Trattamento dell'iperparatiroidismo secondario: calciomimetici, attivatori selettivi del recettore della vitamina D (VDRAs) o terapia combinata

Abstract non disponibil

Il trattamento dell'iperparatiroidismo secondario con gli analoghi della vitamina D:

Abstract non disponibil

A novel PNPLA2 mutation causing total loss of RNA and protein expression in two NLSDM siblings with early onset but slowly progressive severe myopathy

Neutral lipid storage disease with myopathy (NLSDM) is a rare autosomal recessive disorder, due to an enzymatic error of lipid metabolism. Patients present always with skeletal muscle myopathy and variable cardiac and hepatic involvement. NLSDM is caused by mutations in the PNPLA2 gene, which encodes the adipose triglyceride lipase (ATGL). Here we report the molecular characterization and clinical findings of two NLSDM siblings carrying the novel c.187+1G > C homozygous PNPLA2 mutation, localized in the splice site of intron 2. Molecular analyses revealed that neither aberrant PNPLA2 mRNA isoforms, nor ATGL mutated protein were detectable in patient's cells. Clinically, both patients presented early onset muscle weakness, in particular of proximal upper limb muscles. In almost 15 years, muscle damage affected also distal upper limbs. This is a NLSDM family, displaying a severe PNPLA2 mutation in two siblings with clinical presentation characterized by an early onset, but a slowly evolution of severe myopathy

MiRNAs as biomarkers of phenotype in neutral lipid storage disease with myopathy

BACKGROUND: Neutral lipid storage disease with myopathy (NLSDM) is a rare lipid metabolism disorder. In this study, we evaluated some circulating miRNAs levels in serum samples and the MRI of three affected siblings. METHODS: Three members of one NLSDM family were identified: two brothers and one sister. Muscles of lower and right upper extremities were studied by MRI. Expression profile of miRNAs, obtained from serum samples, was detected using qRT-PCR. RESULTS: Two brothers presented with progressive skeletal myopathy, while the sister had severe hepatosteatosis and diabetes. NLSDM patients showed a significant increase of muscle-specific miRNAs expression compared with healthy subjects. We found a correlation between hepatic damage and elevation of miRNAs expression profile of liver origin. CONCLUSIONS: The dysregulation of miRNAs might represent an indicator of skeletal and hepatic damage and it might be useful to monitor the progression of NLSDM

Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM

Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids. Here, we report the derivation of NLSDM-induced pluripotent stem cells (NLSDM-iPSCs) from fibroblasts of two patients carrying different PNPLA2 mutations. The first patient was homozygous for the c.541delAC, while the second was homozygous for the c.662G>C mutation in the PNPLA2 gene. We verified that the two types of NLSDM-iPSCs possessed properties of embryonic-like stem cells and could differentiate into the three germ layers in vitro. Immunofluorescence analysis revealed that iPSCs had an abnormal accumulation of triglycerides in LDs, the hallmark of NLSDM. Furthermore, NLSDM-iPSCs were deficient in long chain fatty acid lipolysis, when subjected to a pulse chase experiment with oleic acid. Collectively, these results demonstrate that NLSDM-iPSCs are a promising in vitro model to investigate disease mechanisms and screen drug compounds for NLSDM, a rare disease with few therapeutic options

Neutral lipid storage diseases as cellular model to study lipid droplet function

Neutral lipid storage disease with myopathy (NLSDM) and with ichthyosis (NLSDI) are rare autosomal recessive disorders caused by mutations in the PNPLA2 and in the ABHD5/CGI58 genes, respectively. These genes encode the adipose triglyceride lipase (ATGL) and \u3b1-\u3b2 hydrolase domain 5 (ABHD5) proteins, which play key roles in the function of lipid droplets (LDs). LDs, the main cellular storage sites of triacylglycerols and sterol esters, are highly dynamic organelles. Indeed, LDs are critical for both lipid metabolism and energy homeostasis. Partial or total PNPLA2 or ABHD5/CGI58 knockdown is characteristic of the cells of NLSD patients; thus, these cells are natural models with which one can unravel LD function. In this review we firstly summarize genetic and clinical data collected from NLSD patients, focusing particularly on muscle, skin, heart, and liver damage due to impaired LD function. Then, we discuss how NLSD cells were used to investigate and expand the current structural and functional knowledge of LD

Recurrent N209* ABHD5 mutation in two unreported families with Chanarin Dorfman Syndrome

ABHD5 protein is widely involved in lipid and energy homeostasis. Mutations in the ABHD5 gene are associated with the onset of Neutral Lipid Storage Disease with Ichthyosis (NLSDI), historically known as Chanarin Dorfman Syndrome (CDS). CDS is a rare autosomal recessive lipid storage disease, characterized by non-bullous congenital ichthyosiform eritrhoderma (NCIE), hepatomegaly and liver steatosis. Myopathy, neurosensory hearing loss, cataracts, nystagmus, strabismus, and mental impairment are considered additional findings. To date, 151 CDS patients have been reported all over the world. Here we described two additional families with patients affected by CDS from Turkey. Our patients were a 42 and 22-years old men, admitted to the Hospital for congenital ichthyosis. Hepatic steatosis and myopathy were also detected in both patients. ABHD5 molecular analysis revealed the presence of N209* mutation. Our data enlarge the cohort of CDS patients and provide a revision of muscle clinical findings for this rare inborn error of neutral lipid metabolism

Foxc2 disease mutations identified in lymphedema distichiasis patients impair transcriptional activity and cell proliferation

FOXC2 is a member of the human forkhead-box gene family and encodes a regulatory transcription factor. Mutations in FOXC2 have been associated with lymphedema distichiasis (LD), an autosomal dominant disorder that primarily affects the limbs. Most patients also show extra eyelashes, a condition known as distichiasis. We previously reported genetic and clinical findings in six unrelated families with LD. Half the patients showed missense mutations, two carried frameshift mutations and a stop mutation was identified in a last patient. Here we analyzed the subcellular localization and transactivation activity of the mutant proteins, showing that all but one (p.Y109*) localized to the nucleus. A significant reduction of transactivation activity was observed in four mutants (p.L80F, p.H199Pfs*264, p.I213Tfs*18, p.Y109*) compared with wild type FOXC2 protein, while only a partial loss of function was associated with p.V228M. The mutant p.I213V showed a very slight increase of transactivation activity. Finally, immunofluorescence analysis revealed that some mutants were sequestered into nuclear aggregates and caused a reduction of cell viability. This study offers new insights into the effect of FOXC2 mutations on protein function and shows the involvement of aberrant aggregation of FOXC2 proteins in cell death

Peering into the extended X-ray emission on megaparsec scale in 3C 187

Context. The diffuse X-ray emission surrounding radio galaxies is generally interpreted either as due to inverse Compton scattering of nonthermal radio-emitting electrons on the cosmic microwave background (IC/CMB), or as due to thermal emission arising from the hot gas of the intergalactic medium (IGM) permeating galaxy clusters hosting such galaxies, or as a combination of both. In this work, we present an imaging and spectral analysis of Chandra observations for the radio galaxy 3C 187 to investigate its diffuse X-ray emission and constrain the contribution of these various physical mechanisms. Aims. The main goals of this work are the following: (i) to evaluate the extension of the diffuse X-ray emission from this source; (ii) to investigate the two main processes, IC/CMB and thermal emission from the IGM, which can account for the origin of this emission; and (iii) to test the possibility that 3C 187 belongs to a cluster of galaxies, which can account for the observed diffuse X-ray emission. Methods. To evaluate the extension of the X-ray emission around 3C 187, we extracted surface flux profiles along and across the radio axis. We also extracted X-ray spectra in the region of the radio lobes and in the cross-cone region to estimate the contribution of the nonthermal (IC/CMB) and thermal (IGM) processes to the observed emission, making use of radio (VLA and GMRT) data to investigate the multiwavelength emission arising from the lobes. We collected Pan-STARRS photometric data to investigate the presence of a galaxy cluster hosting 3C 187, looking for the presence of a “red sequence” in the source field in the form of a tight clustering of galaxies in the color space. In addition, we made use of observations performed with the COSMOS spectrograph at the Victor Blanco Telescope to estimate the redshift of the sources in the field of 3C 187 to verify if they are gravitationally bound, as we would expect in a cluster of galaxies. Results. The diffuse X-ray emission around 3C 187 is found to extend in the soft 0.3 − 3 keV band up to ∼850 kpc along the radio lobe direction and ∼530 kpc in the cross-cone direction, and it appears enhanced in correspondence with the radio lobes. Spectral X-ray analysis in the cross-cones indicates a thermal origin for the emission in this region with a temperature ∼4 keV. In the radio lobes, the X-ray spectral analysis in combination with the radio data suggests a dominant IC/CMB radiation in these regions, however we do not rule out a significant thermal contribution. Assuming that the radiation observed in the radio lobes is due to the IGM, the emission from the N and S cones can be interpreted as arising from hot gas with temperatures of ∼3 keV and ∼5 keV, respectively, and found to be in pressure equilibrium with the surrounding gas. Using Pan-STARRS optical data we found that 3C 187 belongs to a red sequence of ∼40 optical sources in the field whose color distribution is significantly different from background sources. We were able to collect optical spectra for only one of these cluster candidates and for 22 field (i.e., noncluster candidates) sources. While the latter show stellar spectra, the former feature a galactic spectrum with a redshift close to 3C 187 nucleus. Conclusions. The diffuse X-ray emission around 3C 187 is elongated along the radio axis and enhanced in correspondence with the radio lobes. This indicates a morphological connection between the emission in the two energy bands and thus suggests a dominating IC/CMB mechanism in these regions. This scenario is reinforced by multiwavelength radio X-ray emission, which in these regions is compatible with IC/CMB radiation. The X-ray spectral analysis however does not rule out a significant contribution to the observed emission from thermal gas, which would be able to emit over tens of gigayears and in pressure equilibrium with the surroundings. Optical data indicate that 3C 187 may belong to a cluster of galaxies, whose IGM would contribute to the X-ray emission observed around the source. Additional X-ray and optical spectroscopic observations are however needed to secure these results and get a more clear picture of the physical processes at play in 3C 187

Peering Into the Extended X-ray Emission on Megaparsec Scale in 3C 187

Context. The diffuse X-ray emission surrounding radio galaxies is generally interpreted either as due to inverse Compton scattering of non-thermal radio-emitting electrons on the Cosmic Microwave Background (IC/CMB), or as the thermal emission arising from the hot gas of the intergalactic medium (IGM) permeating galaxy clusters hosting such galaxies, or as a combination of both. In this work we present an imaging and spectral analysis of Chandra observations for the radio galaxy 3C 187 to investigate its diffuse X-ray emission and constrain the contribution of these different physical mechanisms. Aims. The main goals of this work are: (i) to evaluate the extension of the diffuse X-ray emission from this source, (ii) to investigate the two main processes that can account for its origin - IC/CMB and thermal emission from the IGM - and (iii) to test the possibility for 3C 187 to belong to a cluster of galaxies, that can account for the observed diffuse X-ray emission. Methods. To evaluate the extension of the X-ray emission around 3C 187 we extracted surface flux profiles along and across the radio axis. We also extracted X-ray spectra in the region of the radio lobes and in the cross-cone region to estimate the contribution of the non-thermal (IC/CMB) and thermal (IGM) processes to the observed emission, making use of radio (VLA and GMRT) data to investigate the multi-wavelength emission arising from the lobes. We collected Pan-STARRS photometric data to investigate the presence of a galaxy cluster hosting 3C 187, looking for the presence of a "red sequence" in the source field in the form of a tight clustering of the galaxies in the color space...Comment: 32 pages, 13 figures, accepted for publication on A&A on 12/19/202