Mitochondrial Disorders

Question 1

How much of our energy do the mitochondria produce?

Answer 1

90%

Question 2

Mitochondrial DNA (mtDNA)

Answer 2

16,569 bp
37 genes
No introns
Double stranded ring
Continuously replicated
No homologous recombination of meiosis
High mutation rate

Answer 3

7 genes - Complex I subunits
1 gene - Complex III subunits

Question 4

What is Primary Mitochondrial Disease?

Answer 4

Disorders impacting the structure or function of mitochondria as a result of either nuclear DNA or mitochondrial DNA mutations

Question 5

Leigh Syndrome (AKA subacute necrotizing encephalomyelopathy)

Answer 5

Most Common Genes: MTATP6 (mtDNA), SURF1 (nuclear), PDHA1 (PDH) (X-Linked, treatable with ketogenic diet)

Question 6

NARP: Neuropathy, Ataxia, and Retinitis Pigmentosa

Answer 6

Dev delays, numbness, balance problems, etc.

Milder form of Leigh Syndrome

High level of heteroplasmy may cause Leigh Syndrome (90-100) but 70-80 in NARP

Question 7

MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes)

Answer 7

Stroke-like episodes, seizures, headaches
Treatable: Citrulline and Arg
mtGene

Question 8

Maternally Inherited Diabetes-Deafness (MIDD)

Answer 8

85% due to m.3243A>G mutation
Bilateral SNHL

Question 9

MERRF (Myoclonic Epilepsy with Ragged Red Fibers)

Answer 9

Myoclonus
Seizures, ataxia
Short stature
Cardiomyopathy, dysrhythmias
Hearing loss
Opthalmoplegia, ptosis
Exercise intolerance
Periph neuropathy

Question 10

Leber Hereditary Optic Neuropathy (LHON)

Answer 10

Vision loss, movement disorders, tremors, neuropathy, arrhythmia

Loss of visual acuity, optic nerve edema, vascular changes, optic nerve pallor and atrophy

More common in males

Treatment: AAV gene therapy

Question 11

mtDNA deletion syndromes

Answer 11

Pearson Syndrome, Kearns Sayre Syndrome, CPEO

Question 12

Pearson syndrome

Answer 12

mitochondrial disease that also includes bone marrow failure

lactic acidosis

Question 13

Kearns Sayre Syndrome

Answer 13

FTT
Ataxia
Diabetes
Adrenal insufficiency

Question 14

CPEO (Chronic Progressive External Oph

Answer 14

Ptosis
Limb weakness
exercise intolerance

Question 15

Mitochondrial Neurogastrointestinal Encephalopathy Disease (MNGIE)

Answer 15

Dysmotility, cachexia, ptosis, leukoencephalopathy, demyelenating peripheral neuropathy

Dx: TYMP

Question 16

POLG-related disorders

Answer 16

Alpers-Huttenlocher (AHS)
Childhood myocerebrohepatopathy spectrum (MCHS)
Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
Ataxis neuropathy spectrum (ANS)
AR Progressive External Ophthalmoplegia (arPEO)
one more PEO

Question 17

Non-syndromic hearing loss

Answer 17

MT-RNR1 (late-onset) or aminoglycoside ototoxicity - antibiotics can trigger
MT-TS1 (early onset)

Question 18

What biochemical findings would we be looking for in mitochondrial diseases?

Answer 18

Elevated lactate and elevated alanine on biochemical testing

Lactate/pyruvate ratio; only useful if lactate is elevated >5uM

Question 19

Biopsies

Answer 19

Morphological analysis

Electron microscopy

Biochemical

Molecular

Fibroblast, muscle, heart, liver most common tissue types (muscle typically best, but tissue type is usually phenotype driven)

POLG: liver or fibroblast

Question 20

Imaging

Answer 20

Brain/Spine MRI
etc.

Question 21

Treatment

Answer 21

Supportive care
PT/OT
“Mitochondrial cocktail”
- Co Q10
- antioxidants
- carnitine
- riboflavin
- vit E
- vit C

Avoidance
- Valproic acid, aminoglycoside antibiotics