Mosaic Angelman Syndrome: expanded phenotype spectrum of Angelman syndrome caused by mosaic imprinting defect

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of function of the imprinted UBE3A gene. Deficient expression of the maternal UBE3A allele - due to deletions, paternal uniparental disomy, mutations or imprinting defect - leads to the typical phenotype. The main clinical features include severe developmental delay, intellectual disability, language impairment, movement disorders, microcephaly, seizures and a happy demeanor.
The majority of the imprinting defects are sporadic epimutations. Thirty-forty % of these occur post-zygotically resulting in somatic methylation mosaicism with hypomethylation of the maternal allele. The affected individuals have a partial loss of UBE3A expression which leads to an atypical mosaic Angelman syndrome (mAS) phenotype. The clinical features of mAS are overall less severe in contrast with typical AS. The developmental delay is obligate but milder, all patients achieve walk, movement disorders are less likely and there is ability to communicate verbally and participate in self-care. The neurobehavioral profile is similar to AS with regard to the happy demeanor and hyperexcitability but in mAS hyperactivity and anxiety are of major concern. Hyperphagia and obesity are common overlapping symptoms with Prader Willi syndrome (PWS). Epileptic seizures and microcephaly in mAS are less likely.
We present a 3-year-old boy with a neurodevelopmental delay showing markedly disharmonic developmental profile. There is a considerable discrepancy between his average range receptive and significantly delayed expressive language skills. Concentration difficulties are pronounced. He has a general happy demeanor with refusal behaviour and high level of anxiety. He had initial feeding difficulties and failure to thrive followed by a food seeking behaviour and overweight with BMI above 97 centile.
Genetic testing with methylation-specific MLPA of the 15q11-q13 region detected a decreased methylation level on the maternal allele compatible with a mosaic methylation defect. Deletion and uniparental disomy were excluded by SNP array. An imprinting defect leading to somatic methylation mosaicism was concluded manifesting with the clinical features of mAS.
The diagnosis of mAS has to be considered in patients with mild to moderate non-specific intellectual disability, discrepancy between receptive and expressive language skills with retained speech, uncharacteristically happy demeanor especially if PWS symptoms are also present.