Mitochondrial Disorders

Question 1

Most important functions of mitochondria is the production of ?

Answer 1

Reactive oxygen species (ROS)

Very dangerous

Necessary for cell signaling

Question 2

What organ contains the most mitochondria?

Answer 2

The brain

Second = skeletal and cardiac muscle

Question 3

Most common process that is damaged in mitochondrial diseases

Answer 3

Respiratory chain or oxidative phosphorylation

Question 4

What DNA controls the function of mito

Answer 4

The nuclear DNA (not its own DNA…)

The complexes are ‘double coded’ with both nuclear and mito DNA coded subunits

Nuclear DNA codes for most of the subunits

Question 5

Consequences of mito disorders

Answer 5

Energy failure, decreases in ATP production and latered cellular processes

Increased ROS —> lipid membrane damage and cell death

Question 6

Clinical presentation

Answer 6

Encephalopathy - brain disesae that alters brain function or structure

Myopathy

Cardiomyopathy

Liver disease

Children will be more severely affected than adults

Question 7

Leigh Disease

Answer 7

Basal ganglia disease - in the brain control multiple functions (heart rhythm, thermoreuglation, breathing, etc)

Becomes hyperactive and form symmetric cystic legions and die

Most common presentation of mitochondrial diseases

If also have lactic academia - progressive dystonia (involuntary movement) it is called LEIGHT SYNDROME!

Question 8

Maternal inheritance

Answer 8

All mitos are derived from the ovum

Males and females can be affected

NO affected male has effected offspring

Question 9

Semiautonomous replication

Answer 9

MtDNA replication is partially under nDNA control

Dysfunction in nDNA genes such as Polg, Twinkle, SUCLA2, SUCLG1 —> can cuase secondary myDNA deletions or mitochondrial depletion syndromes

—> decreased amount of functional mtDNA

Question 10

Heteroplasmy

Answer 10

The mito in the egg are not identical, but are a mixed population

In most somatic cells, there are mutated and healthy mtDNA strands

Important for considering the severity of mito disease

Question 11

Threshold effect (penetrance)

Answer 11

Heteroplasmy causes a threshold effect

Not all mutations will be passed on to the fetus

Patients must have a certain % of the bad myDNA to show clinical features

Question 12

High mutation load

Answer 12

Unlike nDNA —> mtDNA has limited DNA repair mechanism

Fusion and fission to combat DNA damage

Will reshuffle healthy and mutated mtDNA populations within the cell

Fusion = increase in mito mass

Fission = increase mito #

This process is very random so it will not remove all mutant DNA

Question 13

MELAS

Mito encephalopathy, lactice acidosis, stroke-like episdoes

Answer 13

One of the most common mito disorders

Mutations in mtDNA (as opposied to mutations in nDNA that lead to mito dysfunction)

Many body systems affects

Regression, serizures, cardomyopathy

Question 14

SUCLG1, SUCLA2, TK2, POLG1, Twinkle

Especially POLG1

Answer 14

Nuclear genes that are involved in mtDNA replication

Mutations in these —> symptoms

• lactic acidosis
• e-transport chain defects
• mtDNA depletion in muscle

Autosomal recessive inheritance

Question 15

Alpers syndrome

Answer 15

AR caused by mutation in the gene for the mtDNA polymerase (POLG…POLG1 gene)

Epilepsy, liver failure, lactic academia, and facila coarsening

Question 16

When to suspect mito disorder

Answer 16

When a patient has a multisystem presentation

• lactate elevation
• abnormal urine organic acids (byproducts of Krebs that get backed up)
• abnormal imaging (Leigh syndrome will show break down of basal ganglia in imaging)
• PROGRESSION

Question 17

Diagnosing mito disorders

Answer 17

Easiest way = muscle biopsy but this is highly invasive

Lab values and imaging are evaluated to determine if a muscle biopsy is warranted

1. Phenotype with lab reports of blood and urine and brain imaging suggest mito
2. Mito disease score
3. MtDNA analysis and consider nuclear DNA panels
4. Next generation sequencing
5. Functional analysis