Flashcards in Diseases of Mitochondrial Inheritance Deck (35)
When evaluating a patient for mitochondrial disease the first tier of testing should include:
-Chromosome microarray studies
- Plasma and urine amino acids
- lactate and Pyruvate levels
-carnitine, plasma total and free
-Coenzyme Q10 level
- Urine organic acids
When evaluating a patient for mitochondrial disease the second tier of testing should include?
-mitochondrial enzyme and/or DNA testing
- Rett Syndrome DNA testing
- PTEN mutational analysis (also with macrocephaly)
- NLGN3, NLGN4X, SHANK3, SNRPN gene testing
- lysosomal enzyme testing
-peroxide disease testing
- CSF studies for lactate and pyruvate, amino acids and neurotransmitters
- Brain MRI
Before embarking on a mitochondrial evaluation make sure you screen for other disorders like:
- chromosome abnormalities
-Other inborn errors of metabolism
-other disorders that could explain the clinical presentation
What are two causes of mitochondrial energy disorders?
- alteration in gene
- toxic effect of external factors such as medication (ex. chemotherapy)
What are the 5 organ systems most affected by Mitochondrial diseases?
- GI including liver
What symptoms are seen in the brain with mitochondrial diseases?
-atypical cerebral palsy
What symptoms are seen in the nerves with mitochondrial diseases?
- absent reflexes
- neuropathic pain
- weakness (may be intermittent)
- Dysautonomia (temperature instability
What symptoms are seen in the pancreas and other glands with mitochondrial diseases?
- diabetes and exocrine pancreatic failure
- parathyroid failure
What symptoms are seen in the muscles with mitochondrial diseases?
What symptoms are seen in the GI with mitochondrial diseases?
-irritable bowel syndrome
-diarrhea or contsitpation
What symptoms are seen in the kidneys with mitochondrial diseases?
renal tubular acidosis or wasting
What symptoms are seen in the heart with mitochondrial diseases?
-cardiac conduction defects (heart blocks)
What symptoms are seen in the liver with mitochondrial diseases?
What symptoms are seen in the ears & eyes with mitochondrial diseases?
-visual loss & blindness
-hearing loss and deafness
What symptoms are seen systemically with mitochondrial diseases?
-failure to gain weight
- unexplained vomiting
What are the most common problems with mitochondrial diseases?
- CNS - developmental delays, autism, loss of function, seizures, hypotonia & weakness
- chronic fatigue
- failure to thrive
-GI issues such as chronic constipation
- Autonomic dysfunction - irregular HR, BP and temperature instability
What are the 5 common misperceptions about mitochondrial diseases?
1. only a childhood disorder
2. only maternally inherited (only 37 out of 1500)
3. why test when there is no cure (but there is treatment)
4. cannot have mitochondrial disease if you survive beyond 4
5. no such thing as mitochondrial diseases
What are the two sets of inherited genetic material?
nuclear genes (from both parents)
mitochondrial genes (exclusively through Mom)
What are the features of the mitochondrial nuclear genes?
proteins are responsible for the control of electron transport chain structure, function, and assembly
What type of inheritance pattern is most common with pediatric patients with mitochondrial disorders?
autosomal recessive inheritance of nuclear gene defects
What are the features of mtDNA?
-inherited exclusively through maternal line
-circular molecules with 37 genes
-mutated mtDNA may be present in varying amounts with wild type DNA (heteroplasmy)
How is mitochondrial diseases diagnosed?
several tiers of testing
- functional testing - examine OXPHOS energy pathway
- gene testing - evaluation of mtDNA and nuclear mitochondrial genes
- biomarker studies - lactate and pyruvate levels, CSF lactate, CPK urine organic acids, carnitine levels
-radiographic studies - mito related imaging abnormality
-published criteria - Bernier Criteria
What findings are strongly suggestive of mitochondrial diseases?
- brain changes suggestive of Leigh disease or abnormalities in white matter in brain
- persistent, elevations of lactate especially if in brain
- problems in many both systems (cardiomyopathy, seizures, NO DIRECT LINK
What are three different criteria for diagnosing mitochondrial diseases?
1 - clinical features, physical findings, and minimal laboratory/radiographic studies
2. clinical phenotypes consistent with MELAS and confirmed by single gene test
3. Clinical features and findings suggestive of mitochondrial disease - complex biomarker testing, tissue studies or extensive gene analysis completed
How are muscle tissues used to diagnose Mitochondrial energy disorders?
1- abnormalities in mitochondrial structure/size/shape/number on tissue biopsy
2. enzymatic abnormalities on testing of the energy producing system (ETC)
3. Respiratory studies measures oxygen consumption in all the complexes
4. Blue and clear native gels studies assess protein complexes; can identify assembly defects
How often are ragged red fibers actually seen when trying to diagnose mitochondrial disorders?
less than 2.5%
pediatric cases are often normal
**age dependent, more often seen over 50
How can you use skin fibroblasts & buccal swab samples to diagnose mitochondrial disease?
OXPHOS enzyme assay
-good screening tool
- still under development
What are some metabolic abnormalities that are supportive of mitochondrial disease?
- increased blood and/or CSF lactate and pyruvate
- decreased plasma carnitine
- increased blood alanine
-increase lactate, pyruvate, Kreb cycle intermediates
What causes tRNA 3243 mtDNA mutation?
What causes tRNA 8344 mutation?
What causes SURF-1 mutations associated with Leigh disease?
Complex IV (death by 5)
What are three treatment modalities for mitochondrial disease?
symptomatic - treat existing problems
Preventative - early detection
Therapeutics - limited; include CoQ10, L-carnitine, Riboflavin, alpha lipoic acid & creatine
What is autism?
complex neurological disorder that typically lasts throughout life. Part of a group of disorders known as Autism Spectrum Disorder (ASD) and affects the ability to communicate and related to others.
How likely is an individual to be diagnoses with autism?
1 in 66