Mitochondrial Myopathies - Part 2 Flashcards
Describe MELAS syndrome.
Onset 5-15 years.
Clinical features:
- Stroke-like episodes / seizures / migraine / vomiting / hemiparesis / PEO / aphasia / dementia.
- Myopathy (with RRFs on biopsy).
- SNHL / cortical blindness / hemianopsia.
- Diabetes mellitus / short stature / renal disease/
- Cardiomyopathy.
Genetics:
- Mitochondrial - 80% have A3243G mutation in MT-TL1; others have mutations in MT-ND5 gene.
- AR forms are rare - POLG.
What is the most common mutation in MELAS syndrome?
Genetics:
- Mitochondrial - 80% have A3243G mutation in MT-TL1; others have mutations in MT-ND5 gene.
Describe MERRF syndrome.
Onset 5-15 year.
Clinical features:
- Myoclonus / generalised epilepsy / ataxia / dementia.
- Myopathy (with ragged red fibres).
- SNHL / optic atrophy.
- Short stature / cardiomyopathy with WPW syndrome / multiple symmetrical lipomatosis.
Genetics:
- Mitochondrial - 80% have G8344A mutation and 10% have T8356C/G8363A/G8316A in MT-TK; rarely mutations in MT-TF/MTTP.
What is the most common mutation seen in MERRF syndrome?
Genetics:
- Mitochondrial - 80% have G8344A mutation and 10% have T8356C/G8363A/G8316A in MT-TK; rarely mutations in MT-TF/MTTP.
Describe LHON.
Onset 12-30 years.
Clinical features:
- Male to female ratio (4:1).
- Subacute painless visual loss sequentially affecting both eyes.
- Other neurological symptoms are rare.
Genetics:
- Mitochondrial (G3460A and G11778A mutations in MT-ND1/T14484C mutation in MT-ND6; usually homoplasmic with variable penetrance.
- Mitochondrial mutations that cause LHON are usually homoplasmic.
Describe Kearns-Sayre Syndrome (KSS).
Onset is earlier than 20 yrs.
May see a child with deafness but it is difficult to diagnose until the full phenotype has evolved.
Clinical features:
- Cerebellar ataxia / PEO.
- Pigmentary retinopathy / SNHL.
- Growth failure / endocrine deficiencies.
- Cardiac conduction block.
- CSF protein >0.1 g/L.
Genetics:
- Mitochondrial - 90% have a single large mitochondrial deletion +/- duplication.
- There is an AR form involving RRM2B that is very rare.
What mutation causes most cases of Kearns-Sayre Syndrome (KSS)?
Genetics:
- Mitochondrial - 90% have a single large mitochondrial deletion +/- duplication.
- There is an AR form involving RRM2B that is very rare.
Describe Progressive External Opthalmoplegia (PEO).
Onset 20-30 years.
Clinical features:
- Ptosis with restricted eye movements / proximal limb weakness / pharyngeal weakness.
- Tremor / ataxia / peripheral neuropathy / depression.
- SNHL / cataracts.
- Endocrine dysfunction.
Genetics:
- Mitochondrial - 50% have single mitochondrial DNA deletions.
- Can get AR forms - POLG / RRM2B.
- Can get AD forms - POLG / POLG2 / C10orf2 / SLC25A4 / RRM2B.
Describe Mitochondrial DNA depletion syndromes.
Mitochondrial depletion syndromes occur when the amount of mitochondrial DNA present in tissues is far less than normal. This occurs due to abnormal mitochondrial DNA replication.
Onset is from neonatal period to mid-childhood.
Combinations of tissues involved can sometimes help you determine which genes are involved.
Phenotype (genotypes):
- Hepato-cerebral disease (POLG / DGUOK / C10orf2 / MPV17).
- Navajo neurohepatopathy (MPV17).
- Progressive myopathy (TK2).
- Encephalo-myopathy with Leigh-like lesions +/- mild MMA (SUCLA2/SUCLG1).
- Cerebro-renal disease (RRMB2).
Investigations.
- Need to look at mtDNA copy number to diagnose - decreased mtDNA copy number in muscle or liver.
- Normal or increased complex II levels with decreased complex I/III/IV levels. Complex II doesn’t have any mitochondrially coded subunits and so it shouldn’t be affected.
Outline how you might go about investigating a patient with a suspected mitochondrial disorder.
1) . There is a history and clinical features of mitochondrial disease.
2) . If there is indication of a specific syndrome then you can directly test for that via a specific genetic test or biochemical test in blood or urine.
3) . If no specific syndrome is indicated then carry out a muscle or liver biopsy. Muscle biopsy is usually preferred because it is less invasive than a liver biopsy and it also carries less risk of adverse events compared to a liver biopsy.
4) . With muscle/liver you look at histology and histochemistry. Depending on what you find may point you towards specific molecular genetic studies.
5) . Can also look at biochemistry including CoQ10 and respiratory complexes. If you find isolated complex I-V deficiency, multiple complex deficiency, mitochondrial DNA depletion or coenzyme Q10 deficiency may point towards specific molecular genetic tests.
Outline how you might go about deciding what molecular genetic tests to perform for mitochondrial disorders.
1) . If you recognise a specific syndrome then look for common mtDNA point mutations and/or mtDNA deletions and duplications. May have multiple mtDNA deletions = Mutation analysis of POLG/POLG2/PEO1/SLC25A4/TYMP/OPA1/RRM2B.
2) . If you don’t recognise a specific syndrome and there is a maternal history then that suggests a disorder showing mitochondrial inheritance - look for mutations in mtDNA not nuclear DNA.
If you get a mosaic pattern of COX staining with lots of drop outs it also suggests mitochondrial mutations rather than nuclear DNA mutations.
If you get multiple complex deficiencies it is again more likely that you are going to have mtDNA mutations rather than nuclear DNA mutations.
3) . If you have maternal history, mosaic pattern of COX deficiency or multiple complex deficiencies then go down the route of mtDNA sequencing. May throw up novel variants whose pathogenicity may have to be resolved using single fibre studies together with family studies.
4) . If you DON’T have maternal history, mosaic pattern of COX deficiency or multiple complex deficiencies then you should first check to see if it is possible that you are looking at a mitochondrial depletion syndrome. Specific tests such as ratio of complex II to Complex I/III/IV and also the quantification of mtDNA in muscle or liver. If these studies suggest that it is a mitochondrial deletion syndrome then need to look at genes such as POLG / PEO1 / TK2 / DGUOK / RRM2B / SUCLA2 / SUCLG1 / TYMP / MPV17 on mutation analysis.
5) . If you DON’T have maternal history, mosaic pattern of COX deficiency or multiple complex deficiencies but you have a deficiency of coenzyme Q10 or of just 1 respiratory complex. In this case can do mutation analysis of genes encoding specific mitochondrial and nuclear subunits and assembly factors. However there a vast numbers of related genes and this gets complex.
Conclusions about mitochondrial disorders:
- Mitochondrial disorders are not rare.
- They usually demonstrate mitochondrial inheritance in adults and autosomal recessive inheritance in children.
- MDs in adults are often syndromic.
- Muscle biopsy is the key diagnostic test.
- Clinical features and muscle biopsy findings can help to direct genetic testing.
- Expert help is available for undiagnosed cases - e.g. one of the national teams for rare mitochondrial disease.
