Mitochondrial DNA abnormalities


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Mitochondrial DNA abnormalities in ophthalmological disease Gorman, G.S., Taylor, R.W. Mitochondrial DNA abnormalities in ophthalmological disease. Saudi Journal of Ophthalmology (2011),: 

Mitochondrial DNA abnormalities in ophthalmological disease Gorman , G.S., Taylor, R.W. Mitochondrial DNA abnormalities in ophthalmological disease . Saudi Journal of Ophthalmology (2011), Dhruba Jyoti Sarma MSc 1 st sem MBM11025


Contents Introduction. Basic mitochondrial genetics. The laboratory diagnosis of mitochondrial disease Ocular manifestations of mitochondrial disease. Concluding remarks.


Introduction Mitochondrial disorders are a group of clinically heterogeneous diseases, commonly defined by lack of cellular energy. affect organs heavily dependent on aerobic metabolism Neuro ophthalmic symptom of mitochondrial disorders are common includes retinal, mascular and optic nerve dysfunctions, external ophthalmoplegia with ptosis and gradual visual loss.

Basic mitochondrial genetics: 

Basic mitochondrial genetics mitochondria are under the dual genetic control of both nuclear DNA and the mitochondrial genome ( mtDNA ) mtDNA a small (16.6 kb) multicopy , double-stranded circular DNA molecule. which encodes 13 essential polypeptides of the respiratory chain and the necessary RNA machinery for their translation.

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the heavy (H) strand of the genome the light (L) strand The human mitochondrial genome. Human mtDNA encodes: 2 mt-rRNA genes RNR1 (12S rRNA ) and RNR2 (16SrRNA) 22 mt-tRNAs 13 essential respiratory chain polypeptides: 7 subunits (ND1–ND6 and ND4L) of complex I CYTB of complex III COI–COIII ) of complex IV and ATP6 ATP8 of complex V 16.6 kb D-loop

Laboratory diagnosis of mitochondrial disease: 

Laboratory diagnosis of mitochondrial disease Different factors are involved: the lack of clear genotype-phenotype correlations, selective organ involvement and complex interactions between the nuclear and mitochondrial genome. Many patients with mtDNA disease show histological and histochemical changes -ragged-red fibres and COX-deficient fibres which signal mtDNA involvement mtDNA rearrangements (deletions and duplications) are assessed by Southern blotting or PCR-based strategies. In case of Chronic Progressive External Ophthalmoplegia (CPEO) it requires muscle biopsy which can identify the ragged red fibers. ragged-red fibres

Ocular manifestations of mitochondrial disease: 

Ocular manifestations of mitochondrial disease Chronic Progressive External Ophthalmoplegia (PEO): bilateral , slowly progressive loss of extraocular muscle mobility, orbicularis oculi weakness and ptosis . When PEO and ptosis are associated with other neurological or multisystem abnormalities,are termed as ophthalmoplegia - plus (PEO+) syndromes. Kearns–Sayre Syndrome (KSS) is the most common form of a PEO+ syndrome, a systemic disorder.

Primary mtDNA mutations causing CPEO: 

Primary mtDNA mutations causing CPEO Late onset-PEO is the most common form of extraocular mitochondrial myopathy which often arises spontaneously. Heteroplasmic , single large-scale mtDNA rearrangements predominantly mtDNA deletions but occasionally associated duplications. The recognized cause of mitochondrial PEO is mutation in MTTL1 gene in m.3243A>G. Rarer mtDNA mutations can be found in mitochondrial-encoded mRNA genes but more typically tRNA genes.

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Approximately 20% of patients with PEO demonstrate a Mendelian pattern of inheritance, implicating nuclear DNA abnormalities Involving POLG gene. Mendelian PEO can be dominantly- or recessively-inherited. a patient with mitochondrial CPEO, extraocular motility in cardinal directions of gaze is severely reduced.

Autosomal dominant (ad) PEO: 

Autosomal dominant (ad) PEO Mutation in the folloing gene develops to ad PEO POLG, which encodes the mitochondrial catalytic subunit pol γ PEO1, which encodes mitochondrial helicase twinkle. RRM2B, encodes a subunit of p53, which maintains balanced mitochondrial dNTP pools. SLC25A4, encodes adenine nucleotide transolcator 1. Other genes includes PLOG2,OPA1 etc. Autosomal recessive ( ar ) PEO Ar PEO are associated with PLOG mutations.

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The polymerase domain of Human polymerase γ is encoded by POLG gene. Exonuclease domain Linker region Polymerase domain


OTHER MITOCHONDRIAL OPTHALMOLOGICAL DISEASES mitochondrial disorders associated with MUTATION Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes(MELAS) m.3243A>G point mutation Myoclonic epilepsy, myopathy with ragged-red fibres (MERRF) m.8344A>G mutation Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Mutations TYMP gene encoding Thymidine phosphorylase Neurogenic weakness, ataxia and retinitis pigmentosa (NARP) mutation at m.8993 in the MTATP6 gene Leber hereditary optic neuropathy (LHON) 95% of known cases of LHON are due to mutation in m.3460G>A, m.11778G>A, m.14484T>C

Concluding remarks: 

Concluding remarks The spectrum of mitochondrial disorders is vast and new patterns of disease are increasingly recognised . Diagnostic accuracy has significantly improved over the last decade with ability to detect many of the common mtDNA pathogenic mutations non-invasively. Muscle biopsy is done to detect primary and secondary mtDNA abnormalities, particularly in patients with PEO. It has been suggested that the diagnosis of mitochondrial disease should be considered in all cases of ocular muscle dysmotility and in patients with visual failure of acute or insidious onset.


References Copeland, W.C., 2008. Inherited mitochondrial diseases of DNA replication. Annu . Rev. Med. 59, 131–146. Yu-Wai-Man, P., Griffiths, P.G., Hudson, G., et al., 2009. Inherited optic neuropathies. J. Med. Genet. 46, 145–158. Gerald C. Karp.,Cell and Molecular Biology:201-203

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