Clinical Aspects of Mitochondrial Disorders Part Two Flashcards
Outline the three main classifications of mitochondrial diseases.
1). Primary mtDNA disorders: - Maternal inheritance - mtDNA point mutations such as m.2343A>G (MELAS), m.8344A>G (MERRF), m.8993T>C/G (NARP, Leigh Syndrome), m.11778G>A (LHON).- Sporadic - mtDNA deletions (CPEO, Kearns-Sayre syndrome, Pearson syndrome).2). mtDNA maintenance disorders (secondary mtDNA disorders).- Autosomal recessive mtDNA deletion syndrome, due to genes including POLG, DGUOK, TK2.- Autosomal dominant or recessive PEO, due to genes including POLG, C10orf2 (Twinkle), RRM2B.3). Nuclear gene disorders with no effect on mtDNA.- Autosomal disorders affecting subunits of the respiratory chain or assembly factors, such as recessive Leigh syndrome due to SURF1.- Autosomal disorders of impaired mitochondrial protein translation, such as recessive pontocerebellar hypoplasia due to RARS2.- Autosomal disorders of impaired mitochondrial dynamics, such as dominant optic atrophy due to OPA1 (although note that mitochondrial dynamics appears important in mtDNA stability, and so abnormal function, including due to OPA1 mutation, can also disrupt mtDNA maintenance).
What are the 2 main subtypes of primary mtDNA disorders?
There are 2 main subtypes of primary mtDNA disorders.1). Point mutations:- Mainly occur in tRNA genes (m.3243A>G) or protein coding genes (LHON - m.11778G>A, MILS - m.8993T>G/C).- Often heteroplasmic (unless LHON).- Maternally inherited.2). mtDNA rearrangements:- Typically large (approximately 2-8 kb) deletions.- Heteroplasmic.- Usually sporadic.
Summarise some of the common maternally inherited mitochondrial DNA point mutations causing primary mtDNA disorders.
Primary mtDNA disorders - Point mutations.1). m.2343A>G - MELAS mutation.- Present in about 1 in 400 individuals but most of those will only have maternally inherited diabetes or maternally inherited deafness late onset after the age of 50 generally.2). m.11778G>A, m.3460G>A and m.14484T>C.- Together these 3 mutations account for >90% of LHON.- Usually homoplasmic, but heteroplasmic in some families.- Lead to missesnse mutations in complex I subunits MT-ND4, MT-ND1 and MT-ND6 respectively.3). m.8344A>G.- Primarily associated with MERRF (myoclonic epilepsy wth ragged red fibres).- Heteroplasmic, relatively uniform distribution between tissues.- MT-TK encoding tRNA.4). m.8993T>C/G/- Primarily associated with maternally inherited Leigh syndrome and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa).- Heteroplasmic (often very high levels), relatively uniform distribution between tissues.- Missense mutation in complex V (ATP synthase) subunit MT-ATP6.
Describe Leiber’s Inherited Optic Neuropathy (LHON).
LHON:- m.11778G>A, m.3460G>A and m.14484T>C.- Together these 3 mutations account for >90% of LHON.- Usually homoplasmic, but heteroplasmic in some families.- Lead to missesnse mutations in complex I subunits MT-ND4, MT-ND1 and MT-ND6 respectively.- One of the first mt condition to be described but we still don’t know why symptoms will affect some individuals with the mutations but not others.- If you are male your risk of going blind is increased - 5:1 sex ratio for males to females but varies dependant on mutation. - Affected mother increased chance of symptoms.- Males>females - ratio varies with mutation.- The appearance of the optic disk is optic atrophy - retinal ganglion cells degenerate so that the axons leaving the eye and going to the brain degenerate as a result of loss of these cell bodies.- If you have a fairly large optic disk thus lost of nerves in that bundle then you are less likely to go blind. - Genetic factors can affect prognosis. The 3460 mut has a better prognosis than 11778. Certainly likely to be additional nuclear encoded factors. People have looked for X-linkage and have found a trend towards it but no specific genes have been identified. Some have looked at other genome screens and in some ethnic groups polymorphisms in a gene called PARL has been identified. mtDNA haplotype J is another risk factor - may be due to mitochondrial coupling.- Environmental factors may also affect prognosis of LHON - Smoking is a strong risk factor and can increase risk of going blind. Alcohol may also increase risk. In women there are 2 age peaks in prevalence, one the same as men in adolescence and one at menopause - ?oestrogen may be protective.- LHON shows a strictly maternal pattern of inheritance.- LHON is usually homoplasmic with little correlation between level of mutant and severity.- Commonest mutations:- 11778 = 80%- 3460 = 15%- 14484 = 5%- Some individuals also have associated neurological problems.- With rare mutations there is a LHON/Leighs spectrum within the same pedigree - e.g. 14459.PHENOTYPE OF LHON:- Loss of vision.- Patients may get a visual field defect involving the most acute area of the retina and spreading outwards around the periphery called a CC-scotoma.- Dyschromatopsia colour vision defect.- Get a pale optic disk as a result of atrophy of the retinal ganglion cells and the optic nerv axons projecting from them.
Describe the phenotype of LHON.
PHENOTYPE OF LHON:- Loss of vision.- Patients may get a visual field defect involving the most acute area of the retina and spreading outwards around the periphery called a CC-scotoma.- Dyschromatopsia colour vision defect.- Get a pale optic disk as a result of atrophy of the retinal ganglion cells and the optic nerve axons projecting from them.
What mutation may cause a LHON/Leighs spectrum withing the same pedigree?
With rare mutations there is a LHON/Leighs spectrum within the same pedigree - e.g. 14459.
What are the commonest mutations in LHON?
Commonest mutations:- 11778 = 80%- 3460 = 15%- 14484 = 5%
Outline pre-symptomatic testing for LHON.
- Pre-symptomatic testing is often requested but is not always helpful.- If mother affected then male offspring has 77% chance of loosing vision and female offspring 50% chance.- If mother unaffected then male have 50% chance of loosing vision and females only 9%.- If you have an affected sib the males have a 30% chance of loosing vision and an 8% chance if you are a female.
Describe Sporadic Mitochondrial Rearrangements.
- Sporadic mtDNA rearrangements are a type of primary mtDNA disorder.- Sporadic mtDNA rearrangements are deletions and duplications that tend to cause CPEO, Kearns-Sayre syndrome and Pearson syndrome.- Heteroplasmic. Individuals with a high dose of mutant tend to present earlier than those with a low dose of mutant. Similarly the distribution of the mutant depends on age - adult will have high levels of mutant in muscle but low levels in blood - young individuals will have high levels of mutant in all tissues.
Sporadic mtDNA rearrangements are a type of primary mtDNA disorder, what conditions do these kind of rearrangements tend to cause?
Sporadic mtDNA rearrangements are deletions and duplications that tend to cause CPEO, Kearns-Sayre syndrome and Pearson syndrome.
What investigation might you use when investigating an individual presenting with clinical features indicating mitochondrial rearrangements?
- Blood lactate- Muscle biopsy followed by histochemistry and mtDNA analysis.- mtDNA analysis via LPCR, Southern blot, may also screen for specific mutations.- Resp. chain- Blood DNA for POLG common mutations and LPCR in the young.
What are secondary mtDNA disorders?
- Secondary mtDNA disorders are mtDNA maintenance disorders.- The first of these is autosomal recessive mtDNA depletion syndrome, due to genes including POLG, DGUOK, and TK2.- Also include autosomal dominant or recessive PEO, due to genes including POLG, C10orf2 (Twinkle), RRM2B.
Describe mtDNA depletion syndrome.
- mtDNA depletion syndrome is a secondary mtDNA disorder (mtDNA maintenance disorder).- mtDNA depletion syndrome is usually caused by mutations in the POLG gene. POLG gene encodes the mitoch- May also be due to mutations in DGUOK or TK2 genes which are genes that are important in providing the dNTP substrates for use by the mitochondria.- Defects in mitochondrial DNA maintenance are a unique group of disorders because they involve defects in both of the genomes within human cells. Primary nuclear gene defects in a gene that affects mitochondrial DNA replication / maintenance and secondary mitochondrial DNA defect - tissue specific.- In autosomal disorders of mitochondrial maintenance the cell may start off being normal, but because there is poor copy capacity for copying mitochondrial DNA some cells will become depleted and some will develop multiple DNA deletions.- These are tissue specific disorders and the disease symptoms tend to be chronic progressive external ophthalmoplegia in older individuals and tend to be mitochondrial depletion in younger.- Mutations in POLG genes can occur in catalytic or linker region of gene. Those that arise in the linker region are on the whole milder than those in the exonuclease catalytic domain.- The patient’s muscle mtDNA is qualitatively normal but reduced in quantity compared with nuclear DNA.
Overview defects in mtDNA replication.
- Scientific background.- Disorders of mtDNA maintenance- Adults - mild- Childhood onset - severe- Cells from these patients demonstrate abnormal mtDNA distribution and synthesis.- A possible role for mtDNA depletion is multifactorial disease.
