Mitochondrial cytopathy

Barbiroli B., Frassineti C., Martinelli P., Iotti S., Lodi R., Cortelli R, and Montagna P. (1997). Coenzyme Q10 improves mitochondrial respiration in patients with mitochondrial cytopathies. An in vivo study on brain and skeletal muscle by phosphorous magnetic resonance spectroscopy. Cell Mol. Biol. (Noisy, -le-grand) 43 741-749. 

Barbiroli B., Medori R., TritschlerH. J., KlopstockT., Seibel P., Reichmann H., Iotti S., Lodi R., and Zaniol P. (1995). Lipoic (thioctic) acid increases brain energy availability and skeletal muscle performance as shown by in vivo 31P-MRS in a patient with mitochondrial cytopathy. J. Neurol. 242 472-477. 

Lipolal aldol condensation derivatives, (n), prepared by Haj-Yehia (4) were effective as reactive oxygen species scavengers and used in treating conditions associated with oxidative stress or free radical injury including mitochondrial cytopathies and HIV infection. 

Mitochondrial cytopathies can be very varied. Since the distribution of defective mtDNA may vary from organ to organ, a mutation that in one person would cause liver disease might in another cause a brain disorder. The severity of the defect may be great or small some may cause exercise intolerance , with no serious illness or disability other defects can have severe body-wide impacts. 

Table 16.2 lists some common mitochondrial cytopathies, caused by mutations within the mitochondrial genome, the nuclear genome that encodes mitochondrial proteins, or a combination of the two they may exhibit non-Mendelian or Mendelian inheritance. 

Sometimes arterial occlusion is demonstrated by angiography in migrainous stroke and the cause is hypothesized to be in-situ thrombosis complicating vasospasm. No provoking factors are known. Other possible causes of stroke in the context of headache must be considered carotid dissection, mitochondrial cytopathy, ruptured vascular malformation, antiphospholipid antibody syndrome and CADASIL (cerebral autosomal dominant arterio-pathy with subcortical infarcts and leukoencephalopathy). Migraine auras without headache may be confused with TIA (Ch. 8). 

Mitochondrial cytopathy may present with stroke-like episodes often complicated by epilepsy and encephalopathy, a particular example of which is MELAS. Scanning with CT may show hypodensities, particularly in the occipital regions, and calcification of the... 

Fig. 6.10. A CT brain scan of a 40-year-old man with mitochondrial cytopathy, showing calcification of the basal ganglia and hypodensity in the left temporal...

Fig. 6.11. These T2-weighted MRI images of the brain are from a patient with mitochondrial cytopathy and show...

Initially, most of the adverse effects seen with zidovudine use (in particular hematological effects) were attributed to interference with cellular DNA replication. However, DNA replication also occurs in mitochondria. Mitochondrial DNA encodes some of the enzymes used for oxidative phosphorylation. Only recently has it been hjrpothesized that inhibition of this pathway could lead to mitochondrial toxicity and be responsible for most of the toxicity seen with NRTIs, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, exocrine pancreas failure, bone marrow failure, and proximal tubular dysfunction (11). These adverse effects are also a compilation of the clinical features seen in several genetic mitochondrial cytopathies. 

Niaudet P, Rotig A. The kidney in mitochondrial cytopathies. Kidney Int 1997 51 1000-1007. 

Although the overall prevalence of these inborn mitochondrial cytopathies remains unknown, the frequency of the A3243G mtDNA point mutation alone is estimated to be 1.6 in 10,000 in a Finnish population (Majamaa et al. 1998). Overall, clinically patent mitochondrial cytopathies could exist with a frequency of around 1 in 5,000 children (Haas et al. 2007). 

Mitochondrial cytopathies affect mitochondrial respiration, which may secondarily inhibit p-oxidation, as explained above. Mitochondrial cytopathies may therefore be revealed during the administration of drugs that have mitochondrial effects. Thus, the administration of valproate, which inhibits mitochondrial p-oxidation and pyruvate-supported respiration, may reveal a previously latent mitochondrial cytopathy (Chabrol et al. 1994 Lam et al. 1997 Krahenbiihl et al. 2000). For the same reasons, valproate administration can also reveal an inborn p-oxidation defect (Nj0lstad et al. 1997 Kottlors et al. 2001). 

The presence of diverse comorbid factors that also impair mitochondrial function (such as inborn mitochondrial cytopathies, inborn (3-oxidation defects, viral infections, obesity-associated NASH, or pregnancy) may play an important role in the idios3tncratic occurrence of these drag-induced adverse effects. 

Acknowledgement. The authors are indebted to the Princess Beatrix Ponds, which supported our research on mitochondrial cytopathies during the past decade. 

Tarnopolsky, M.A., B.D. Roy, and J.R. MacDonald, A randomized, controlled trial of creatine monohydrate in patients with mitochondrial cytopathies. Muscle Nerve, 20 1502-1509, 1997. 

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