Angelman syndrome

Neurogenetic disorder caused by loss of the maternal *UBE3A* gene (15q11–13) due to genomic imprinting; characterized by severe developmental delay, absent speech, ataxic gait, seizures, and an inappropriately happy demeanor.

• Classic example of genomic imprinting in human disease (maternal gene lost). Recognizing Angelman syndrome in a nonverbal, ataxic child with unusual happy affect prevents misdiagnosis (e.g., as autism or cerebral palsy) and prompts appropriate genetic testing and support.

• Developmental delays evident by 6–12 months; by age 2, intellectual disability is severe and speech is minimal (often <5 words). Often microcephaly develops by age 2.
• Gait is ataxic and jerky (sometimes described as "puppet-like"); may have tremors and hand-flapping movements.
• Unique happy, excitable demeanor with frequent smiling/laughter. Hand-flapping, hyperactivity, and short attention span are common; sleep disturbances (short sleep) also occur.
• Seizures occur in ~80% (often onset by 2–3 years); EEG shows characteristic high-amplitude slow spike waves even without clinical seizures.
• Other features: tend to have fair skin/light-colored hair (if chromosome 15 deletion includes the *OCA2* pigment gene), and scoliosis can develop in adolescence.

1. Suspect Angelman in a child with the combination of profound developmental delay, lack of speech, ataxia, and inappropriate laughter (especially if microcephaly or seizures are present).
2. Confirm diagnosis with genetic testing: first-line is DNA methylation analysis of 15q11–13 region (detects maternal deletions or uniparental disomy). If initial testing is negative but clinical suspicion remains high, perform *UBE3A* gene sequencing (to detect mutations) or imprinting center analysis.
3. An abnormal EEG (with diffuse slow-spike waves) can support the diagnosis even before seizures occur. Early genetic confirmation allows for tailored therapy and family counseling (most cases are de novo with low recurrence risk).

1. No cure – management is supportive and multidisciplinary.
2. Anti-seizure medications to control epilepsy (commonly needed long-term; e.g., levetiracetam or valproate; avoid meds that may exacerbate seizures).
3. Therapies: physical and occupational therapy for ataxia and motor skills; speech therapy focusing on nonverbal communication (sign language, communication devices) since spoken language is minimal.
4. Behavioral therapy for hyperactivity; consider melatonin or other sleep aids for sleep disturbances.
5. Family support and genetic counseling (educate that most cases are de novo mutations or imprinting errors, hence low recurrence in siblings).

• Mnemonic: MAMA – Maternal gene deleted in AngelMan (vs paternal deletion in Prader-Willi). Remember: no MAMA, no laughter (Angelman).
• Historical term: "happy puppet" syndrome describes the inappropriate laughter and puppet-like ataxic gait (outdated term but a classic board reference).

• Diagnosis of autism or cerebral palsy that doesn't fully fit (e.g., child is overly happy, has ataxia or microcephaly) → consider Angelman syndrome and pursue genetic testing.
• Angelman patients normally have a happy affect; if an Angelman child shows persistent irritability or pain behavior, investigate for an underlying medical issue (they may not communicate pain well).

1. Global developmental delay noted in infancy → perform thorough evaluation (don't assume idiopathic autism).
2. If happy demeanor + ataxia + absent speech are present → suspect Angelman → order genetic testing (e.g., methylation study or microarray for 15q11–13).
3. If initial genetic test is positive for maternal 15q deletion or UBE3A defect → confirm Angelman diagnosis; if negative but clinical suspicion remains → proceed to UBE3A sequencing or specialized imprinting tests.
4. After diagnosis: address medical issues (start anti-epileptic therapy if seizures, monitor for scoliosis, etc.), and begin early intervention (PT/OT, communication therapy).
5. Coordinate multidisciplinary care (neurology, genetics, therapy services) and provide ongoing support for behavior, sleep, and developmental needs.

• A toddler with developmental delay, absent speech, frequent laughter, hand-flapping, an unsteady gait, and seizures → Angelman syndrome.
• Genetics question: maternal 15q11–13 deletion (loss of *UBE3A* maternal allele) with only paternal allele active (imprinted) → Angelman (contrast with paternal deletion → Prader-Willi).