Syndrome, mitochondrial

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

Defects in mitochondrial iron transport and utilization can result in mitochondrial iron overload. There is extensive iron accumulation in erythroblast mitochondria of both patients with X-linked sideroblastic anemia due to defective erythroid-speeifie 5-aminolevulinic acid synthase (eALAS) and those with ring sideroblasts associated with myelodysplastic syndrome. Mitochondrial iron overload has also been documented in patients with Friedreich s ataxia with defective frataxin" and in those with sideroblastic anemia with ataxia from defects in the Fe-S transporter ABC7. In addition, studies with yeast, the best studied eukaryotic model of Fe-S cluster synthesis, showed that defects in any of the enzymes of the Fe-S cluster assembly pathway caused mitochondrial iron accumulation and lack of normal mitochondrial function. ... 

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

This complex contains 11 polypeptide subunits of which only one is encoded by mtDNA. Defects of complex III are relatively uncommon and clinical presentations vary. Fatal infantile encephalomyopathies have been described in which severe neonatal lactic acidosis and hypotonia are present along with generalized amino aciduria, a Fanconi syndrome of renal insufficiency and eventual coma and death. Muscle biopsy findings may be uninformative since abnormal mitochondrial distribution is not seen, i.e., there are no ragged-red fibers. Other patients present with pure myopathy in later life and the existence of tissue-specific subunits in complex III has been suggested since one of these patients was shown to have normal complex 111 activity in lymphocytes and fibroblasts. 

Mutations (eg, point mutations, or in some cases deletions) in the genes (nuclear or mitochondrial) encoding various proteins, enzymes, or tRNA molecules are the fundamental causes of the inherited cardiomyopathies. Some conditions are mild, whereas others are severe and may be part of a syndrome affecting other tissues. 

Hoschele D (2006) Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. Toxicol In Vitro 20(5) 535-546 Itescu S, Brancato LJ et al (1989) A sicca syndrome in HIV infection association with HLA-DR5 and CDS lymphocytosis. Lancet 2(8661) 466 68 Itescu S, Brancato LJ et al (1990) A diffuse infiltrative CDS lymphocytosis syndrome in human immunodeficiency virus (HIV) infection a host immune response associated with HLA-DR5. Ann Intern Med 112(1) 3-10... 

Acute leukemia, acute lymphoma, short-bowel syndrome, liver disease (decreased clearance), diabetes mellitus, mitochondrial disease, and congenital enzyme deficiencies... 

D/C all antiretrovirals symptomatic support with fluids some patients require IV bicarbonate, hemodialysis, parenteral nutrition, or mechanical ventilation once syndrome resolves, consider using NRTIs with 4- mitochondrial toxicity (ABC, TDF, 3TC, or FTC) monitor lactate after restarting NRTIs some clinicians use NRTI-sparing regimens. 

Renal Effects. The characteristics of early or acute lead-induced nephropathy in humans include nuclear inclusion bodies, mitochondrial changes, and cytomegaly of the proximal tubular epithelial cells dysfunction of the proximal tubules (Fanconi s syndrome) manifested as aminoaciduria, glucosuria, and phosphaturia with hypophosphatemia and increased sodium and decreased uric acid excretion. These effects appear to be reversible. Characteristics of chronic lead nephropathy include progressive interstitial fibrosis, dilation of tubules and atrophy or hyperplasia of the tubular epithelial cells, and few or no nuclear inclusion bodies, reduction in glomerular filtration rate, and azotemia. These effects are irreversible. The acute form is reported in lead-intoxicated children, whose primary exposure is via the oral route, and sometimes in lead workers. The chronic form is reported mainly in lead workers, whose primary exposure is via inhalation. Animal studies provide evidence of nephropathy similar to that which occurs in humans, particularly the acute form (see Section 2.2.3.2). 

Important studies were performed by Trush and coworkers [42], who showed the advantages of applying lucigenin-amplified CL for the measurement of superoxide production by mitochondria in unstimulated monocytes and macrophages as well as by isolated mitochondria [43,44]. Later on, these authors have shown that mitochondrial superoxide production measured by lucigenin-amplified CL increased in the liver of rats treated with the promoter of hepatocarcinogenesis ethinyl estradiol [45], in liver from obese mice [46], and in children with Down syndrome [47]. 

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. 

Belanger, M., Ahboucha, S., Desjardins, P. and Butterworth, R.F. Upregulation of peripheral-type (mitochondrial) benzodiazepine receptors in hyperammonemic syndromes consequences for neuronal excitability. Adv. Mol. Cell Biol. 31 983-997,2004. 

Mitochondrial dysfunction produces syndromes involving mainly muscle and the central nervous system 706... 

NING, C., KUHARA, T INOUE, Y, ZHANG, C.H., MATSUMOTO, M., SHINKA, T., FURUMOTO, T., YOKOTA, K., MATSUMOTO, I., Gas chromatographic mass spectrometric metabolic profiling of patients with fatal infantile mitochondrial myopathy with De Toni-Fanconi-Debre syndrome, Acta Paediatrica Japonica, 1996,38,661-666. 

Mitochondrial genes are not known to affect the expression of Marfan syndrome (choice C). 

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