Mitochondrial Encephalomyopathies

Mitochondrial functions:

• cellular energy metabolism

• cell signaling

• apoptosis

• intermediary metabolism

• metabolism of AA, lipids, cholesterol, steroids and nucleotides

• intracellular sequestration of calcium

• detoxification of ammonia

Mitochondrial genetics:

• circular double stranded ring of DNA

• 2 ribosomal RNAs, 22 transfers RNAs, 13 polypeptides of complexes I, III, IV, and V of the respiratory chain

• 2-10 mtDNA rings per mitochondria

• cells contain thousands of mitochondria

Clinical testing:

• resting serum lactate – often elevated due to increase anaerobic metabolism

• CPK – muscle involvement

• TSH, glucose, Hgb A1C – endocrine dysfunction

• serum AA, urine organic acids, VLCFA, serum biotinidase – metabolic screen

• CSF lactate – more sensitive than serum

• ECG – cardiac involvement common

• EEG – may show slowing

• audiography – often have impaired hearing

• EMG/NCS – help to localize problem to muscle

• CT/MRI – often show atrophy and related ventriculomegaly, white matter changes, calcification (esp brain stem and BG)

• Muscle Biopsy

• H&E, Succinate Dehydrogenase, Modified Gomori-Trichrome, Cytochrome C Oxidase

• Molecular Studies (Southern Blot, PCR, biochemistry on cultured fibroblasts for respiratory complex activity)

“Common” mitochondrial encephalomyopathies:

LHON – Leber’s hereditary optic neuropathy

• Acute or subacute, painless, central visual loss in 3^rd-4^th decade
• Also dystonia and cardiac conduction defects
• Fundoscopy- peripapillary telangiectasia, microangiopathy, pseudoedema, tortuous retinal vessels

MELAS – Mitchondrial encephalopathy with lactic acidosis and stroke-like episodes

• Stroke-like episodes, muscle weakness, and encephalopathic episodes with high lactate
• Also seizures, dementia, short stature, migraines, episodic vomiting

MERFF – Myoclonic epilepsy with ragged red fibers

• Progressive myoclonic epilepsy, action myoclonus, ataxia
• Progressive muscle weakness/atrophy, hypertrophic cardiomyopathy, dementia, deafness, multiple lipomata
• Ragged red fibers on muscle biopsy

Leigh syndrome

• Not classically one genetic disorder, but arise from different mutations
• Developmental delay/regression, central hypoventilation, early hypotonia/late spasticity
• Optic atrophy, pigment degeneration, nystagmus, ataxia, dystonia, multifocal myoclonus, seizures

Kearns-Sayre syndrome

• Caused by large deletions in mtDNA
• Progressive external ophthalmoplegia, pigmentary retinopathy, complete heart block, cerebellar ataxia, CSF protein > 100 mg/dl
• Progressive external ophthalmoplegia (PEO) can occur independently

Management of mitochondrial disorders:

• Symptomatic support for seizures, endocrine abnormalities, etc.
• Unclear role for coenzyme Q10, biotin, thiamine, vitamins C & K3, carnitine, dichloroacetate

Reference: Taylor RW & Turnbull DM. (2005). Mitochondrial DNA mutations in human disease. Nature Rev Gen. 6:389-402.