Mitochondrial Diseases Flashcards
How doe mitochondrial genes have homoplasy and heteroplasy?
Mitochondria are all maternally inherited however there are multiple copies per cell
This can result in homoplasy where all the copies of mitochondria in the cell have the same genome or heteroplasy where mitochondria within a cell have different genomes
What are the features of mitochondria disease?
There is a threshold effect where there is either a required numbers of copies of the mutant genome are required to be present in the same mitochondria, this threshold will change with the mutation and tissue types
There is clonal expansion of the mitochondria
There is mitochondrial bottleneck
These conditions often display a mosaic pattern
What is the mitochondrial bottle neck?
Due to the fact that there are several mitochondria in each cell there are several possible ways for the condition to be inherited
The child can inherit no mutant copies of mitochondria, only mutant copies or a mix of the two
How rare are mitochondrial DNA mutations?
There is mitochondrial disease in 1 in 11,000 people and 1 in 6000 people are mutation carriers
What are the features of clinical syndromes in mitochondrial disease?
The symptoms are extremely variable
The age of presentation is variable, if there are mutations in nuclear encoded genes tending to occur in infancy and early childhood, mutations in mitochondrial genes in childhood or adulthood
Both reflect the level of mutation and severity of the biochemical defect
What are the features of mtDNA point mutations?
These are usually maternally inherited
Occur in protein, tRNA and rRNA genes
Mutations in protein coding affects Respiratory chain complex function
Mutations in tRNA impair overall mitochondrial translation
Usually heteroplasmic
Display clinical heterogeneity
What are the mtDNA rearrangements?
Usually large scale deletions which can span several genes like KSS and CPEO
They occur sporadically early in development
Multiple deletions may be due to mutations in nuclear genes involved in mtDNA maintenance and replication
Increase with age in postmitotic tissues and in individuals with neurodegenerations
What is Leigh’s syndrome?
This is a severe neurological condition which typically arises in the first year of life
Difficulties in feeding and swallowing leading to a “failure to thrive”
May have severe dystonia
Lesions formed in the brain
Individuals usually die in the first few years of life
What is the cause of Leigh’s Syndrome?
This can be due to mutations in mitochondrial genes eg m8993t>c or mutations in nuclear genes like SURF1 gene there have been over 26 defects identified
What is depletion syndrome?
Severe neurological condition which typically arises during infancy
Typically have severe muscle weakness, progressive encephalopathy or liver failure
Caused by a reduction in the mtDNA copy number in affected tissues (low mtDNA/nDNA ratio) resulting in reduced activity of the respiratory chain
How can depletion syndrome be treated?
This condition is tissue specific so may respond to organ transplantation
What is MELAS syndrome?
This is mitochondrial encephalopathy, lactic acidosis and stroke like episodes
It typically presents with stroke like episodes with seizures with over 80% have the common m.3243A>G mutations in MT-TL1 gene and is heteroplasmic
What is LHON?
Lebers Hereditary Optic Neuropathy
Symptoms include impaired vision, targets retinal ganglion cells of the optic nerve
Homoplasmic mutations usually in ND genes (ND 1, ND4 and ND6) which are protein coding genes
Typically males aged 20-40
What are secondary mitochondrial mutations?
These are mitochondrial disease but they are caused by genes which have been moved to the nucleus and thus are inherited in a Mendelian fashion
What are the diagnostic tests for mitochondrial disease?
There is histological testing using COX/SDH staining and ragged red fibres
Biochemical testing determines individual Respiratory chain complex activities usually in muscles
Molecular genetic testing sequencing or RFLP for point mutations or realtime PCR for deletions
