Prediction of the disease course in Friedreich ataxia

We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA

Nonataxia symptoms in Friedreich Ataxia

Objective To provide a systematic evaluation of the broad clinical variability in Friedreich ataxia (FRDA), a multisystem disorder presenting mainly with afferent ataxia but also a complex phenotype of nonataxia symptoms.Methods From the large database of the European Friedreich’s Ataxia Consortium for Translational Studies, 650 patients with genetically confirmed FRDA were included. Detailed data of medical history documentation, questionnaires, and reports on clinical features were analyzed to provide in-depth description of the clinical profile and frequency rates of phenotypical features with a focus on differences between typical-onset and late-onset FRDA. Logistic regression modeling was used to identify predictors for the presence of the most common clinical features.Results The most frequent clinical features beyond afferent ataxia were abnormal eye movements (90.5%), scoliosis (73.5%), deformities of the feet (58.8%), urinary dysfunction (42.8%), cardiomyopathy and cardiac hypertrophy (40.3%), followed by decreased visual acuity (36.8%); less frequent features were, among others, depression (14.1%) and diabetes (7.1%). Most of these features were more common in the typical-onset group compared to the late-onset group. Logistic regression models for the presence of these symptoms demonstrated the predictive value of GAA repeat length on the shorter allele and age at onset, but also severity of ataxia signs, sex, and presence of neonatal problems.Conclusions This joint European effort demonstrates the multisystem nature of this neurodegenerative disease encompassing most the central nervous, neuromuscular, cardiologic, and sensory systems. A distinct and deeper knowledge of this rare and chronic disease is highly relevant for clinical practice and designs of clinical trials

An Archaeal Photosignal-Transducing Module Mediates Phototaxis in Escherichia coli

Halophilic archaea, such as Halobacterium salinarum and Natronobacterium pharaonis, alter their swimming behavior by phototaxis responses to changes in light intensity and color using visual pigment-like sensory rhodopsins (SRs). In N. pharaonis, SRII (NpSRII) mediates photorepellent responses through its transducer protein, NpHtrII. Here we report the expression of fusions of NpSRII and NpHtrII and fusion hybrids with eubacterial cytoplasmic domains and analyze their function in vivo in haloarchaea and in eubacteria. A fusion in which the C terminus of NpSRII is connected by a short flexible linker to NpHtrII is active in phototaxis signaling for H. salinarum, showing that the fusion does not inhibit functional receptor-transducer interactions. We replaced the cytoplasmic portions of this fusion protein with the cytoplasmic domains of Tar and Tsr, chemotaxis transducers from enteric eubacteria. Purification of the fusion protein from H. salinarum and Tar fusion chimera from Escherichia coli membranes shows that the proteins are not cleaved and exhibit absorption spectra characteristic of wild-type membranes. Their photochemical reaction cycles in H. salinarum and E. coli membranes, respectively, are similar to those of native NpSRII in N. pharaonis. These fusion chimeras mediate retinal-dependent phototaxis responses by Escherichia coli, establishing that the nine-helix membrane portion of the receptor-transducer complex is a modular functional unit able to signal in heterologous membranes. This result confirms a current model for SR-Htr signal transduction in which the Htr transducers are proposed to interact physically and functionally with their cognate sensory rhodopsins via helix-helix contacts between their transmembrane segments