Prader-Willi and Angelman Syndrome

Genomic Imprinting in the 15q11-q13 Region

• The 15q11-q13 chromosomal segment contains multiple imprinted genes whose expression is controlled by parent-of-origin-dependent DNA methylation patterns established in the germline
• In PWS, the paternal allele is normally active while the maternal allele is silenced by methylation; loss of paternal gene expression results in disease
• In AS, the maternal allele is normally active while the paternal allele is silenced; loss of maternal gene expression causes disease
• This region contains >100 genes, with key imprinted genes including SNRPN, NDN, MKRN3, and UBE3A

Molecular Mechanisms in Prader-Willi Syndrome

• Paternal gene loss: Deletion (70%), maternal uniparental disomy (mUPD, ~25%), or imprinting center defects (~1-3%) result in absence of paternally derived gene products
• Loss of paternal SNRPN (small nuclear ribonucleoprotein) and NDN (necdin) disrupts hypothalamic neuropeptide production, including decreased neuropeptide Y (NPY) and agouti-related peptide (AgRP), which are critical appetite suppressants
• Deficiency in MAGEL2 and other paternal transcripts impairs energy homeostasis and contributes to metabolic dysfunction
• Hypotonia results from abnormal development of motor nuclei and spinal cord pathways secondary to loss of neurotrophic support

Molecular Mechanisms in Angelman Syndrome

• Maternal gene loss: Deletion (70%), paternal uniparental disomy (pUPD, ~2-3%), imprinting center defects (~1-3%), or mutations in the maternal UBE3A gene (~10%) cause disease
• UBE3A encodes an E3 ubiquitin ligase that is maternally expressed in neurons; loss results in impaired degradation of synaptic proteins and abnormal synaptic plasticity
• Accumulation of ubiquitinated protein substrates, particularly those involved in synaptic regulation, disrupts excitatory/inhibitory balance in cortical circuits
• Seizures arise from neuronal hyperexcitability secondary to altered GABAergic inhibition and glutamatergic transmission
• The distinctive behavioral phenotype (happy demeanor, frequent smiling) results from altered limbic system development and serotonergic/dopaminergic dysfunction

Prader-Willi Syndrome

• Paternal deletion of 15q11-q13 (~70% of cases): Most common cause; typically de novo; rarely inherited if father carries balanced translocation
• Maternal uniparental disomy (mUPD) (~25% of cases): Both chromosome 15 copies inherited from mother; associated with advanced maternal age; usually de novo
• Imprinting center defects (~1-3% of cases): Defective imprinting marks on paternal chromosome 15; may be inherited from carrier mothers
• Balanced translocations: 2-3% of cases; carriers of balanced translocations have increased recurrence risk

Angelman Syndrome

• Paternal deletion of 15q11-q13 (~70% of cases): Most common cause; de novo; paternal carriers rarely affected
• Maternal uniparental disomy (pUPD) (~2-3% of cases): Both chromosome 15 copies inherited from father; unusual etiology
• ***UBE3A* mutations** (~10% of cases): Point mutations, small insertions/deletions affecting maternal UBE3A; inheritance pattern varies (de novo or inherited from carrier mother)
• Imprinting center defects (~1-3% of cases): Impaired maternal imprinting establishment or maintenance
• Chromosomal rearrangements: Translocations or other structural variants involving 15q11-q13

Prader-Willi Syndrome

• Severe infantile hypotonia ("floppy infant")
• Weak cry and poor feeding with failure to thrive initially
• Decreased fetal movements

• Transition to hyperphagia: Around 2-4 years of age, insatiable appetite develops with food-seeking behaviors
• Rapid weight gain despite appropriate caloric intake; obesity becomes evident by school age
• Hypogonadism: Small genitalia, cryptorchidism, incomplete pubertal development
• Short stature and growth hormone deficiency
• Distinctive facial features: narrow bifrontal diameter, almond-shaped eyes, triangular mouth
• Strabismus

• Intellectual disability: Mild to moderate (IQ typically 60-85); learning difficulties with particular weakness in verbal comprehension
• Behavioral problems: stubbornness, tantrums, skin picking, compulsive behaviors
• Temperature instability and high pain threshold
• Sleep-disordered breathing and central sleep apnea
• Hypoventilation, particularly during sleep

Angelman Syndrome

• Generally appear relatively normal at birth
• Developmental delay becomes apparent by 6-12 months
• Hypotonia with progressive improvement (unlike PWS)

• Severe developmental delay: Particularly speech development; nonverbal or minimal speech
• Seizures (80% of patients): Onset typically 6-36 months; myoclonic, atonic, and atypical absence seizures predominate; often refractory to standard anticonvulsants
• Distinctive behavioral phenotype: Frequent smiling/laughing, happy demeanor, easily amused (often inappropriately)
• Hyperactivity and short attention span
• Movement disorder: ataxia, tremor, jerky movements ("puppet-like" gait)

• Characteristic facial features: Wide mouth, protruding tongue, prognathism, midface hypoplasia
• Hypopigmentation: Light skin and hair compared to family members (in non-albino individuals)
• Microcephaly
• Strabismus and refractive errors
• Scoliosis in some cases

• Persistent severe intellectual disability (profound to moderate)
• Continued seizure activity, often difficult to control
• Progressive movement disorder with worsening ataxia
• Behavioral problems: impulsivity, aggression
• Speech remains severely limited or absent

Diagnostic Approach to Prader-Willi Syndrome

• Clinical presentation of infantile hypotonia with transition to early-onset obesity
• History of poor feeding progressing to food-seeking behavior
• Small genitalia and growth hormone deficiency

• Methylation-specific PCR or Southern blot: Detects parent-of-origin-specific methylation patterns at the SNRPN locus; abnormal paternal methylation pattern indicates PWS (sensitivity >99%)
• Chromosomal microarray (CMA) or fluorescence in situ hybridization (FISH): Identifies 15q11-q13 deletions (~70% of PWS cases)
• Quantitative fluorescent PCR (QF-PCR): Rapidly detects aneuploidies and can identify mUPD (~25% of cases)
• SNP microarray or microsatellite analysis: Confirms maternal uniparental disomy; shows no heterozygosity across chromosome 15

• Growth hormone stimulation test: Demonstrates GH deficiency (baseline <5 ng/mL; post-stimulation <7 ng/mL)
• IGF-1 levels: Low-normal or decreased
• Testosterone levels: Low in males; assess gonadal function

• Sleep studies: Screen for obstructive sleep apnea and central hypoventilation
• Metabolic panel: Assess for dyslipidemia and glucose intolerance
• DEXA scan: Assess bone density

Diagnostic Approach to Angelman Syndrome

• Severe developmental delay with speech impairment or absence
• Seizures with onset in infancy/early childhood
• Characteristic "happy puppet" appearance with inappropriate smiling
• Ataxic gait

• Methylation-specific PCR, Southern blot, or MS-MLPA: Identifies abnormal maternal methylation pattern at SNRPN and UBE3A loci (maternal allele should be unmethylated/active)
• If maternal methylation is abnormal (appears paternal), AS diagnosis is likely

Second-line tests for genotype determination

• Chromosomal microarray (CMA): Identifies 15q11-q13 deletions in 70% of molecularly confirmed AS cases
• FISH or qPCR: Confirms microdeletion if CMA shows abnormality
• UBE3A gene sequencing: Identifies point mutations and small indels in ~10% of AS cases; required if methylation abnormal but no deletion detected
• Quantitative fluorescent PCR or SNP array: Detects uniparental disomy (rare in AS)

• EEG: Characteristic 4-6 Hz rhythmic theta activity, high-amplitude posterior activity, and generalized slowing; spike-and-wave discharges may be present
• Brain MRI: Usually normal or shows mild nonspecific abnormalities; thin corpus callosum may be noted
• Developmental assessment: Confirms severe global developmental delay

Diagnostic Criteria

Prader-Willi Syndrome Management

• Mechanism: rhGH improves linear growth, increases lean body mass, decreases adiposity, improves metabolic function
• Dosing: 0.05-0.1 mg/kg/day subcutaneously; adjusted based on response
• Indications: Growth hormone deficiency confirmed by testing; typically started in early childhood
• Monitoring: Measure height, weight, IGF-1 levels every 3-6 months; assess for side effects
• Benefits: Improved final height, reduced obesity, improved muscle tone and strength
• Contraindications: Active malignancy (relative); monitor for glucose intolerance

• Testosterone (in males): Intramuscular or transdermal at physiologic doses starting in late childhood/early puberty
• hCG or GnRH analogues: Alternative agents for inducing puberty
• Monitor sexual development, bone age, and hematocrit

• Caloric restriction with structured meal planning; 1000-1400 kcal/day often needed (vs. 2000+ for age-matched peers)
• Supervised environment: Restrict unsupervised access to food; lock refrigerators/pantries in severe cases
• Behavioral interventions: Reward-based systems for appropriate eating; education for families and caregivers
• Regular physical activity: Exercise programs essential; goal ≥30-60 minutes moderate activity daily
• Monitor weight and BMI monthly; target BMI <25 kg/m² if achievable

• Annual glucose tolerance testing: Screen for diabetes mellitus; assess insulin resistance
• Lipid panel: Screen for dyslipidemia; treat if indicated
• Thyroid function tests: Screen for hypothyroidism

• Polysomnography: Screen for obstructive sleep apnea and central hypoventilation
• CPAP/BiPAP: Indicated for obstructive sleep apnea
• Monitor for hypoventilation, especially during sleep; consider assisted ventilation if CO₂ retention occurs

• Cognitive-behavioral therapy for behavioral problems, compulsive eating, skin picking
• Structured routines and clear boundaries
• SSRIs if obsessive-compulsive features present (sertraline, fluoxetine)

• Screening for scoliosis; orthopedic intervention if necessary
• Physical therapy to improve mobility and strength

Angelman Syndrome Management

• First-line anticonvulsants:
• Valproic acid (sodium valproate): Most effective; initial dose 15-20 mg/kg/day divided doses; target 30-60 mg/kg/day; monitor liver function and ammonia
• Ethosuximide: Particularly effective for absence seizures; dose 15-40 mg/kg/day
• Levetiracetam: Well-tolerated alternative; dose 20-60 mg/kg/day; fewer drug interactions
• Lamotrigine: Useful adjunct; slow titration required (risk of rash); dose 0.5-15 mg/kg/day

• Second-line agents: Topiramate, clonazepam, benzodiazepines (lorazepam, diazepam)
• Management approach: Monotherapy preferred when possible; combination therapy often needed as seizures often refractory
• Emergency seizure management: Rectal diazepam or intranasal midazolam for prolonged seizures
• EEG monitoring: Baseline and periodic EEGs to assess seizure control; some seizures may be clinical only

• Early intervention programs starting in infancy
• Special education: Severe intellectual disability requires intensive specialized educational services
• Occupational therapy: Address fine motor skills, activities of daily living
• Physical therapy: Improve gait, balance, reduce ataxia
• Speech therapy: Augmentative and alternative communication (AAC) devices essential given speech limitations

• Structured environment with consistent routines
• Behavioral modification techniques for hyperactivity and impulsivity
• Consider psychotropic medications for severe behavioral problems:
• SSRIs (sertraline, fluoxetine): For anxiety, aggression; dose standard
• Stimulants (cautiously): May help attention in some cases
• Antipsychotics (risperidone, haloperidol): For severe aggression or behavioral dyscontrol; use lowest effective dose due to metabolic side effects

• Physical therapy and occupational therapy for ataxia and jerky movements
• Clonazepam: May provide modest improvement in tremor (0.5-2 mg/day divided)
• Assistive devices (walkers, orthoses) as needed

• Important for familial cases (particularly UBE3A mutations)
• Recurrence risk assessment for family planning

The one-line discriminators

• Parent-of-origin rule: P for Prader-Willi = loss of the Paternal 15q11.2-q13 contribution; Angelman = loss of the maternal contribution (UBE3A). The identical deletion produces opposite phenotypes — the classic imprinting vignette.
• UPD direction: PWS arises from maternal UPD 15 (two maternal copies, no paternal expression); AS from the much rarer paternal UPD 15. Examiners love reversing these.
• Neonatal hypotonia + weak suck + poor feeding that later flips to insatiable hyperphagia is PWS until proven otherwise; the happy puppet child with absent speech, ataxia, and seizures is AS.

Single best next step

• DNA methylation analysis of the 15q11.2-q13 imprinted region (SNRPN locus) is the first test for either syndrome — it detects deletion, UPD, and imprinting-center defects in one assay (>99% of PWS, ~80% of AS). ACMG and GeneReviews-based practice put methylation testing first; only after an abnormal result do you order microarray/UPD studies to define mechanism for counseling.
• Distractor to avoid: FISH or karyotype as the initial test. FISH finds only the deletion and will be falsely reassuring in UPD and imprinting defects. Likewise, a normal methylation study does not exclude AS — a maternal UBE3A sequence variant remains possible, so sequencing is the next step.

Associations examiners test

• Ghrelin is elevated in PWS, contributing to hyperphagia; these patients are not leptin-deficient. Hyperphagia is life-threatening (gastric rupture, choking, morbid obesity) — supervised food access is a genuine safety intervention.
• Growth hormone (somatropin) is FDA-approved in PWS and improves body composition and linear growth, but evaluate sleep-disordered breathing/adenotonsillar hypertrophy before and after starting given reported sudden death, per Pediatric Endocrine Society–endorsed consensus guidance.
• AS EEG: high-amplitude rhythmic delta/theta with spike-and-wave, often present before seizures. Avoid carbamazepine, oxcarbazepine, and vigabatrin, which can worsen myoclonic and atypical absence seizures.
• Recurrence risk is <1% for de novo deletion or UPD, but can approach 50% for maternal UBE3A mutations and inherited imprinting-center defects — the reason mechanism must be defined.