Mitochondrial circular dsDNA

- 2 rRNA

- 22 tRNA

- 13 polypeptides of complex I, III, IV, and V of respiratory transport chain (complex II is nuclear)

- 2-10 circular rings of DNA


Homoplasmy - all normal mt in cell

Heteroplasmy - some abnormal mt


Maternal inheritance = mitochondrial inheritance


Mitochondrial concepts

- dependence on nuclear DNA

- mitochondrial segregation

- migrational isolation - unequal division of mt in cell division

- relaxed replication - not based on cell cycle

- tissues with high metabolic demands more affected - CNS, muscle (skeletal, cardiac), eyes, endocrine tissue


CNS changes

- neuronal loss

- demyelination

- spongiform changes

- gliosis


Muscle changes

- ragged red fibers


Mt diseases

- Prevalence 10-15 per 100,000

- Multi-organ involvement


Red flags

Diabetes, deafess, dementia, degeneration, short stature



- optic atrophy

- opthalmoplegia

- deafness

- enlarged heart

- muscle dysfunction



- serum lactate, pyruvate - anaerobic metabolism

- CPK - muscle involvement

- TSH, glc, HbA1c - endocrine dysfunction

- serum AA, urine org acids, VLCFA, serum biotinidase - metabolic screen

- CSF lactate - more sensitive than serum


- EEG - slowing

- audiography



- muscle biopsy - H&E, succinyl DH, modified Gomori-Trichrome, cytC oxidase, molecular studies


Complex I disorders

LHON - Leber's hereditary optic neuropathy

MELAS - mt encephalomyelopathy with lactic acidosis and stroke- like episodes

LHON and dystonia


Complex I and IV dysfunction

MERRF - myoclonic epilepsy with ragged red fibers


Leigh's syndrome - any complex, even complex II


Kearns-Sayre syndrome - large deletion (or point mutation), sporadic occurence


Leber’s Hereditary Optic Neuropathy


•         most common cause of blindness in young men

•         onset in 3rd or 4th decade of life

•         caused by errors in genes encoding the proteins that compose Complex I


Clinical Features

•         acute or subacute onset of painless, central visual loss

•         usually unilateral involvement ΰ bilateral (within 2 months) ΰ progressive deterioration of vision in both eyes

•         may also show dystonia

•         rarely have cardiac conduction defects


Fundoscopic Features

•         peripapillary telangiectasia

•         microangiopathy

•         pseudoedema

•         tortuous retinal vessels


Pathological Features

•         degeneration of retinal ganglion cell layer

•         sparing of the retinal pigment epithelium and photoreceptor layer

•         marked cell body and axonal degeneration, with associated demyelination and atrophy from the optic nerves to the lateral geniculate bodies


MELAS – mitochondrial encephalomyelopathy with lactic acidosis and stroke-like episodes


•         generally occurs in individuals <20 years of age

•         maternal inheritance pattern

•         due to A3243G mutation in gene encoding mitochondrial tRNAleu(UUR)


Clinical Features

•         muscle weakness (87%)

•         stroke-like episodes (100%)

•         encephalopathic episodes associated with high plasma and CSF levels of lactic acid

•         may also be associated with…

Ψ      seizures (focal & generalized) (85-96%)

Ψ      dementia (60-90%)

Ψ      migraines, episodic vomiting, short stature


Pathological Features

•         multifocal necrosis microscopically indistinguishable from infarcted tissue

•         lesions do not respect vascular territories

•         basal ganglia calcification

•         spongiform degeneration with capillary proliferation and neuronal loss in cortex and cerebellum


MERRF – myoclonic epilepsy with ragged red fibers


•         generally occurs in individuals <20 years of age

•         maternal inheritance pattern

•         due to A8344G mutation in gene encoding mitochondrial tRNAlys

•         results in Complex I and IV dysfunction


Clinical Features

Early Symptoms

•         progressive myoclonic epilepsy

•         action induced polymyoclonus

•         ataxia

Late Symptoms

•         progressive muscle weakness and atrophy

•         hypertrophic cardiomyopathy

•         dementia

•         deafness

•         multiple lipomata


Pathological features

•         muscle ragged-red fibers

•         preferential neuronal degeneration in cerebellum, brain stem, and spinal cord

•         associated astrocytosis and demyelination


Leigh’s syndrome


•         progressive neurodegenerative syndrome of infancy and childhood

•         onset < 1 year, death < 5 years of age

•         may be x-linked recessive, autosomal recessive, or maternal

•         may cause defects in pyruvate dehydrogenase or complexes I, II, IV or V depending


Clinical Features

•         developmental delay and regression

•         central hypoventilation syndrome

•         central hypotonia (early) ΰ spasticity (late)

•         Others…

–        optic atrophy, pigment degeneration, nystagmus

–        ataxia (if able to stand)

–        dystonia, multifocal myoclonus

–        seizures


Pathological Features

•         bilateral symmetrical foci of necrosis in basal ganglia, thalamus, midbrain and pons

•         mainly affects grey matter

•         associated with vascular proliferation, gliosis, neuronal loss, demyelination and cystic cavitation

•         may see spongy degeneration of cortex


Kearns-Sayre Syndrome

•         occurs in individuals <20 years of age

•         sporadic occurrence

•         no predilection in race or gender

•         caused by large deletions or point mutations of mtDNA

•         death within 3rd or 4th decade of life


Clinical Features

All of…

•         age of onset <20 years

•         progressive external ophthalmoplegia

•         pigmentary retinopathy

•         complete heart block


•         CSF protein > 100 mg/dl

•         cerebellar ataxia


Spectrum of Disease

•         progressive external ophthalmoplegia only = PEO or  CPEO

•         CPEO + pigmentary retinopathy & complete heart block (if <20 years) = KSS

•         CPEO + pigmentary retinopathy & complete heart block (if >20 years) = ophthalmoplegia plus syndrome


Pathological Changes

•         vacuolation of WM in brainstem > cerebellum > cerebrum

•         neuronal loss primarily in brainstem and cerebellum

•         demyelination in cerebrum and cerebellum

•         mineral deposits

•         ragged red fibres on muscle biopsy



•         Neuropathy, Ataxia, & Retinitis Pigmentosa

•         seizures, proximal weakness, sensory neuropathy


Complex Deficiencies

•         nonspecific phenotype, no known mutation

•         biochemical testing shows decreased activity of specific part of ETC


Non-brain mitochondrial diseases


Pearson’s Syndrome

•         sideroblastic anemia, pancytopenia, exocrine pancreas dysfunction

Mitochondrial Depletion Syndrome

•         not enough mitochondria

•         liver, muscle and kidneys most affected

•         encephalopathy, respiratory failure

•         fatal by 3 years


Management of mitochondrial disorders



•         seizure control

•         correct endocrine abnormalities

•         antiarrhythmics if conduction defect present

•         cochlear implants?


Questionable Efficacy

•         coenzyme Q10 (ubiquinone) up to 300 mg/day

•         biotin > 50 mg/day

•         thiamine > 300 mg/day

•         vitamins C & K3

•         carnitine

•         dichloroacetate



•         adding wild-type mitochondrial DNA

•         selective removal of mutant mitochondrial DNA