppet children', with their unusual arm position and jerky movement.2 The term 'happy puppet syndrome' is no longer used owing to its derogatory implications. Nonetheless, children with Angelman syndrome share common behavioural phenotype with easy excitation, happy demeanor and frequent laughter; and are also hypermotoric with jerky movement and difficulty with balance. Like our index patient, they usually have normal prenatal and birth history, normal growth parameters at birth, normal biochemical profiles and brain imaging. Developmental delay usually becomes apparent by 6-12 months, followed by occurrence of seizure between 1 to 3 years.3 Most of them are severely intellectually impaired and do not have any spoken language at all, even though many of them can communicate using nonverbal communication system. For clinical and molecular findings of Chinese patients with Angelman syndrome in Hong Kong, a good summary has just been published by Luk et al.4
What are the diagnostic criteria for Angelman syndrome?
Consensus criteria for diagnosis of Angelman syndrome was published by an expert panel in 1995 and subsequently revised in 2005 (See Table 1).5,6
What are the genetic anomalies associated with Angelman syndrome?
The gene responsible for Angelman syndrome is UBE3A, located at chromosome 15q11-q13. The region also contains the SNRPN gene, which is used as a marker during methylation study in this case. UBE3A codes for an ubiquitin protein ligase, which may play a role in posttranslational processing of precursor proteins involved in synaptogenesis and at synaptic receptor level. This gene is paternally imprinted in the brain, meaning that the paternal copy of the gene is silenced and that expression of the gene depends entirely on the maternal copy. However, the gene remains normally expressed elsewhere in the body.
There are four ways in which UBE3A can be affected:3
Most deletions and uniparental disomies are sporadic, where the recurrence rate is low. However, in cases due to maternally inherited UBE3A mutations,9,10 the recurrence risk can be as high as 50%. Half of the imprinting defects are also caused by maternal inheritance of a submicroscopic imprinting centre deletion.11 As such it is important to offer maternal screening in cases with UBE3A mutations or imprinting defects.
DNA methylation study is the first line investigation in the diagnostic algorithm of Angelman syndrome. If it is negative, then UBE3A mutation analysis should be performed. If it is positive, then the patient should be tested for microdeletion (either by fluorescent in situ hybridisation (FISH) or microarray, as in this case), and if there is no microdeletion, uniparental disomy testing should also be performed.3,11 If both are negative, then imprinting centre mutation analysis should be performed. If all of the above are negative, Angelman-like syndromes should be considered.
What are the differential diagnoses?
In around 10% of the suspected cases of Angelman syndrome, no abnormality with the UBE3A gene can be found.12 These are either due to some unknown genetic mechanism or misdiagnosis. Indeed there are many mimickers of Angelman syndrome, including various copy number variations and single gene disorders. Features that should alert one to a non-Angelman syndrome diagnosis include developmental regression (Rett syndrome, Christianson syndrome), MRI brain anomalies (Phelan Mcdermoid syndrome/2q13 deletion, Pitts Hopkins syndrome, FOXG1 haploinsufficiency syndrome) as well as congenital anomalies (Mowat Wilson syndrome).13,14
We would like to acknowledge the patient and his family for their contribution. Informed consent was obtained for publication.
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