Mitochondrial encephalopathy

The condition known as fatal infantile mitochondrial myopathy and renal dysfunction involves severe diminution or absence of most oxidoreductases of the respiratory chain. MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) is an inherited condition due to NADHiubiquinone oxidoreductase (complex I) or cytochrome oxidase deficiency. It is caused by a muta-... 

Thiamine deficiency results in early decreases in activity of the mitochondrial enzyme a-ketoglutarate dehydrogenase in brain. Wernicke s encephalopathy, also known as the Wernicke-Korsakoff syndrome is a neuropsychiatric disorder characterized by ophthalmoplegia, ataxia and memory loss. Wernicke s encephalopathy is encountered in chronic alcoholism, in patients with HIV-AIDS and in other disorders associated with grossly impaired nutritional status. The condition results from thiamine deficiency. 

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes (MELAS) Mitochondrial tRNA (leu)... 

HPPD hallucinogen persisting perception disorder MF.l.AS mitochondrial myopathy, encephalopathy, lactic... 

The clinical symptoms of mitochondrial diseases are highly varied and include seizures, vomiting, deafness, dementia, stroke-like episodes, and short stature. Although there are many types of mitochondrial disorders, four of the most common types are as follows Kearns-Sayre syndrome, Leber s hereditary optic atrophy, MELAS (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) and MERRE (myoclonic epilepsy with ragged red fibres). 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

Al. Abe, K., Fujimura, H., Nishikawa, Y., Yorifuji, S., Mezaki, T., Hirono, N., Nishitani, N., and Kameyama, M., Marked reduction in CSF lactate and pyruvate levels after CoQ therapy in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Acta Neurol. Scand. 83, 356-359 (1991). 

Cll. Chomyn, A., Enriquez, J. A., Micol, V., Fernandez-Silva, P., and Attardi, G., The Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated human mitochondrial 1 k A1 11 k i mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes. J. Biol. Chem. 275, 19198—19209 (2000). 

K3. King, M. P., Koga, Y., Davidson, M., and Schon, E. A., Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALe (UUR> mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. Mol. Cell. Biol. 12, 480-490 (1992). 

Cerebral WM changes (WMC) are found in a number of diseases of adulthood, such as the debated Binswanger s disease, multiple sclerosis, acute demyelinating encephalomyelitis, posterior reversible leukoencephalopathy syndrome, cerebral anoxia, leukodystrophies, and mitochondrial encephalopathies, among others. The term leukoaraiosis (LA) is applied for nonspecific WMC, primarily in the elderly, that cannot be attributed to a... 

The clinical syndrome of acute neonatal hyper-ammonemic encephalopathy described in the case report represents the classical presentation of a patient with a urea cycle disorder (UCD). It is important to note that this neonatal course represents only the most common and severe presentation of a UCD. This holds true for all the diseases listed in Table 18-1, with the exceptions of arginase (ARG-1) deficiency, which results in progressive spasticity of the lower limbs, and of the mitochondrial membrane transporters citrin and ornithine transporter 1 (ORNT-1). Deficiency of citrin results in adult-onset encephalopathy deficiency of... 

Citrulline is exchanged for ornithine across the inner mitochondrial membrane by ORNT-1. Ornithine is produced in the cytosol as the final step in the urea cycle and must be returned to the mitochondrial matrix for transcarbamoyla-tion by OTC. A second ornithine-citrulline antiporter (ORNT-2) is also expressed in the liver mitochondria and may attenuate the severity of disease in patients with HHH (Hyperammonemia, Hyperornithinemia, Homocitrullinuria) disease due to ORNT-1 deficiency. This disorder typically manifests later in life with intermittent hyperammonemic encephalopathy and protein aversion. Intramitochondrial ornithine deficiency causes both hyperammonemia and hyperornithinemia due to a lack of substrate for OTC. Homocitrullinuria occurs due to the use of lysine by OTC as an alternate substrate. The diagnosis is confirmed by mutation analysis. 

The final step of the urea cycle is the cleavage of arginine to release urea and regenerate ornithine. Ornithine then reenters the mitochondria via the ORNT-1 ornithine-citrulline antiporter. ARG-1 is a cytosolic homotrimeric enzyme of 35-kd monomers that is expressed in fiver and red blood cells. A second mitochondrial arginase (ARG-2) most likely plays a role in nitric oxide synthesis and is most abundant in brain, kidney, and prostate. ARG-1 deficiency is unique among the urea cycle deficiencies as patients do not present with hyperammonemia and encephalopathy but rather develop progressive spasticity of the lower limbs. Biochem-... 

MELAS syndrome (mitochondrial encephalopathy lactic acidosis with stroke-like episodes)... 

MNGIE (mitochondrial neurogastrointestinal encephalopathy) Progressive external ophthalmoplegia... 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

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... 

Gellera C, Uziel G, Rimoldi M, Zeviani M, Laverda A, Carrara 28. F, DiDonato S. Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. Neurology 1990 40 495-499. 

EMA aciduria maybe associated with several other inherited and acquired conditions, including (1) glutaric acidemia type II (some cases are actually labeled to have ethylmalonic adipic aciduria),(2) disorders of the intramitochon-drial flavin adenine dinucleotide pathway, (3) mitochondrial respiratory chain disorders, and (4) ethylmalonic encephalopathy. Jamaican vomiting sickness (due to ingestion of unripe ackee fruit containing the poison hypoglycin A) and ifosfamide treatment represent two additional causes of ethylmalonic aciduria. 

Tiranti V, D Adamo P, Briem E, Ferrari G, Mineri R, Lamantea E, et al. Ethylmalonic encephalopathy is caused by mutations in ETHEl, a gene encoding a mitochondrial matrix protein. Am J Hum Genet 2004 74 239-52... 

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