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Prader-Willi syndrome and Angelman syndrome

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Overview

  • 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)

Both syndromes are caused by a loss of gene function in the same region of chromosome 15 (15q11-q13). The resulting phenotype depends on which parental chromosome carries the defect.

Prader-Willi Syndrome (PWS)

  • Patho/Etiology
    • Prader-Willi = Paternal gene deletion/defect.
    • Due to a loss of function of genes that are normally expressed only on the chromosome inherited from the father. This occurs via:
      1. Deletion of the paternal 15q11-q13 region (~70% of cases).
      2. Maternal Uniparental Disomy (UPD): The individual inherits two copies of the maternal chromosome 15 and no paternal copy (~25% of cases).
  • Clinical Presentation
    • Infancy: Severe hypotonia (“floppy baby”), poor suck, and feeding difficulties leading to failure to thrive.
    • Childhood: Onset of hyperphagia (insatiable hunger) leading to morbid obesity. This is the most common genetic cause of life-threatening childhood obesity.
    • Common Features:
      • Mild to moderate intellectual disability.
      • Behavioral problems (temper tantrums, skin picking).
      • Hypogonadism (underdeveloped genitals, delayed puberty).
      • Distinctive facies: narrow forehead, almond-shaped eyes, thin upper lip.
      • Small hands and feet.
      • Short stature, often due to growth hormone deficiency.

Angelman Syndrome (AS)

  • Patho/Etiology
    • Angelman = Maternal gene deletion/defect (A and M in the name).
    • Due to a loss of function of the UBE3A gene, which is normally expressed only on the chromosome inherited from the mother. This occurs via:
      1. Deletion of the maternal 15q11-q13 region (~70% of cases).
      2. Paternal Uniparental Disomy (UPD): The individual inherits two paternal chromosome 15s and no maternal copy.
      3. Mutation in the maternal UBE3A gene (~11% of cases).
  • Clinical Presentation
    • “Happy Puppet” is the classic description.
    • Common Features:
      • Severe intellectual disability.
      • Minimal to no speech.
      • Seizures are very common.
      • Ataxic gait and jerky arm movements (hence “puppet-like”).
      • Inappropriate, frequent laughter and a happy demeanor.
      • Microcephaly and a flat back of the head.
      • Hyperactivity and a short attention span.

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