The syndrome that proves which parent's DNA is active in your neurons. Mom's UBE3A runs the show. Lose hers, and a child who cannot speak will laugh constantly while seizing and stumbling across the room.
Section 1 of 4
Two parents. Same chromosomal address. Silence one parent and you get a happy child who cannot speak. Silence the other and you get a child who cannot stop eating. Toggle the silencer below and watch the syndrome flip.
Normal: Both Alleles Present
Both copies of chromosome 15 are present and intact. In neurons, the maternal UBE3A allele (Mom) is the only active copy. The paternal copy is silenced by an antisense RNA (a molecular brake from the paternal locus). Mom runs the neurons. Dad steps aside.
ANGELMAN SYNDROME
Maternal contribution at 15q11-13 is gone (deletion, UPD, or imprinting defect). The paternal UBE3A was already silenced in neurons. Result: zero UBE3A in neurons. Protein recycling in neurons fails. Happy demeanor, absent speech, seizures, and ataxic gait follow.
PRADER-WILLI SYNDROME
Paternal contribution at 15q11-13 is gone. The maternal UBE3A is still working fine in neurons. But the paternal PWS-region genes (SNRPN, NDN) that control feeding, tone, and hormones are exclusively expressed from the paternal allele. Lose Dad's copy: hyperphagia (compulsive overeating), hypotonia (low muscle tone), obesity, and hypogonadism.
The Imprinting Logic Chain
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Section 2 of 4
The child who laughs at nothing, cannot talk, and walks like their limbs are operated by separate motors. Tap each card to see the board-level detail.
Hand-Flapping
Repetitive, excited arm movements. Angelman children flap when happy or stimulated. Distinguish from the hand-wringing of Rett syndrome (which is a washing motion, not flapping). Happy affect is the context: flapping when joyful.
Ataxia: Puppet-Like Gait
AtaxiaAtaxia: uncoordinated, wobbly movement. From Greek "a-" (without) + "taxis" (order). The gait looks jerky and stiff, like a marionette puppet.: wide-based, lurching gait with jerky arm movements. Called "happy puppet" historically because of the gait plus the happy affect. The puppet analogy fits the stiff, irregular limb movements.
Severe Intellectual Disability
Profound, global intellectual disability. Nearly all children are nonverbal or have at most a few words. Speech is always more impaired than receptive language: they understand more than they can express. EEG shows characteristic high-amplitude rhythmic delta slowing.
Inappropriate Laughter
Paroxysmal, frequent laughter and smiling with minimal social trigger. It is not laughter at something funny: it erupts spontaneously. This is one of the most recognizable features clinically. The child appears perpetually delighted regardless of context.
Seizures
Occur in approximately 80% of patients, often starting in the first 1-2 years of life. Multiple seizure types: myoclonic, atonic, and generalized tonic-clonic. Characteristic EEG: large-amplitude rhythmic theta-delta activity, often triggered by eye closure. Seizures can be drug-resistant.
| Feature | Angelman Syndrome | Prader-Willi Syndrome |
|---|---|---|
| Parent lost | MATERNAL 15q11-13 | PATERNAL 15q11-13 |
| Key gene | UBE3A (maternal copy) | SNRPN, NDN (paternal copies) |
| Speech | Near absent (few to no words) | Delayed but present |
| Behavior | Happy, laughing, excitable | Food-obsessed, rage outbursts |
| Gait | Ataxic, puppet-like, jerky | Hypotonic (floppy), waddling |
| Body | Normal weight, microcephaly | Obesity, short stature, small hands/feet |
| Seizures | Severe (80% of patients) | Mild or absent |
| Mnemonic | HAILS · Angel from Mom | POP: Prader, Obesity, Paternal |
| UPD pattern | Paternal UPD (both from Dad) | Maternal UPD (both from Mom) |
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Angelman Syndrome
Prader-Willi Syndrome
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Section 3 of 4
Three questions the boards will test you on. Answer each before the explanation reveals. Get them all right and you own this algorithm.
From the Attending
Normal methylation on chromosome 15 is the trap they set every time. It rules out deletion, UPD, and imprinting center defect. It does NOT rule out a UBE3A point mutation. If the clinical picture screams Angelman and methylation is normal, you sequence UBE3A. That is the move. Know your clues. Every time.
Step 1 of 3: A 2-year-old girl has severe intellectual disability, absent speech, seizures, ataxic gait, and paroxysmal laughter. Which first-line molecular test gives you the most information in a single result?
Step 2 of 3: Methylation analysis returns normal. The clinical picture is still strongly consistent with Angelman syndrome. What is the most appropriate next diagnostic step?
Step 3 of 3: A 3-year-old boy has classic Angelman features. Genetic testing finds that BOTH chromosome 15 copies are from his father. There is no maternal chromosome 15. Which mechanism explains this?
Section 4 of 4
Five patients just walked into the clinic. You know the mechanism, you know the mnemonic, you know the trap. Prove it under exam conditions.