Mitochondrial disorders

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The mitochondrial genome demonstrates strict maternal inheritance.

  • Highest yield point on the USMLE about mitochondrial disorders.
  • Disease is inherited strictly through mothers. 
  • Zero percent of fathers pass mitochondrial diseases to offspring.

Mitochondrial disorders share very characteristic pathologies that are easy to identify in Qs

  • The combination of visual + hearing problems, hypotonia, and lactic acidosis is exceedingly HY and reflective of a mitochondrial disorder.
Lactic acidosis is common in mitochondrial diseases; tissues with high metabolic rates are affected first (i.e., muscle, eyes, ears, neural tissue).

Heteroplasmy is exceedingly HY for mitochondrial genetics

  • Heteroplasmy 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., some cells contain one type of mitochondrial genome; other cells contain a different type, similar to mosaicism).
  • In turn, mitochondrial diseases frequently vary in severity among individuals because of varying ratios of diseased vs wild-type mitochondrial genes inherited.

Similar genetics terms:

Variable expressivity

  • Everyone with diseased genotype has diseased phenotype (i.e., everyone with diseased gene 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, and pheochromocytoma, Lisch nodules, etc., whereas another individual might simply have axillary/groin freckling and that’s it. This even when both individuals may carry the same exact mutation.
  • 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).

“Ragged red fibers” is buzz-wordy for mitochondrial inheritance

  • Seeing “ragged red fibers” in a question for a mitochondrial inheritance is akin to seeing malar rash in an SLE question. Both too easy.
“Ragged red fibers” on microscopy is a phrase the USMLE likes to throw around for mitochondrial inheritance.

They’re classically associated with MERRF syndrome (myoclonic epilepsy with ragged red fibers).

Myoclonic epilepsy with ragged red fibers (MERRF)

  • This is a mitochondrial disorder characterized by seizures, ataxia, hearing loss, and myopathy.
  • Ragged red fibers are abnormal mitochondria accumulating under the sarcolemma. They are red with trichrome stain.
If you look closely, you might be able to see ragged red fibers. Don’t worry, you’ll never need to rely on an image like this on the real exam. They’ll just tell you in the vignette literally, “ragged red fibers.” (Image compliments of Wiki)

MELAS

  • MELAS stands for mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.

Leber hereditary optic neuropathy

  • Characterized by painless, subacute, usually adult-onset (classically males in their 20s) bilateral blindness w/ multiple sclerosis-like Sx, movement disorders, and arrhythmia.

Kearns-Sayre syndrome

  • Characterized by progressive ophthalmoplegia, pigmentary retinopathy, cerebellar ataxia, and heart block.

1. In what pattern are mitochondrial diseases inherited?

2. Which of the following best characterizes mitochondrial diseases? (Select all that apply)

 
 
 
 

3. What is heteroplasmy?

4. What is variable expressivity vs incomplete penetrance?

5. Name four mitochondrial diseases.