Authors

B.G.M. van Engelen, M.D., Ph.D., Professor of Neuromuscular Diseases
J.A.M. Smeitink, M.D., Ph.D., Professor of Pediatrics
B.W. Smits, M.D.

Clinical features
Mitochondria are subcellular organels found in all nucleated cells. Every cell contains hundreds or thousands of mitochondria.Their main function is to provide the cell with adenosine triphosphate (ATP), a small molecule which serves as a source of energy needed for cellular function. Mitochondrial disorders comprise a group of perhaps several hundred different genetic diseases, with a large variety in clinical features. Each individual disorder is rare, but collectively they account for substantial use of health care resources. In recent years, the role of mitochondria in aging, apoptosis and cancer has been a new field of study. Read more

Differential diagnosis
Chronic progressive external ophthalmoplegia (CPEO) CPEO is characterised by slowly progressive bilateral ptosis and paresis of eye musculature. Some patients also have mild proximal muscle weakness and cardiac conduction defects. Age at onset is variable, with many patients noticing ptosis in the third or fourth decade of life. The commonest genetic defect is a single deletion at 4977 bp, but other single mitochondrial DNA (mtDNA) deletions, mitochondrial tRNA mutations and nucleair DNA mutations (dominant and recessive) have been found. Kearns-Sayre syndrome The onset of ophthalmoparesis and pigmentary retinopathy before the age of 20 is characteristic of a more clearly defined disorder known as Kearns-Sayre syndrome. This sporadic condition is the result of large single deletions, complex rearrangements, or point mutations of mtDNA. Other clinical features include cerebellar ataxia, proximal myopathy, complete heart block, and raised cerebrospinal fluid (CSF) protein concentrations. Read more

Ancillary investigations
Several non specific investigations can support the diagnosis of a mitochondrial disorder. Lactate levels are often raised in blood or CSF. Electrocardiography will provide information about cardiac conduction velocity. Electromyography (EMG) can reveal non specific myopathic changes mainly in proximal muscles: motor units of short duration, reduced amplitude and increased polyphasia. Computed tomography and magnetic resonance imaging are particularly useful in Leigh’s syndrome (symmetrical hypodensities of brainstem, thalamus and basal ganglia) or MELAS (basal ganglia calcification). Read more

Genetics
Mitochondrial DNA (mtDNA) Mitochondria are the only organelles of the cell besides the nucleus that contain their own DNA (called mtDNA) and their own machinery for synthesizing RNA and proteins. The human mtDNA is a 16,569-bp, double-stranded, circular molecule containing 37 genes. Of these, 24 are needed for mtDNA translation, and 13 encode subunits of the respiratory chain: seven subunits of complex I, one subunit of complex III (cytochrome b ), three subunits of cytochrome c oxidase and two subunits of ATP synthase. Mitochondrial genetics differs from mendelian genetics in three major aspects: maternal inheritance, heteroplasmy, and mitotic segregation. Maternal Inheritance As a general rule, all mitochondria (and all mtDNAs) in the zygote derive from the ovum. Therefore, a mother carrying an mtDNA mutation passes it on to all her children, but only her daughters will transmit it to their progeny. Read more

Therapy
Coenzyme Q10 supplementation therapy can dramatically reverse disease in coenzyme Q10 deficiency but apart from this rare disorder, there is no cure available for mitochondrial disorders. Small clinical trials and case reports suggested benefical effects of dichloroacetate, co-enzyme Q10, nicotinamide, riboflavin, vitamin E and corticosteroids, but none of these agents have been studied in larger clinical trials. Futhermore, since we do not have a clear picture of the natural history of mitochondrial disorders the reported clinical improvements may just reflect a fluctuating disease course rather than a real effect of treatment.

Links

http://www.umdf.org/
http://www.mitomap.org/
www.neuro.wustl.edu/neuromuscular/mitosyn.html#myop
http://go.to/ncmd