Angelman vs Prader-Willi syndromes

Imprinting means receiving one allele from each parent but one is preferentially silenced.

• Maternal imprinting means mom’s allele is silenced; only dad’s allele is expressed.
• Paternal imprinting means dad’s allele is silenced; only mom’s allele is expressed.
• For many genes, it is normal that although two copies are received (one from each parent), only one copy may be expressed due to the other being preferentially silenced (via methylation).
• This is one of the reasons why two individuals of the same gender cannot produce an offspring through in vitro techniques, even if the combination of chromosomes is balanced.

Uniparental disomy means both of an individual’s alleles for a gene are received from the same parent (i.e., instead of getting one from each parent).

• • Maternal uniparental disomy means receiving both alleles from mom.
  • Paternal uniparental disomy means receiving both alleles from dad.
  • Uniparental heterodisomy means getting one copy of each of the parent’s alleles (i.e., one from each chromosome).
  • Uniparental isodisomy means getting two copies of the same allele from the same parent (i.e., from the same chromosome).
    • (I talk about in this article a HY point about how this relates to CF).

Prader-Willi syndrome (PWS)

• Due to maternal imprinting

Maternal imprinting in PWS

• Accounts for majority of PWS cases
• Maternal imprinting (gene received from mom is silenced) + paternal gene deletion/mutation
• This means the mom’s gene is received and silenced (as normal), but dad’s defective gene is responsible for the disease.
• In other words, in order to not get Prader-Willi syndrome, the allele received from dad must be normal. Mom’s allele can by all means be mutated, but it doesn’t matter because it’s silenced.
• “Willi hates his dad” because dad’s gene is deleted/mutated.

Angelman syndrome (AS)

• Due to paternal imprinting

Paternal imprinting in AS

• Accounts for majority of AS cases
• Paternal imprinting (gene received from dad is silenced) + maternal gene deletion/mutation
• This means the dad’s gene is received and silenced (as normal), but mom’s defective gene is responsible for the disease.
• In other words, in order to not get Angelman syndrome, the allele received from mom must be normal. Dad’s allele can by all means be mutated, but it doesn’t matter because it’s silenced.
• “Mom is not an angel” because mom’s gene is deleted/mutated.

Maternal uniparental disomy in PWS

• Accounts for minority of PWS cases
• Both alleles are received by mom, and both are silenced.
• Even if they are completely normal / non-mutated, because they’re both silenced, the child does not have any expressed allele and therefore has the disease (i.e., it’s as though he has two deleted or mutated copies).

Paternal uniparental disomy in AS

• Accounts for minority of AS cases
• Both alleles are received by dad, and both are silenced.
• Even if they are completely normal / non-mutated, because they’re both silenced, the child does not have any expressed allele and therefore has the disease (i.e., it’s as though he has two deleted or mutated copies).

If one were to make the argument that both alleles could be inherited from the non-imprinted parent and both are mutated, we would probably be talking about extraordinarily rare cases of uniparental isodisomy where the allele coming from the non-imprinted parent is silenced in that parent. The bottom line is: for the sake of the USMLE, don’t over-think things and memorize/remember the above specific inheritance associations.

Classically presents as a patient with mental impairment who laughs a lot and/or is easily made happy (“happy puppet”)

Classically presents as an obese patient with mental impairment and hyperphagia

Both chromosome 15.

PWS: many associated genes

AS: UBE3A gene

Methylation is most often associated with genomic silencing.

Acetylation is most often associated with genomic activation.