Section: USMLE

15) A couple has a daughter who is ataxic and has a seizure disorder. She also has a strange affect characterized by excessive laughter at inappropriate times. Cytogenetic analysis demonstrates a normal genotype with 46 chromosomes and no apparent deletions. These symptoms are most likely due to

1. confined placental mosaicism
2. expansion of a trinucleotide repeat
3. a point mutation in an autosome
4. random inactivation of the X chromosome
5. uniparental disomy

The child described is exhibiting the features of Angelman (happy puppet) syndrome. This disorder is generally caused by a deletion of band q12 in the maternal copy of chromosome 15, i.e., [(del (15)(q11q13)]. A similar deletion in the paternal chromosome 15 produces Prader-Willi syndrome. The disparate expression of the effects of deletions in the paternal vs. the maternal chromosomes, called genomic imprinting, implies that the same genetic loci are expressed quite differently in maternal and paternal chromosomes. Angelman syndrome can also occur if uniparental disomy occurs for chromosome 15, such that the embryo receives two copies of the maternal chromosome 15 without the paternal chromosome 15 to “balance” the maternal contribution.

Confined placental mosaicism is due to a mutation occurring within trophoblast or extraembryonic precursor cells of the inner cell mass and is an important cause of intrauterine growth retardation.

Expansion of a trinucleotide repeat is associated with Fragile X syndrome and Huntington disease.

Point mutation in autosomes has not been associated with Angelman syndrome.

Random inactivation of the X chromosome occurs normally, as postulated in the Lyon hypothesis.