Mitochondrial Inheritance

What are two lab results that suggest a mitochondrial disease?

1) Elevated urine TCA Cycle intermediate levels 2) Elevated serum Acylcarnitine levels

The genes corresponding to the proteins that function within the mitochondria come from what sources?

1) From the mitochondrial DNA 2) From the nuclear DNA. These protein precursors have special sequences that direct them to the mitochondria, where they are used.

What are the two mechanisms that contribute to the non-Mendelian nature of mt DNA inheritance?

1) Maternal inheritance 2) mt DNA that is transmitted is variable in amount

What are three major symptoms of Kearns-Sayre Syndrome?

1) Ptosis (droopy eyelids) 2) Chronic Progressive External Opthalmoplegia (inability to move eyes to track) 3) Retinal degeneration that leads to night blindness

What is Kearns-Sayre Syndrome?

A mitochondrial disorder most often involving large deletions of mitochondrial DNA.

Homoplasmy

All of the mitochondrial DNA in a cell is identical (whether normal or mutant)

Heteroplasmy

All of the mitochondrial DNA in a cell is of two or more different types (both normal and mutant exist)

What types of symptoms are common for mitochondrial disorders?

Ataxia and muscle problems.

What is the differential diagnosis for MELAS and MERRF?

Both diseases can have Ragged Red Fibers showing up, especially in muscle tissue. Both diseases also feature seizures, though only MERRF has "epileptic" seizures. - In MELAS, we see lactic acidosis, stroke-like episodes, and mycolonal encephalopathy (seizures). - In MERRF, we see myoclonal "jerking," epilpetic seizures, and ataxia.

MERRF (Myoclonic Epilepsy with Ragged Red Fibers)

Characterized by brief, sudden muscle jerks (myoclonus), epileptic seizures, ataxia, and ragged red fibers. 80% have mutant mt DNA coding for tRNA (Leucine).

What is one result of the bottleneck effect?

Children may have variable disease that is either more or less severe than the mother. If the mother has 20% mutant mt DNA but, due to bottleneck, the child has 80%, the kid will have more severe disease. The child can also be less severe.

MELAS (Myocolonal Encephalopathy, Lactic Acidosis, and Stroke-like episodes)

Decreased protein synthesis in the mitochondria due to a defect in the tRNA for Leucine (in 80% of cases) leads to myoclonal encephalopathy, lactic acidosis, and stroke-like episodes.

Mutations in the mitochondrial DNA primarily effects:

Energy-generating processes (such as defective enzymes and proteins for aerobic respiration and beta oxidation). tRNAs are also affected, which can have more global effects.

What dye detects Ragged Red Fibers?

Gomori Trichrome Stain

Is mt DNA smaller or larger than nuclear DNA?

It is smaller, containing fewer genes.

Mitochondria have their own ___

Mitochondrial DNA

How well can mitochondrial DNA repair itself?

Mitochondrial DNA has poor repair processes, and therefore has a higher rate of mutation.

How is mitochondrial DNA inherited?

Mitochondrial DNA is inherited maternally. The paternally-inherited mt DNA is destroyed by the embryo.

What does the mt DNA disease pedigree look like?

Mothers pass on the disease to all children (though not all will express the disease fully). Affected males never pass it on to their children.

How many mitochondria do cells have?

Multiple mitochondria.

What tissues tends to have Ragged Red Fibers?

Muscle

Are Ragged Red Fibers diagnostic of MERRF?

No, because some patients with MELAS also have them.

Is mitochondrial inheritance Mendelian?

No, due to the existence of multiple mitochondria which may or may not have the same DNA.

Does mt DNA have histone proteins?

No.

Does mt DNA have introns?

No.

Is the genetic code for mt DNA and nuclear DNA the same?

Not always; TGA in nuclear DNA is stop, and in mitochondria, is tryptophan.

What are Ragged Red Fibers?

Ragged Red Fibers are clumps of diseased mitochondria. They cluster in the subsarcolemmal region of muscle. Always seen in MERRF, but may apeear in MELAS.

What organelle performs vital functions such as the beta oxidation of fatty acids to ATP or the aerobic oxidation of carbohydrates to generate ATP?

The mitochondria

What is one potential "cure" for mitochondrial diseases?

The nuclear transfer of healthy mt DNA from a fertilzied donor embryo into the fertilized egg destined to be affected by a mitochondrial disorder.

What type of genes are included in mitochondrial DNA?

There are 22 tRNA genes (genes coding for tRNAs) and 13 protein-coding genes (they code for things important for mito function, like ATP Synthase or NADH Dehydrogenase).

Explain the "bottleneck effect" as it relates to mt DNA inheritance.

When the mother (with, say, 20% mutant mt DNA) creates oocytes, not all of the eggs receive the same sampling of mt DNA. Therefore, some may receive 20% mutant mt DNA overall, and others, 80% overall. This difference in founding populations alters how many mutant mt DNAs exist for the rest of the child's life: the "bottleneck" or "founder" effect.

What is a disease threshold as it pertains to mt DNA inheritance?

You need a certain percentage of your mitochondria to have mutant mt DNA before you reach a disease state.

Due to having multiple types of mitochondrial DNA and due to maternal-only inheritance, mt DNA follow:

non-Mendelian inheritance.