Overview

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• Definition: genetic syndromes caused by microdeletion (at 15q11-q13) in combination with genomic imprinting or uniparental disomy.
  • Genomic inprinting: an epigenetic phenomenon that results in silencing of one of the alleles of a gene depending on whether the allele was paternally or maternally inherited.
  • Uniparental disomy: a chromosomal abnormality in which offspring receive two copies of one chromosome from one parent and no copies from the other parent
• Etiology: The resulting condition depends on the affected gene copy.
  • Angelman syndrome
    • Deletion or mutation of maternal UBE3A (chromosome 15) gene copy and paternal gene methylation (silencing)
    • In ∼ 5% of cases, it results from paternal uniparental disomy (i.e. both copies of chromosome 15 are inherited from the father).
  • Prader-Willi syndrome
    • Deletion or mutation of paternal gene copy and maternal gene methylation (silencing)
    • Caused by maternal uniparental disomy in about 20–35% of cases
• Diagnosis: genetic tests
  • Fluorescence in situ hybridization (FISH)

Prader-Willi syndrome

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• Clinical features
  • Muscular hypotonia and poor feeding in infants
  • Increased appetite (hyperphagia) and obesity
  • Cryptorchidism, hypogonadism, genital hypoplasia
  • Facial dysmorphia (e.g., almond-shaped eyes, thin upper lip)
  • Developmental delays (e.g., delayed achievement of milestones), intellectual disability
  • Behavioral problems (e.g., temper tantrums, stubbornness, obsessive-compulsive behavior)
• Treatment
  • Calorie restriction
  • Substitution of growth hormone and sex hormones
• Complications
  • Sleep apnea (most common)
  • Type 2 diabetes mellitus
  • Choking episodes
  • Gastric distention and rupture

Angelman syndrome

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• Clinical features
  • Delayed mental development and acquisition of motor skills in infants and young children; absent speech development
  • Intellectual disability
  • In more than 80% of cases, pronounced epileptic seizures
  • Ataxia, tremulous movements of the limbs
  • Characteristic happy demeanor with frequent laughing (inappropriate laughter)