A 3-year-old boy presents with severe developmental delay, absent speech, and a characteristic ataxic gait with jerky arm movements. His parents note he has frequent inappropriate laughter and a happy demeanor despite his severe disability. EEG shows high-voltage 2–3 Hz delta waves with posterior triphasic activity. The pedigree shows this is a de novo case. The chromosomal region marked **A** in the diagram (15q11-q13 imprinted region) is affected. Which of the following BEST explains the clinical presentation and the parental origin of the lesion in this child?

Explanation

## Why Loss of maternally expressed UBE3A gene due to maternal deletion or paternal uniparental disomy, resulting in Angelman syndrome is right The clinical triad of severe intellectual disability, absent/minimal speech, ataxic "puppet-like" gait with jerky arm movements, and inappropriate laughter with happy demeanor is pathognomonic for Angelman syndrome (AS). The characteristic EEG finding of high-voltage 2–3 Hz delta waves with posterior triphasic activity provoked by eye closure is a hallmark of AS epilepsy. The region marked **A** (15q11-q13) is an imprinted region where the MATERNAL allele of UBE3A is normally expressed and the paternal allele is silenced. Loss of the maternal copy—whether through maternal deletion (70% of cases) or paternal uniparental disomy (both chromosome 15s from father, 3–5% of cases)—results in complete absence of UBE3A protein, causing AS. This is a classic example of genomic imprinting where the SAME chromosomal lesion at 15q11-q13 produces a DIFFERENT syndrome depending on parental origin (Nelson Pediatrics 21e Ch 98; Harrison 21e Ch 460). ## Why each distractor is wrong - **Loss of paternally expressed SNRPN and NDN genes due to paternal deletion or maternal uniparental disomy, resulting in Prader-Willi syndrome**: This describes Prader-Willi syndrome (PWS), which presents with infantile hypotonia, poor feeding, failure to thrive, and later hyperphagia and obesity—NOT the severe intellectual disability, absent speech, ataxia, and happy demeanor seen here. PWS also does not produce the characteristic AS EEG pattern. - **Autosomal recessive inheritance with both parents as carriers of a 15q11-q13 mutation**: Genomic imprinting is an epigenetic, parent-of-origin-specific phenomenon, not simple autosomal recessive inheritance. The clinical presentation and pedigree pattern (de novo case) are inconsistent with autosomal recessive inheritance, which would require two mutant alleles from carrier parents. - **X-linked dominant mutation affecting imprinted genes on the X chromosome**: The 15q11-q13 region is on chromosome 15, not the X chromosome. While some imprinted genes exist on the X chromosome, they do not explain the clinical features or the characteristic methylation pattern at 15q11-q13 seen in Angelman syndrome. **High-Yield:** Genomic imprinting at 15q11-q13: MATERNAL UBE3A loss → Angelman (ataxia, seizures, laughter); PATERNAL SNRPN/NDN loss → Prader-Willi (hypotonia, hyperphagia, obesity). Same deletion, opposite parent = opposite syndrome. [cite: Nelson Pediatrics 21e Ch 98; Harrison 21e Ch 460]