The USMLE biochemistry assessment tests medical students' understanding of key concepts in biochemistry, including metabolic pathways, molecular biology, enzyme kinetics, and genetics. It consists of multiple-choice questions and clinical vignettes to assess their knowledge and application of bioch...
1. An 18-month-old girl is brought to the GP for developmental concerns. She demonstrates poor
eye movements and her blood lactate levels are elevated. Audiometry reveals reduced hearing
across all frequencies. Family history is remarkable for an older brother who has hypotonia and who
uses a wheelchair. Her mother has required bilateral hearing aids since childhood. Which of the
following best explains this patient’s presentation?
A) Autosomal recessive inheritance
B) Autosomal dominant inheritance
C) Variable expressivity
D) Incomplete penetrance
E) Heteroplasmy
F) Imprinting
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The answer is E.
Heteroplasmy1 is the presence of more than one type of mitochondrial DNA in the same individual.
This means there is a non-uniformity of mitochondrial genes inherited (i.e., cells carry different
proportions of mitochondrial genes).
In turn, mitochondrial diseases frequently vary in severity among individuals because of differing
ratios of diseased vs wild-type mitochondrial genes inherited.
Mitochondrial disorders are classically associated with hypotonia, reduced hearing and extraocular
muscle function, and increased serum lactate.2 Inheritance is strictly maternal, i.e., inherited through
the mother only. Tissues high in mitochondrial density such as the skeletal muscles, inner ear
sensory cells, and extraocular muscles are usually affected3, 4
Tangential but HY genetics terms:
Variable expressivity
• All individuals with diseased genotype have diseased phenotype (i.e., everyone with
diseased allele shows it outwardly), but individuals merely vary in presentation.
• USMLE-favorite example is NF1, where some individuals may have, e.g., neurofibromas,
cafe au lait spots, pheochromocytoma, Lisch nodules, etc., whereas other individuals might
only have axillary/groin freckling. This is even when both individuals may carry the same
exact mutation.
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• In the case of heteroplasmy, the variable presentation among individuals is due to different
proportions of diseased mitochondrial genes inherited.
Incomplete penetrance
• Not everyone with diseased genotype has diseased phenotype (i.e., not everyone shows it
outwardly; it “skips” some people).
• An example is BRCA1/2 mutations – i.e., not everyone with the mutation will go on to
develop cancer (usually breast).
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.
Bottom line: Heteroplasmy is an important term to know for mitochondrial inheritance.
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