Friedreich’s ataxia is caused by a deficit in the mitochondrial protein frataxin. The present work demonstrates that in vivo yeast frataxin Yfh1p and Isu1p, the mitochondrial scaffold protein for the ...Fe–S cluster assembly, have tightly linked biological functions, acting in concert to promote the Fe–S cluster assembly. A synthetic lethal screen on high iron media with the mild G107D
yfh1 mutant has specifically identified Isu1p. Analysis of the cellular phenotypes resulting from pairwise combinations of
yfh1 and
isu1 mutations, and cross-linking experiments in isolated mitochondria provide evidence for a direct interaction between Yfh1p and Isu1p.
Abstract In the clinical MRI practice, it is common to assess liver iron overload by T2* multi-echo gradient-echo images. However, there is no full consensus about the best image analysis approach ...for the T2* measurements. The currently used methods involve manual drawing of a region of interest (ROI) within MR images of the liver. Evaluation of a representative liver T2* value is done by fitting an appropriate model to the signal decay within the ROIs vs. the echo time. The resulting T2* value may depend on both ROI placement and choice of the signal decay model. The aim of this study was to understand how the choice of the analysis methodology may affect the accuracy of T2* measurements. A software model of the iron overloaded liver was inferred from MR images acquired from 40 thalassemia major patients. Different image analysis methods were compared exploiting the developed software model. Moreover, a method for global semiautomatic T2* measurement involving the whole liver was developed. The global method included automatic segmentation of parenchyma by an adaptive fuzzy-clustering algorithm able to compensate for signal inhomogeneities. Global liver T2* value was evaluated using a pixel-wise technique and an optimized signal decay model. The global approach was compared with the ROI-based approach used in the clinical practice. For the ROI-based approach, the intra-observer and inter-observer coefficients of variation (CoVs) were 3.7% and 5.6%, respectively. For the global analysis, the CoVs for intra-observers and inter-observers reproducibility were 0.85% and 2.87%, respectively. The variability shown by the ROI-based approach was acceptable for use in the clinical practice; however, the developed global method increased the accuracy in T2* assessment and significantly reduced the operator dependence and sampling errors. This global approach could be useful in the clinical arena for patients with borderline liver iron overload and/or requiring follow-up studies.
Polymicrogyria (PMG) and periventricular nodular heterotopia (PNH) are two developmental brain malformations that have been described independently in multiple syndromes. Clinically, they present ...with epilepsy and developmental handicaps in both children and adults. Here we describe their occurrence together as the two major findings in a group of at least three cortical malformation syndromes. We identified 30 patients as having both PNH and PMG on brain imaging, reviewed clinical data and brain imaging studies (or neuropathology summary) for all, and performed mutation analysis of FLNA in nine patients. The group was divided into three subtypes based on brain imaging findings. The frontal-perisylvian PNH–PMG subtype included eight patients (seven males and one female) between 2 days and 10 years of age. It was characterized by PNH lining the lateral body and frontal horns of the lateral ventricles and by PMG most severe in the posterior frontal and perisylvian areas, occasionally with extension to the parietal lobes beyond the immediate perisylvian cortex. The posterior PNH–PMG subtype consisted of 20 patients (15 male and 5 female) between 5 days and 40 years of age. It was characterized by PNH in the trigones, temporal and posterior horns of the lateral ventricles, and PMG most severe in the temporo-parieto-occipital regions. The third type was found in 2 females aged 7 months and 2 years, and was characterized by severe congenital microcephaly and more diffuse cortical abnormality. The PNH–PMG subtypes described here have distinct imaging and clinical phenotypes that suggest multiple genetic aetiologies involving defects in multiple genes, and a shared pathophysiological mechanism for PNH and PMG. The frontal-perisylvian and posterior subtypes both had skewing of the sex ratio towards males, which suggests the possibility of X-linked inheritance. Delineation of these syndromes will also aid in providing more accurate diagnosis and prognostic information for patients with these malformations.
Iron induced cardiomiopathy is the main cause of mortality in thalassemic population. Thus, the improvement of chelation regimens, to reduce cardiac disease, has the highest priority. Efficient ...evaluation of cardiac iron status and careful epidemiologic assessment of thalassemic patients play an important role in this matter. T2* magnetic resonance imaging (MRI) is a unique technique to quantify myocardial iron overload and useful to tailor the chelation therapy. Effective and reproducible assessment of myocardial iron loading using the multislice multiecho T2* approach for segmental and global myocardial iron distribution, has been demonstrated at the MRI centre in Pisa 1,2. Aim of this work is to build within the MIOT (Myocardial Iron Overload in Thalassemia) project a reliable network of haematological and paediatric centers specializing in thalassemia care and MRI centers able to perform feasible and reproducible heart and liver iron overload assessments for a consistent number of thalassemia patients in a standardized and robust manner.
First, the transferability of the multislice multiecho T2* technique was assessed. Heart multislice multiecho T2* and liver multiecho T2* sequences were installed on 1.5 T MRI scanners (GE Healthcare) at six different sites in Italy. Five healthy subjects at each site (n=30) were scanned to verify the homogeneity of normal ranges (T2* lover limit of normal 20ms). Then, five thalassemia major (TM) patients were scanned at the reference site and were rescanned locally (n=25) within one month. T2* images were analysed using a previously validated software (HIPPO MIOT®). T2* values of healthy subjects showed inter-sites homogeneity. On TM patients, for global heart T2* values the correlation coefficient was 0.97, Coefficients of Variation (CoVs) ranged from 0.04 to 0.12 and Intraclass Coefficients (ICCs) ranged from 0.94 to 0.99. The mean CoV and ICC for segmental T2* distribution were 0.198 and 88, respectively.
After the assessment of MRI technique reproducibility, patients enrolling started in September 2006. Since the project's beginning, 695 thalassemia patients have been involved in the network. Six hundred and thirteen patients (88%) successfully underwent MRI examination. Each MRI center had a specific absorption capacity that seemed to remain constant over time, but the network was capable of sustaining an increasing number of patients due to continuous enrolment of new centers. The mean distance from the patients' home locations to the MRI centers where the patients underwent the exams, which is considered an indicator of patient comfort, significantly decreased during the network's evolution. In Figure, the average distances from the thalassemia centers which sent the patients for MRI examination are plotted versus time. With the activation of delocalized MRI centers, average distances tend to be comparable.
In conclusion, the multislice multiecho T2* technique is transferable among scanners with good reproducibility. The MIOT network seems to be a robust and scalable system in which T2* MRI-based cardiac and liver iron overload assessment is available, accessible and reachable for a significant and increasing number of thalassemia patients in Italy, reducing the mean distance from the patients' locations to the MRI sites. A solid, wide and homogeneous database will constitute an important scientific resource, shortening the time scale for diagnostic, prognostic and therapeutical evidence-based research on the management of thalassemia disease.
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