Introduction: Genomic Imprinting on Chromosome 15q11-q13

Prader-Willi Syndrome (PWS) and Angelman Syndrome (AS) are classic examples of genomic imprinting, where the expression of a gene depends on its parental origin. Both disorders involve the 15q11-q13 region, but they result from the loss of different genes due to epigenetic silencing.

Correction Note: The original text mentions “Trisomy 15.” This is clinically inaccurate. PWS and AS are not caused by an extra chromosome (trisomy), but rather by the absence of expression of specific genes on one of the two homologous chromosomes in pair 15.

Prader-Willi Syndrome (PWS)

PWS results from the loss of expression of paternally inherited genes in the 15q11-q13 region. Because the maternal copies of these genes are epigenetically silenced (imprinted), the loss of the paternal contribution leads to a total deficiency.

Pathophysiology and Genetics

1. Paternal Microdeletion (65–75%): A de novo deletion of the 15q11-q13 region on the paternal chromosome.
2. Maternal Uniparental Disomy (mUPD) (20–30%): The individual inherits two copies of chromosome 15 from the mother and none from the father. This often correlates with a higher incidence of obesity and a lower risk of behavioral challenges compared to deletions.
3. Imprinting Center Defects (1–3%): Mutations in the imprinting center that cause the paternal chromosome to carry a maternal methylation pattern.

Clinical Presentation & Progression

PWS is a biphasic disorder:

• Infancy: Characterized by severe neonatal hypotonia (“floppy baby”), poor suck reflex, failure to thrive, and cryptorchidism in males.
• Childhood/Adolescence: Emergence of hyperphagia (typically between ages 2–8). This is not merely hunger but a failure of the satiety mechanism, leading to life-threatening obesity if not strictly managed.

Multisystemic Clinical Features

• Endocrine: Growth Hormone (GH) deficiency (short stature, increased fat mass), hypogonadotropic hypogonadism (delayed puberty, infertility), and insulin resistance/Type 2 Diabetes.
• Dermatologic/Morphologic: Small hands and feet, almond-shaped eyes, and narrow bifrontal diameter.
• Neuropsychiatric: Mild to moderate intellectual disability; OCD tendencies; skin picking; and temper tantrums resulting from rigidity in routine.
• Respiratory: Obstructive Sleep Apnea (OSA) secondary to obesity and hypotonia.

Evidence-Based Management

A multidisciplinary approach is mandatory:

• Growth Hormone (GH) Therapy: Now the standard of care. Early initiation of recombinant GH improves linear growth, increases lean body mass, and improves cognitive development.
• Environmental Control: Because hyperphagia cannot be treated pharmacologically at this time, “food security” is critical. This involves locking kitchens/pantries to prevent binge eating.
• Endocrine Monitoring: Regular screening for T2DM, hypertension, and lipid profiles.
• Psychiatric Support: Behavioral therapy and potentially SSRIs for OCD or anxiety.

Angelman Syndrome (AS)

Angelman Syndrome results from the loss of function of the UBE3A gene (Ubiquitin Protein Ligase E3A). In neurons, only the maternal copy of UBE3A is active; therefore, a loss of the maternal allele leads to the syndrome.

Genetics and Etiology

1. Maternal Deletion (65–75%): Deletion of 15q11-q13 on the maternal chromosome.
2. UBE3A Mutation (10%): Point mutations in the maternal UBE3A gene.
3. Paternal Uniparental Disomy (pUPD) (2–7%): Two paternal copies, neither of which is expressed in the brain.
4. Imprinting Defects (3%): Failure to reset the imprinting mark during oogenesis.

Clinical Presentation

• Neurological: Severe developmental delay, profound speech impairment (minimal to no functional speech), and ataxia (characterized by a “puppet-like” gait).
• Behavioral: A distinct phenotype of frequent laughter, smiling, and an easily excitable personality. Hyperactivity and short attention spans are common.
• Epilepsy: High prevalence of seizures (usually beginning before age 3), often presenting as atypical absence or tonic-clonic seizures; EEG typically shows high-amplitude slow-wave activity.
• Physical: Microcephaly (postnatal slowing of head growth) and protruding tongue.

Diagnostic Workup

The gold standard is DNA Methylation Analysis, which detects the abnormal imprinting pattern (detects $\approx 80\mathrm{\%}$≈80% of cases). If methylation is normal but AS is clinically suspected, UBE3A sequencing is required to find point mutations.

Clinical Management

• Neurological: Aggressive seizure management with antiepileptics (e.g., Valproate, Levetiracetam), though some patients are refractory.
• Communication: Implementation of Augmentative and Alternative Communication (AAC) tools early in life to reduce frustration-based behaviors.
• Physical/Occupational Therapy: Focus on gait stability and prevention of scoliosis or joint contractures.
• Behavioral Intervention: Applied Behavior Analysis (ABA) for hyperactivity and sleep disturbances.

Summary Comparison Table for the Clinician