1 d, e, f). Discussion Sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO) is a characteristic clinical triad, which has been attributed to mutations of the gene encoding the mitochondrial DNA polymerase gamma enzyme (POLG1). Most cases present with an initial stage of sensory neuropathy, a second stage of progressive external ophahlmoplegia and dysarthria, which is then followed by other symptoms, often with epilepsia or myoclonus

(2). Different dominant Inhibitors,research,lifescience,medical and recessive missence mutations of this gene have been described with various clinical phenotypes (3-5). Our patients had a characteristic clinical triad of SANDO, and both with dysphagia/dysarthria. Patient 1 presented with a p.A467T and p.W748S compound heterozygous mutations. Inhibitors,research,lifescience,medical Both mutations are known, and several case histories with these compound mutations have been published (6, 7). Central nervous system involvement is characteristic of these mutations, as epilepsy, myoclonus, headache and bilateral high signal lesions Inhibitors,research,lifescience,medical of the posterior horn. Our patient also presented with central nervous system symptoms, as she had myoclonus, EEG abnormalities, and presumably her anxiety and

depression could also – at least partly – be attributed to metabolic brain disturbances. Vissing and co-workers published case histories of two sisters with features of neurogastrointestinal encephalomyopathy (MNGIE), without signs of leukoencephalopathy Inhibitors,research,lifescience,medical (8). They demonstrated multiple mtDNA deletions, but could not find any thymidine phophorylase (TP) gene mutation, the usual genetic background of MNGIE. Further molecular genetic investigation found three missense mutations in POLG1 gene, of which two (N846S Inhibitors,research,lifescience,medical and P587L) mutations were not described before, and the third one was a known T251I mutation (9). Besides dysphagia, our patient was also suffering from continuous constipation, see more mimicking the symptoms of MNGIE. Gonadal hypofunction and premature menopause have been

described as a sign of multi-organ involvement in POLG1 mutations (4). These symptoms also complicated the clinical picture of our case. Multi-organ involvement and progressive course of our patient support the finding of Tzoulis and colleagues, that compound heterozygous p.A467T and below p.W748S POLG1 mutations present a severe clinical phenotype of SANDO (7). The second patient had p.T251I, and p.G848S compound heterozygous mutations. These mutations have previously been published, only in two publications. Lamantea and co-workers reported a member of a family, with ophthalmoplegia with proximal muscle weakness, but no detailed clinical picture and disease course were described (3). These authors also presented several individuals with an isolated p.T251I heterozygous mutation without any clinical symptoms.

e., the result of model

simulation [26]. Additionally, in many cases mechanisms of allosteric regulation are known but quantitative experiments on parameters like substrate affinity (KM) or inhibitory constants (Ki) are lacking. This enforces the application of parameter estimation to calculate parameter values which are either completely unknown or can be estimated within numerical bounds Inhibitors,research,lifescience,medical based on published data on a different condition or organism. Indeed, such assumptions cause uncertainties, which have to be discussed carefully when interpreting the model output. However, although there might be several uncertainties with respect to regulatory instances involved in every single reaction of metabolism, numerous studies have proven kinetic modeling to be a promising approach to comprehensively analyze complex processes in plant biology. An overview of applications is given by Schallau and Junker [27] exemplarily Inhibitors,research,lifescience,medical comprising the process of photosynthesis [28], leaf carbon metabolism [29], sucrose metabolism Inhibitors,research,lifescience,medical in sugar cane (Saccharum officinarum) [30] or the aspartic acid-derived amino

acid pathway in Arabidopsis thaliana [31]. In contrast to kinetic modeling, the approach of structural modeling is based on the idea of Selleck GF109203X constructing models without kinetic information. This modeling approach refers only to the stoichiometry of the reactions within the system which is summarized Inhibitors,research,lifescience,medical in the stoichiometric matrix N. Considering a metabolic reaction network, each column of N represents a reaction while

rows represent metabolites. Inhibitors,research,lifescience,medical Hence, the elements of N describe the stoichiometric coefficients of metabolites in the reactions. Positive entries indicate that the metabolite is produced by the reaction, while negative values indicate consumption. Entries of zero indicate that the metabolite is not involved in this reaction. The definition of a vector v containing the rates of metabolite interconversions allows for the description of the steady state of the metabolic reaction network by a set of differential equations: (1) where M represents a matrix Electron transport chain containing metabolite concentrations and t is time. Solutions of this equation can be calculated applying linear algebraic rules. The advantage of this approach becomes obvious when considering the large number of reactions in a metabolic system, which can be predicted from an annotated genome sequence. The workflow from metabolic reconstruction to modeling of a metabolic network based on an annotated genome sequence was previously described in detail [32].