Specific Biochemical Defect Research Articles

Treating of focal epilepsy: a patent review.

Focal epilepsy is one of the most frequent specific type of epilepsies, with 30% treatment-resistant patients. There are several directions researchers can follow to improve existing treatment of focal epilepsy: synthesis of new compounds with anticonvulsant activity, repurposing drugs approved for other indications, finding drugs targeted to specific genetic and biochemical defects that underlie focal epilepsy syndromes, development of viral vectors for specific gene therapy, creation of devices and methods for suppression of seizures by electrostimulation and development of methods to increase safety of epilepsy surgery. Improvement of efficacy and safety of current therapies is necessary, as well as developing targeted treatment of genetic epilepsy syndromes that will not only suppress seizures, but stop further epileptogenesis.

A Mixed Effect Emax Model Applied for Determination of Malathion Optimal Dose

Background: Malathion is an organophosphate insecticide and is the most appropriate one used widely in the world. Organophosphate insecticides cause a specific biochemical defect in the body. A major cause of this wastage is inhibition of cholinesterase (ChE) enzyme. Objectives: This study was conducted to determine the optimal dose of the pesticide malathion which inhibited 50% of ChE enzyme. Materials and Methods: An experimental study was conducted on 18 male rats weighing 180-250 g. The rats were randomly divided into 6 groups. The Ellman method was used to measure the acetylcholinesterase (AChE) enzymatic activity. Doses 0, 25, 50, 100, 200 and 400 mg/kg of pesticide malathion was tested on rats to determine the dose of the pesticide malathion with 50% inhibition of the ChE enzyme, at 24, 48, and 72 hours. According to these data, Emax model was fitted, then the median effective doses of the pesticide malathion were estimated at different time intervals, separately. Results: Based on the reduction Emax model, the optimal dose 29.14 mg/kg was determined at 72 time point. Conclusion: Using the mixed effect Emax model instead of the multiple comparison methods, such analysis of variance was suggested to determine the optimal dose of organophosphates such as malathion, which provide more accurate results.

Nutrition and nutritional signaling as therapy targets for mitochondrial disorders

Mitochondrial disorders are degenerative diseases known to be responsible for a number of heterogenous clinical presentations with multi-systemic dysfunctions that often involves the nervous, endocrine, renal and cardiac system. Impaired oxidative phosphorylation leading to a decrease in cellular energy (ATP) production is the most important cause underlying these conditions. Despite significant progress made in the field of mitochondrial medicine during the last two decades, defining the specific biochemical defects and underlying molecular mechanisms, the avaliable information about effective treatment approaches is limited. The goal of nutritional treatment of mitochondrial dysfunction in various neurological syndromes are based primarily in improving theefficiency of the processes of oxidative phosphorylation at the system level. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of new therapeutic agents, such as antioxidants, radical scavangers and cofactors. A literature review of the use of these supplements in mitochondrial disorders is presented.

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review.

Insights from animal models on the immunogenetics of leprosy: a review

A variety of host immunogenetic factors appear to influence both an individual's susceptibility to infection with Mycobacterium leprae and the pathologic course of the disease. Animal models can contribute to a better understanding of the role of immunogenetics in leprosy through comparative studies helping to confirm the significance of various identified traits and in deciphering the underlying mechanisms that may be involved in expression of different disease related phenotypes. Genetically engineered mice, with specific immune or biochemical pathway defects, are particularly useful for investigating granuloma formation and resistance to infection and are shedding new light on borderline areas of the leprosy spectrum which are clinically unstable and have a tendency toward immunological complications. Though armadillos are less developed in this regard, these animals are the only other natural hosts of M. leprae and they present a unique opportunity for comparative study of genetic markers and mechanisms associable with disease susceptibility or resistance, especially the neurological aspects of leprosy. In this paper, we review the recent contributions of genetically engineered mice and armadillos toward our understanding of the immunogenetics of leprosy.

Treatment Guidelines for Pompe Disease: A South European Perspective

Pompe disease is a rare lysosomal disorder of muscle glycogen metabolism due to -glucosidase (acid maltase) eficiency. The prevalence of the disease is estimated to be 1:40,000. The diagnosis is based on the identification of the specific biochemical defect and has to be confirmed by molecular genetic analysis. Since 2006, enzyme replacement therapy (ERT) for Pompe disease has been available in Southern Europe. Several countries in Southern Europe are allowed, once the diagnosis is confirmed, to perform ERT and its costs are fully supported by the Ministries of Health. For example, to our knowledge, either in Portugal or Italy, the drug reimbursement is based on a specific treatment programme which removes those costs from the hospital budget. Since 2006, AIFA (Agenzia Italiana del Farmaco) has approved alglucosidase(Myozyme) for the treatment of Pompe disease patients in Italy, either for infantile or late-onset patients. Authorisation to treat patients with ERT has to be given by a centre specialising in rare diseases. This centre must assess the diagnosis of Pompe disease with absolute certainty before starting treatment. In 2008, a group of leading Italian Pompe disease researchers reviewed, from a multidisciplinary point of view, the current practices in diagnosis, management and treatment of Pompe disease. The main criteria for starting ERT ncludes: (1) confirmed diagnosis; (2) symptoms and clinical signs of muscle weakness; (3) in cases of asymptomatic yperCKaemia, a 6-month follow up has been suggested in an attempt to monitor possible clinically relevant hanges suggesting treatment. In summary, our standard protocol mainly includes evaluation of muscle strength, respiratory assessment and keletal muscle MRI. We have studied over 80 patients treated with ERT coming from 18 different Italian centres ccording to this protocol. In a recent meeting on Pompe disease held in the Netherlands, researchers showed great interest in trying to ssess new criteria for early diagnosis of Pompe disease. In our opinion, there is an emerging role for neuroimaging based on new quantitative techniques (more precise valuation of muscle fat fraction), that should allow an earlier detection of muscle damage in Pompe patients and consequent early start of ERT.

Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases

The molecular apparatus that protects us against infection can also injure us by causing autoimmune or autoinflammatory disease. It now seems that at times, defects within the sensing arm of innate immunity contribute to diseases of this type. The initiation of an immune response is often microbe dependent and, in many cases, Toll-like receptor (TLR) dependent. Positive feedback loops triggering immune activation may occur when TLR signaling pathways stimulate host cells in an unchecked manner. Or, immune activation may persist because of failure to eradicate an inciting infection. Or on occasion, endogenous DNA may trigger specific immune responses that beget further responses in a TLR-dependent autoamplification loop. Specific biochemical defects that cause loop-related autoimmunity have been revealed by random germline mutagenesis and by gene targeting. We have also developed some insight into critical points at which feedback loops can be interrupted.

Fibrinolytic Activity in Patients with Essential Thrombocythemia.

Essential thrombocythemia (ET) is characterized by bleeding tendency, thrombotic complications and qualitative platelet defects. All those abnormalities are likely to contribute to the excessive mortality rate of this disease. Among many specific morphological, biochemical and metabolic platelet defects, a complete loss of platelet responsiveness to epinephrine is the most frequent in these patients. Since an abnormal platelet fibrinolytic activity was suggested to contribute to bleeding tendency, our initial goal was to see if platelet fibrinolysis activity is impaired in patients with ET. 22 patients were enrolled into the study (17 females, 5 males age 57.2±13.0.). This group included: 6 untreated patients, 9 treated with anagrelide, 4 with hydroxyurea, and 3 treated with a combination of both drugs. 8 thrombotic complications and 2 clinically significant bleeding episodes occurred. The control group consisted of 6 females age 33.3±9.9. Platelet count was 777±333 x109/L and 257±70 x109/L p<0.001, for the ET and the control group, respectively. Platelet activation was studied using flow cytometry to detect CD62P expression on the platelet surface. There was no difference between the control and the ET group. Platelet aggregation was measured using adenosine diphosphate and epinephrine as agonists. While 90% individuals from control group responded to epinephrine, in 45% of patients, a lack of epinephrine-induced platelet aggregation was detected. In this 45% of patients a statistically significantly lower expression of CD62P on CD61 positive cells was observed (mean value 1.90% versus 3.82%). Further, urokinase-type plasminogen activator (uPA) concentration was evaluated in plasma and in platelet lysates. Concentration of uPA was statistically significantly higher in patient plasma as compared to the control group (0.049±0.030 versus 0.029±0.015 ng/ml, p<0.05). Mean uPA concentration measured in platelet lysates was similar in both groups (ET 0.114±0.060ng/109 platelets, control group 0.110±0.042 ng/109 platelets). However, in platelets lysates from three patients, an extremely high uPA concentration was detected (more than 0.194 ng/109 platelets). One of these patients had an episode of hypermenorrhea and the second presented a thigh hematoma after a minor trauma. In both of those patients platelet count was above 600 x 109/L. In addition, in one patient very low uPA activity in platelet lysates was observed (0.030 ng/109 platelets). In this patient's medical history, two episodes of DVT occurred. To evaluate platelet fibrinolytic activity, uPA activity was assessed by means of casein zymography. Zymograms have show that similar fibrinolytic activity was present both in patients and the control group and the activity of fibrinolytic enzymes was inhibited by AEBSF, an inhibitor of serine proteases. From the data gathered we concluded that uPA concentration is significantly higher in ET patient plasma as compared to the control group. However, platelet fibrinolytic activity, measured as uPA activity and uPA concentration in platelets lysates obtained from ET patients is not impaired as was initially presumed. Because of the small sample size, we could not precisely assess the clinical importance of extremely high or extremely low uPA activity in platelets lysates. All these data need further evaluation in a larger group of patients.

Mitochondrial defects and oxidative damage in patients with peripheral arterial disease

Abnormal mitochondrial function is present in patients with peripheral arterial disease and may contribute to its clinical manifestations. However, the specific biochemical mitochondrial defects and their association with increased oxidative stress have not been fully characterized. Gastrocnemius muscle was obtained from peripheral arterial disease patients ( n = 25) and age-matched controls ( n = 16) and mitochondrial parameters were measured. Complexes I through IV of the electron transport chain were individually evaluated to assess for isolated defects. Muscle was also evaluated for protein and lipid oxidative changes by measuring the levels of protein carbonyls, lipid hydroperoxides, and total 4-hydroxy-2-nonenal binding and for the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. Mitochondrial electron transport chain complexes I, III, and IV in arterial disease patients demonstrated significant reductions in enzymatic activities and mitochondrial respiration compared to controls. Oxidative stress biomarker analysis demonstrated significantly increased levels of protein carbonyls, lipid hydroperoxides, and 4-hydroxy-2-nonenal compared to control muscle. Antioxidant enzyme activities were altered, with a significant decrease in superoxide dismutase activity and significant increases in catalase and glutathione peroxidase. Peripheral arterial disease is associated with abnormal mitochondrial function and evidence of significant oxidative stress.

The CLN9 Protein, a Regulator of Dihydroceramide Synthase

A new variant of a group of pediatric neurodegenerative diseases known as neuronal ceroid lipofuscinosis (NCL) or Batten disease has been identified. It is termed CLN9-deficient. CLN9-deficient fibroblasts have a distinctive phenotype of rapid growth and increased apoptosis and diminished levels of ceramide, dihydroceramide, and sphingomyelin. Transfection with CLN8 but not other NCL genes corrected growth and apoptosis in CLN9-deficient cells, although the entire CLN8 sequence was normal. CLN8 is one of the TRAM-Lag1-CLN8 proteins containing a Lag1 motif. The latter imparts (dihydro)ceramide synthase activity to yeast cells. Transfection with the yeast gene Lag1 Sc and the human homolog LASS1 increased ceramide levels and partially corrected growth and apoptosis in CLN9-deficient cells. LASS2,-4,,-5, and -6 also corrected growth and apoptosis. Dihydroceramide levels and dihydroceramide synthase activity were markedly diminished in CLN9-deficient cells. Sequencing of LASS1, LASS2, LASS4, LASS5, and LASS6 genes was normal, and expression levels were increased or normal in CLN9-deficient cells by reverse transcription-PCR. N-(4-Hydroxyphenyl)retinamide (4-HPR), a dihydroceramide synthase activator, corrected growth and apoptosis and increased dihydroceramide synthase activity. Ceramide levels dropped further, and there was no increase in de novo ceramide synthesis, probably due to the effects of 4-HPR as activator of dihydroceramide synthase and inhibitor of dihydroceramide desaturase. Fumonisin B1, a dihydroceramide synthase inhibitor, exaggerated the CLN9-deficient phenotype of accelerated growth, decreased ceramide and increased apoptosis. This was neutralized by 4-HPR. We conclude that the CLN9 protein may be a regulator of dihydroceramide synthase and that 4-HPR could be developed as a treatment for CLN9-deficient patients.

Escherichia coli DnaA protein: specific biochemical defects of mutant DnaAs reduce initiation frequency to suppress a temperature-sensitive dnaX mutation

The Escherichia coli dnaA73, dnaA721, and dnaA71 alleles, which encode A213D, R432L, T435K substitutions, respectively, were originally isolated as extragenic suppressors of a temperature-sensitive dnaX mutant. As the A213D substitution resides in a domain that functions in ATP binding and the R432L and T435K substitutions affect residues that recognize the DnaA box motif, they might be expected to reduce ATP and specific DNA binding, respectively. Therefore, a major objective was to quantify the biochemical defects of the mutant DnaAs to understand how the altered proteins suppress the temperature-sensitive phenotype of a dnaX mutant. A second purpose was to address the paradox that mutant proteins with substitutions of amino acids essential for recognition of the DnaA box motifs within the E. coli replication origin ( oriC) may well be inactive in initiation, yet chromosomal dnaA mutants expressing DnaA proteins with the R432L and T435K substitutions are viable at temperatures from 30 to 39 °C. We show biochemically that mutant DnaAs carrying R432L and T435K substitutions fail to bind to the DnaA box sequence. The A213D mutant is sevenfold reduced in its affinity for ATP compared to wild-type DnaA, and its affinity for the DnaA box sequence is also reduced. However, the reduced activity of the A213D mutant in oriC plasmid replication appears to arise from a defect in DnaA oligomerization. Although the T435K mutant fails to bind to the DnaA box sequence, other results suggest that DnaA oligomerization stabilizes the binding of the mutant DnaA to oriC to support its partial activity in initiation in vitro. These results support a model that suppression of dnaX occurs by reducing the frequency of initiation to a manageable level for the mutant DnaX so that viability is maintained.

Tetrahydrobiopterin in Pulmonary Hypertension

The regulation of pulmonary vascular tone is a complex process and represents a balance between constrictor and dilator influences. In pulmonary hypertension, whether caused by hypoxia or flow- and pressure-induced remodeling, the balance is tilted predominantly toward vasoconstriction. Despite decades of research, the initiating events in most patients with primary pulmonary hypertension remain unknown. The causes are probably diverse, and clinical recognition of the disease often occurs after the process is fairly advanced. On presentation, initiating events are obscured by the adaptations that occurred in the pulmonary circulation in response to the hypertension. Thus, the clinically evident disease may be quite distant from the initial cause(s) of pulmonary hypertension. Laboratory investigations of specific biochemical defects that can lead to pulmonary hypertension and vascular remodeling should help us understand these proximate causes. In this issue of Circulation , 2 independent studies1,2 report that a defect in the synthesis of tetrahydrobiopterin (BH4), a cofactor required for the synthesis of nitric oxide (·NO) through the catalytic activity of NO synthase (NOS), results in pulmonary hypertension. The studies confirm that a defect in endothelial NOS (eNOS) function can be an initiating event leading to both pulmonary hypertension and pulmonary vascular remodeling. Their results are consistent with observations of impaired NOS activity and NOS-dependent vasodilation in both patients and animal models with pulmonary hypertension. Such studies provide proof of concept that a specific biochemical defect can cause eNOS uncoupling to remodel the pulmonary vasculature. See pp 2086 and 2126 The mechanisms involved in the opposing responses of pulmonary and systemic vascular beds to hypoxia and oxygen remain unknown; however, rapid progress has been made in understanding the vascular biology of the pulmonary circulation since the discovery of how ·NO plays a protective role in the circulation nearly 2 decades ago. All …

Cofactor treatment improves ATP synthetic capacity in patients with oxidative phosphorylation disorders

Marked progress has been made over the past 15 years in defining the specific biochemical defects and underlying molecular mechanisms of oxidative phosphorylation disorders, but limited information is currently available on the development and evaluation of effective treatment approaches. Metabolic therapies that have been reported to produce a positive effect include coenzyme Q 10 (ubiquinone), other antioxidants such as ascorbic acid and vitamin E, riboflavin, thiamine, niacin, vitamin K (phylloquinone and menadione), and carnitine. The goal of these therapies is to increase mitochondrial ATP production, and to slow or arrest the progression of clinical symptoms. In the present study, we demonstrate for the first time that there is a significant increase in ATP synthetic capacity in lymphocytes from patients undergoing cofactor treatment. We also examined in vitro cofactor supplementation in control lymphocytes in order to determine the effect of the individual components of the cofactor treatment on ATP synthesis. A dose-dependent increase in ATP synthesis with CoQ 10 incubation was demonstrated, which supports the proposal that CoQ 10 may have a beneficial effect in the treatment of oxidative phosphorylation (OXPHOS) disorders.

Nutritional cofactor treatment in mitochondrial disorders

Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5′-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q 10 (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented. J Am Diet Assoc. 2003;103:1029-1038.

Susceptibility and biomarker knowledge for improvement of environmental health

At the international level, environmental health problems are usually most serious in countries that have the least resources to deal with the problems. Therefore, international efforts have been initiated to achieve equitable environmental health globally. One approach is to conduct international collaborative studies. This approach has been successful in the building of scientific infrastructure in these countries so that they can address their own environmental health concerns and to sustain the environmental health programs. Using liver and oral cancers as models for discussion, examples of success in the identification of etiology and the mechanisms for the diseases are provided. For example, biomarkers are used to provide early warning signals for the disease. In addition, the application of the collected information for developing disease prevention and intervention programs is presented. Expertise in genetic susceptibility is used to provide a more precise understanding of the cancer process. With the precise knowledge, the information can potentially be used to screen for high-risk individuals and to develop ”designer” intervention procedures against specific biochemical defects. Success in disease prevention is dependent upon multidisciplinary collaborations at the local and international levels.

Identification of rad27 mutations that confer differential defects in mutation avoidance, repeat tract instability, and flap cleavage.

In eukaryotes, the nuclease activity of Rad27p (Fen1p) is thought to play a critical role in lagging-strand DNA replication by removing ribonucleotides present at the 5' ends of Okazaki fragments. Genetic analysis of Saccharomyces cerevisiae also has identified a role for Rad27p in mutation avoidance. rad27Delta mutants display both a repeat tract instability phenotype and a high rate of forward mutations to canavanine resistance that result primarily from duplications of DNA sequences that are flanked by direct repeats. These observations suggested that Rad27p activities in DNA replication and repair could be altered by mutagenesis and specifically assayed. To test this idea, we analyzed two rad27 alleles, rad27-G67S and rad27-G240D, that were identified in a screen for mutants that displayed repeat tract instability and mutator phenotypes. In chromosome stability assays, rad27-G67S strains displayed a higher frequency of repeat tract instabilities relative to CAN1 duplication events; in contrast, the rad27-G240D strains displayed the opposite phenotype. In biochemical assays, rad27-G67Sp displayed a weak exonuclease activity but significant single- and double-flap endonuclease activities. In contrast, rad27-G240Dp displayed a significant double-flap endonuclease activity but was devoid of exonuclease activity and showed only a weak single-flap endonuclease activity. Based on these observations, we hypothesize that the rad27-G67S mutant phenotypes resulted largely from specific defects in nuclease function that are important for degrading bubble intermediates, which can lead to DNA slippage events. The rad27-G240D mutant phenotypes were more difficult to reconcile to a specific biochemical defect, suggesting a structural role for Rad27p in DNA replication and repair. Since the mutants provide the means to relate nuclease functions in vitro to genetic characteristics in vivo, they are valuable tools for further analyses of the diverse biological roles of Rad27p.

Genetic study of two Tunisian Ehlers Danlos syndrome type VI

Ehlers Danlos syndromes (EDS) represent a clinically and genetically heterogeneous category of connective tissue disorders characterized by hyperextensibility of the skin and hypermobility of the joints.Clinical genetic and biochemical grounds distinguish eight types. The type VI is characterized by specific biochemical defect of lysyl hydroxylase.We report 2 cases of EDS type VI, clinically and biochemically confirmed. We focused our interest on the range of clinical severity in these patients and the comparison between our patient's clinical data and clinical findings reviewed in the literature.

Electrophysiological study of neuromuscular system involvement in mitochondrial cytopathy

Objectives: To define the neuromuscular involvement in ‘mitochondrial’ patients with clinical evidence of a neuromuscular disorder, and to evaluate if the proposed electrophysiological protocol was suitable to reveal a subclinical neuropathy or myopathy in ‘mitochondrial’ patients with no clinical sign of a neuromuscular disturbance. Methods: Quantitative concentric needle electromyography (CNEMG), single fiber electromyography (SFEMG) and nerve conduction studies (NCS) were performed in 33 patients with mitochondrial cytopathies. Lastly, we studied 9 clinically unaffected relatives. Results: NCS were abnormal in 18% of patients, with CNEMG and SFEMG in 58% of cases, but there was not a complete overlapping of the positivity of the different techniques. No asymptomatic relatives showed abnormalities of the electrophysiological studies. Conclusions: Electrophysiological findings did not correlate with any specific biochemical or genetic defect, but were consistent with clinical diagnosis in almost all of the patients with clinical signs of myopathy and/or neuropathy. Increase of both SFEMG jitter and fiber density was significantly tied to a neuropathic process. CNEMG and SFEMG were altered in about 30% of subjects without clinical signs of myopathy or neuropathy and were therefore able to reveal a subclinical involvement of neuromuscular system in some patients who had external ophthalmoplegia or retinitis only.

Mitochondrial disorders.

Mitochondrial respiration, the most efficient metabolic pathway devoted to energy production, is at the crosspoint of 2 quite different genetic systems, the nuclear genome and the mitochondrial genome (mitochondrial DNA, mtDNA). The latter encodes a few essential components of the mitochondrial respiratory chain and has unique molecular and genetic properties that account for some of the peculiar features of mitochondrial disorders. However, the perpetuation, propagation, and expression of mtDNA, the majority of the subunits of the respiratory complexes, as well as a number of genes involved in their assembly and turnover, are contained in the nuclear genome. Although mitochondrial disorders have been known for more than 30 years, a major breakthrough in their understanding has come much later, with the discovery of an impressive, ever-increasing number of mutations of mitochondrial DNA. Partial deletions or duplications of mtDNA, or maternally inherited point mutations, have been associated with well-defined clinical syndromes. However, phenotypes transmitted as mendelian traits have also been identified. These include clinical entities defined on the basis of specific biochemical defects, and also a few autosomal dominant or recessive syndromes associated with multiple deletions or tissue-specific depletion of mtDNA. Given the complexity of mitochondrial genetics and biochemistry, the clinical manifestations of mitochondrial disorders are extremely heterogenous. They range from lesions of single tissues or structures, such as the optic nerve in Leber hereditary optic neuropathy or the cochlea in maternally inherited nonsyndromic deafness, to more widespread lesions including myopathies, encephalomyopathies, cardiopathies, or complex multisystem syndromes. The recent advances in genetic studies provide both diagnostic tools and new pathogenetic insights in this rapidly expanding area of human pathology.

96/04471 Strategies for reducing emissions and depositions in central and eastern European countries. The case of Slovakia

Mitochondrial disorders are degenerative diseases characterized by a decrease in the ability of mitochondria to supply cellular energy requirements. Substantial progress has been made in defining the specific biochemical defects and underlying molecular mechanisms, but limited information is available about the development and evaluation of effective treatment approaches. The goal of nutritional cofactor therapy is to increase mitochondrial adenosine 5′-triphosphate production and slow or arrest the progression of clinical symptoms. Accumulation of toxic metabolites and reduction of electron transfer activity have prompted the use of antioxidants, electron transfer mediators (which bypass the defective site), and enzyme cofactors. Metabolic therapies that have been reported to produce a positive effect include Coenzyme Q10 (ubiquinone); other antioxidants such as ascorbic acid, vitamin E, and lipoic acid; riboflavin; thiamin; niacin; vitamin K (phylloquinone and menadione); creatine; and carnitine. A literature review of the use of these supplements in mitochondrial disorders is presented. J Am Diet Assoc. 2003;103:1029-1038.