Mitochondrial Disorders ✅ Flashcards
Why is there multiple copies of the mitochondrial genome in each cell?
Because each mitochondrion carries a copy of its own genome, and each cell of the body contains multiple mitochondria
What does the genome of the mitochondrion contain?
Genes encoding proteins essential to mitochondrial function
What are mitochondrial disorders?
Disorders caused by mutations in the mitochondrial genome
Are the mutations present in all the mitochondria in mitochondrial disorders?
No, they are usually only present in a proportion of the mitochondria in any given cell, with the remainder having a normal sequence
What is the term used to describe not all mitochondria within any given cell having mutations in the mitochondrial genome in mitochondrial disorders?
Heteroplasmy
What is the clinical relevance of heteroplasmy?
In part, the severity of a disorder depends on the level of heteroplasmy in different tissues
Which parent are mitochondria inherited from?
Exclusively from the mother
Why are mitochondria inherited exclusively from the mother?
Because there are mitochondria in the egg but not in the part of the sperm that forms the zygote
What is the result of all mitochondria being inherited from the mother?
Mitochondrial mutations cannot be passed on by a male
Can you predict the level of heteroplasmy in the eggs of a women?
It is hard to predict
What is the implication of it being hard to predict the level of heteroplasmy of the eggs of a woman?
It is difficult to predict the level or risk of mitochondrial disease in her offspring
In what respects do mitochondrial disorders overlap clinically?
- Tend to affect same organs
- Often show progressive, degenerative course with episodes of decompensation during acute illness
- Lactic acidosis and/or elevated CSF lactate often present
What kind of tissues does mitochondrial dysfunction have a tendency to affect?
Tissues that use a large amount of energy
What tissues use a large amount of energy and therefore tend to be affected by mitochondrial dysfunction?
- Muscle
- Retina
- Kidney
- Nerves
- Brain
What does the effect of mitochondrial dysfunction on the muscle produce?
Myopathy
What does the effect of mitochondrial dysfunction on the retina produce?
Retinitis pigments
What does the effect of mitochondrial dysfunction on the kidney produce?
- Proximal tubulopathy
- Renal failure
What does the effect of mitochondrial dysfunction on the nerves produce?
Neuropathy
What does the effect of mitochondrial dysfunction on the pons and cerebellum produce?
- Pontocerebellar atrophy or hypoplasia
- Ataxia
What does the effect of mitochondrial dysfunction on the brain produce?
- Epilepsy
- Encephalopathy
- Stroke-like episodes
Which parts of the brain in particular do mitochondrial disorders affect?
- Basal ganglia
- Pons
- Cerebellum
What does the effect of mitochondrial dysfunction on the basal ganglia produce?
Dystonia
When in particular might lactic acidosis and/or elevated CSF lactate be present?
During episodes of decompensation
What are the classical mitochondrial phenotypes?
- Myoclonic epilepsy with ragged red fibres (MERRF)
- Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
- Leigh’s syndrome and the overlapping disorder, neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP)
Do mitochondrial disorders always fit into the classical phenotypes?
No
What is Leigh’s syndrome?
Subacute necrotising encephalomyelopathy
Are the classical phenotypes of mitochondrial disorders limited to only mitochondrial genetic abnormalities?
No, can also be caused by autosomal recessive mutations in conventional nuclear genes
Give an example of a classical mitochondrial phenotype that can also be caused by autosomal recessive mutations in conventional nuclear genes?
Leigh’s syndrome
Why is a high index of clinical suspicion required to diagnose mitochondrial disorders?
Due to their variability and wide variety of clinical manifestations
What are the mainstays of clinical diagnosis of mitochondrial disorders?
- Neuroimaging
- Biochemical testing, including blood and CSF lactate
- Muscle biopsy for histology and electron microscopy
- Skin or muscle respiratory chain enzyme analysis
What other investigations may be useful in the diagnosis of mitochondrial disorders?
- Nerve conduction studies
- Urine biochemistry
- Electroretinography
How can DNA testing for mitochondrial disorders be carried out?
- Targeted for specific mitochondrial mutations
- Sequence for panel of common mitochondrial mutations, deletions, and duplications
What is used to target DNA testing for specific mitochondrial mutations?
The presenting phenotype
Is it possible to sequence the entire mitochondrial genome?
Yes (in some labs)
What has allowed the entire mitochondrial genome to be sequenced?
The use of higher throughput techniques
How is sensitivity maximised when DNA sequencing to look for mitochondrial disorders?
- Using methods able to detect mutations at relatively low levels of heteroplasmy
- Analysis of DNA extracted from muscle
Why does analysis of DNA extracted from muscle increase the sensitivity when sequencing to look for mitochondrial disorders?
Mutation load is often higher in muscle
What is also performed when the phenotype is also consistent with mutation in a conventional nuclear gene?
Targeted sequencing and/or copy number analysis of these genes is performed
