Mitochondrial Disorders For Gc Boards

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Mitochondrial Genetics Basics

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13 proteins are encoded by mtDNA and translated on to intra-mito ribosomes (maternal inheritance)
16.6 kb
37 genes ( 13 proteins, 22 t-RNA's,2 r RNA's)

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Pyruvate Dehydrogenase Complex Deficiency

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-most commonly dominant X-linked El alpha deficiency
-early onset: overwhelming lactic acidosis, multi-system failure and death
-late onset: can look like carbohydrate-induced ataxia
-Females can have rearrrange.

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Electron Transport Chain

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Complex 2 entirely nuclear encoded
other complexes have mutDNA and nDNA encoded subunits
complex 1 converts NADH- NAD+
complex 2 converts FADH2 to FAD

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Principles of Maternal Inheritance

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1. Asexual: from mothers only, high recurrence risk
2. Heteroplasmy: varies cell to cell
3. Bottleneck: unstable heteroplasmy
4. Threshold: some tissues need more energy than others

Tissues with High demand more likely affected: NERVES, MUSCLE--Endocrine tissue and Renal Tubule and finally growth

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Kearn-Sayre Syndrome

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-Mito disease due to heteroplasmic primary mtDNA mutations
-think OCULARMYOPATHY AND CARDIAC Conduction defect
-abnormalities in brain, heart, renal tube and endocrine glands
-single most common 4.9 kb deletion (can be other deletions or deletions/duplications, duplications have higher recurrence risk)
-can also look like Pearson syndrome

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MELAS

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Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, Stroke-like episodes
-3243A>G point mutation in tRNA-leu

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LHON

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Leber Hereditary Optic Neuropathy
-most common mtDNA disorder
-rapid vision loss
-most caused by 3 homoplasmic mtDNA mutations in complex 1 genes: 11778G>A(most common), 3460G.A and 14484T>C (visual recovery)
-low penetrance
-sex bias, males 4x more likely

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mtDNA-Associated Hearing Loss

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-can be syndromic or not syndromic
-mutations in 12S-ribosomal RNA and tRNA
-homoplasmic 1555A>G mut in 12S-rNA gene causes hearing loss in multifactorial manner
-common cause of hearing loss in asia
-onset with AMINOGYLOSIDES (some antibiotics)

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Mohr-Tranebjaerg syndrome

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-sensineaural deafness, dystonia, dysphagia, cortical blindness and PARANOIA)
-mutations in DDP1
-involved in Mitochondrial protein import

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Leigh Syndrome

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-Problems with bottom of brain (basal ganglia, cerebellum and brain stem)
-neurodegeneration
-nuclear or mtDNA genes
-many genes: NDUFS, MDUFV, SCO1, COX10

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PEO

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-Progressive External Ophthamoloplegia
-adult onset
-ANT-1 gene, adenine nucelotime
-ragged red fibers
-

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MNGIE

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Mitochondrial neurogastrointestinal encephalomyopathy
-disorder of inter-genomic communication
-AR in thymidine phosphorylase
-too much thymidine can't break it down
-adult onset with diahrrhea and obstruction

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mtDNA Depletion

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* think early onset liver disease*

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Common mutations to know

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MELAS 3243A>G
MERRF (Myoclonic Epilepsy, Ragged Red Fibers) 8344A>G
NARP (Neuropathy, Ataxia, RP) and Maternally Inherited Leigh syndrome 8993G>T or G>C
Maternally inherited deafeness 1555A>G