Pericardial effusion in the course of Fabry disease cardiomyopathy: a case report.

BACKGROUND: Fabry disease (FD) is an X-chromosome-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. CASE SUMMARY: A 51-year-old Japanese woman with a previous diagnosis of FD presented with pericardial effusion. The exudative pericardial fluid contained globotriaosylsphingosine. Left ventricular hypertrophy progressed despite regular administration of agalsidase alfa every 2 weeks over a 7-year period, with increases in plasma levels of globotriaosylsphingosine and interleukin (IL)-18. In addition, the IL-6 level in the pericardial fluid was markedly higher than that in plasma. DISCUSSION: This case suggests that elevated IL-6 and IL-18 levels in pericardial fluid and plasma indicate the severity of FD cardiomyopathy.

High-Quality Heteroepitaxial Growth of Thin Films of the Perovskite Oxynitride CaTaO2N: Importance of Interfacial Symmetry Matching between Films and Substrates.

Perovskite oxynitrides have been studied with regard to their visible light-driven photocatalytic activity and novel electronic functionalities. The assessment of the intrinsic physical and/or electrochemical properties of oxynitrides requires the epitaxial growth of single-crystalline films. However, the heteroepitaxy of perovskite oxynitrides has not yet matured compared to the progress realized in work with perovskite oxides. Herein, we report the heteroepitaxial growth of CaTaO2N thin films with (100)pc, (110)pc, and (111)pc crystallographic surface orientations (where the subscript pc denotes a pseudocubic cell) on SrTiO3 substrates using reactive radio frequency magnetron sputtering, along with investigations of crystallinity and surface morphology. Irrespective of surface orientation, stoichiometric CaTaO2N epitaxial thin films were grown coherently on SrTiO3 substrates and showed clear step and terrace surfaces in the case of low values of film thickness of approximately 20 nm. A (110)pc-oriented film was also more highly crystalline than (100)pc- and (111)pc-oriented specimens. This relationship between crystallinity and surface orientation is ascribed to the number of inequivalent in-plane rotational domains, which stems from the symmetry mismatch between the orthorhombic CaTaO2N and cubic SrTiO3. A CaTaO2N thin film grown on a lattice- and symmetry-matched orthorhombic DyScO3 substrate exhibited a significant crystallinity and a clear step and terrace surface even though the film was thick (∼190 nm). These results are expected to assist in developing the heteroepitaxial growth of high-quality perovskite oxynitride thin films.

High mobility approaching the intrinsic limit in Ta-doped SnO2 films epitaxially grown on TiO2 (001) substrates.

Achieving high mobility in SnO2, which is a typical wide gap oxide semiconductor, has been pursued extensively for device applications such as field effect transistors, gas sensors, and transparent electrodes. In this study, we investigated the transport properties of lightly Ta-doped SnO2 (Sn1-xTaxO2, TTO) thin films epitaxially grown on TiO2 (001) substrates by pulsed laser deposition. The carrier density (ne) of the TTO films was systematically controlled by x. Optimized TTO (x = 3 × 10-3) films with ne ~ 1 × 1020 cm-3 exhibited a very high Hall mobility (µH) of 130 cm2V-1s-1 at room temperature, which is the highest among SnO2 films thus far reported. The µH value coincided well with the intrinsic limit of µH calculated on the assumption that only phonon and ionized impurities contribute to the carrier scattering. The suppressed grain-boundary scattering might be explained by the reduced density of the {101} crystallographic shear planes.

Effectiveness of immunosuppressive therapy for nephrotic syndrome in a patient with late-onset Fabry disease: a case report and literature review.

BACKGROUND: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene, followed by deficiency in α-galactosidase A (α-gal) activity. Nephrotic syndrome, as the renal phenotype of FD, is unusual. Here, we report the rare case of a patient with FD with nephrotic syndrome whose proteinuria disappeared by immunotherapy. CASE PRESENTATION: A 67-year-old Japanese man was admitted to our hospital because of emesis, abdominal pain, and facial edema due to nephrotic syndrome. The patient was diagnosed with focal segmental glomerulosclerosis (FSGS) by renal biopsy before being diagnosed with FD, and immunotherapy was initiated. After treatment, the kidney biopsy results showed typical glycosphingolipid accumulation in the podocytes of this patient. The white blood cell α-gal activity was very low, and genetic analysis revealed a GLA gene variant (M296I), which is known as a late-onset genetic mutation of FD. Immunotherapy (steroids and cyclosporine A) dramatically improved the massive proteinuria. Currently, he has been undergoing enzyme replacement therapy, and his proteinuria has further decreased. There is the possibility that other nephrotic syndromes, such as minimal change nephrotic syndrome or FSGS, may co-exist in this patient. CONCLUSIONS: We experienced the rare case of a FD patient whose nephrotic syndrome disappeared by immunotherapy. These findings suggest that immunosuppressive treatment may be considered if nephrotic syndrome develops, even in patients with FD.

Anion-Substitution-Induced Nonrigid Variation of Band Structure in SrNbO3- xN x (0 ≤ x ≤ 1) Epitaxial Thin Films.

Pervoskite oxynitrides exhibit rich functionalities such as colossal magnetoresistance and high photocatalytic activity. The wide tunability of physical properties by the N/O ratio makes perovskite oxynitrides promising as optical and electrical materials. However, composition-dependent variation of the band structure, especially under partially substituted composition, is not yet well understood. In this study, we quantitatively analyzed the composition-dependent variation of band structure of a series of SrNbO3- xN x (0 ≤ x ≤ 1.02) epitaxial thin films. Electrical conductivity decreased along with the increase of N content x as a result of an increase in Nb valence from 4+ to 5+. Optical measurements revealed that the N 2p band is formed at a critical composition between 0.07 < x < 0.38, which induces charge-transfer transition (CTT) in the visible-light region. These variations in the band structure were explained by first-principles calculations. However, the CTT energy slightly increased at higher N contents (i.e., lower carrier density) on contrary to the expectation based on the rigid-band-like shift of the Fermi level, which suggests a complex combination of the following band-shifting effects induced by N-substitution: whereas (1) reduction of the Burstein-Moss effect causes CTT energy reduction, (2) enhancement of hybridization between Nb 4d and N 2p orbitals and/or (3) suppression of many-body effects enlarge the band gap energy at larger N content. The band structure variation in perovskite oxynitride as presently elucidated would be a guidepost for future material design.

Lateral solid-phase epitaxy of oxide thin films on glass substrate seeded with oxide nanosheets.

We developed a technique to fabricate oxide thin films with uniaxially controlled crystallographic orientation and lateral size of more than micrometers on amorphous substrates. This technique is lateral solid-phase epitaxy, where epitaxial crystallization of amorphous precursor is seeded with ultrathin oxide nanosheets sparsely (≈10% coverage) deposited on the substrate. Transparent conducting Nb-doped anatase TiO2 thin films were fabricated on glass substrates by this technique. Perfect (001) orientation and large grains with lateral sizes up to 10 µm were confirmed by X-ray diffraction, atomic force microscopy, and electron beam backscattering diffraction measurements. As a consequence of these features, the obtained film exhibited excellent electrical transport properties comparable to those of epitaxial thin films on single-crystalline substrates. This technique is a versatile method for fabricating high-quality oxide thin films other than anatase TiO2 and would increase the possible applications of oxide-based thin film devices.

Terminal stage cardiac findings in patients with cardiac Fabry disease: an electrocardiographic, echocardiographic, and autopsy study.

OBJECTIVES: Fabry disease is caused by deficiency of alpha-galactosidase A, and typically causes multi-organ dysfunction. Patients with manifestations limited to the heart, mainly left ventricular hypertrophy (LVH), have been reported as a disease variation. We have reported a 3% prevalence of this cardiac variant in men with LVH, which we designated 'cardiac Fabry disease'. The purposes of this study were to evaluate the terminal stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS: We examined seven terminal stage patients with cardiac Fabry disease. During hospitalization, standard 12-lead electrocardiograms, Holter electrocardiograms, and echocardiograms were obtained. Autopsies were performed and macroscopic along with microscopic findings were evaluated. RESULTS: Six patients died of heart failure and one of ventricular fibrillation. Electrocardiograms revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings revealed LVH in all patients. Localized basal posterior wall thinning of the left ventricle was detected in the six patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells, but not cardiac vascular endothelial cells, showed glycosphingolipid accumulation. No accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction with associated conduction disturbances and ventricular arrhythmias occur in patients with terminal stage cardiac Fabry disease. Furthermore, LVH is present and associated with thinning of the base of the left ventricular posterior wall. In contrast to typical Fabry disease, accumulation of glycosphingolipids was observed in myocardial cells but not in other organs.

[End-stage cardiac manifestations and autopsy findings in patients with cardiac fabry disease].

BACKGROUND: Fabry disease is an X-linked recessive disorder resulting from a deficiency of alpha-galactosidase A with multi-organ dysfunction. Patients with manifestations limited to the heart have been reported recently as a disease variant. We have previously reported a 3% prevalence of this cardiac variant in men with left ventricular hypertrophy, which we designated cardiac Fabry disease. The purposes of the current study were to evaluate the end-stage cardiac manifestations and autopsy findings in patients with cardiac Fabry disease. METHODS AND RESULTS: We evaluated five autopsied male patients with cardiac Fabry disease. One died of ventricular fibrillation and four of heart failure. Electrocardiograms obtained at hospitalization revealed the presence of conduction abnormalities and nonsustained ventricular tachycardia. Echocardiograms and autopsy findings showed the presence of left ventricular hypertrophy in all patients. Localized thinning of the basal posterior wall of the left ventricle was detected in four patients who died of heart failure. All patients had severe left ventricular dysfunction. Histologically, myocardial cells showed glycosphingolipid accumulation in all of the patients but no accumulation was observed in other organs or in systemic vascular endothelial cells. CONCLUSIONS: Severe left ventricular dysfunction, conduction disturbances and ventricular arrhythmias occur in end-stage cardiac Fabry patients. Furthermore, left ventricular hypertrophy commonly associated with thinning of the base of the left ventricular posterior wall is present. The accumulation of glycosphingolipids can be observed in myocardial cells but not in other organs.

Fabry disease: detection of undiagnosed hemodialysis patients and identification of a "renal variant" phenotype.

BACKGROUND: Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient alpha-galactosidase A (alpha-Gal A) activity. Renal failure is a major debilitating complication in classically affected males. To determine if this disorder is underdiagnosed in patients with end-stage renal disease (ESRD), the frequency of unrecognized males with Fabry disease on chronic hemodialysis was determined. METHODS: Plasma alpha-Gal A activity was measured in 514 consecutive males with ESRD on hemodialysis. Patients with low alpha-Gal A activity were evaluated clinically and their alpha-Gal A mutations were determined. RESULTS: Six (1.2%) of 514 hemodialysis patients had low plasma alpha-Gal A activities and a previously identified (E66Q, A97V, M296I) or novel (G373D) missense mutation. At ages 30 to 68 years, five patients lacked the classic manifestations of angiokeratoma, acroparesthesias, hypohidrosis, and ocular opacities, while the sixth lacked angiokeratoma and ocular changes. Five had left ventricular hypertrophy (LVH). CONCLUSION: The clinical spectrum of Fabry disease includes a "renal variant" phenotype in patients without classic symptoms who develop ESRD. Affected males undergoing hemodialysis or renal transplantation can be readily diagnosed by plasma alpha-Gal A assays. These patients and their family members may benefit from enzyme replacement therapy for the later, life-threatening cardiovascular and cerebrovascular complications of Fabry disease.

Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype.

Fabry disease is an inborn error of glycosphingolipid catabolism, resulting from deficient activity of lysosomal alpha-galactosidase A (alpha-Gal A). A rare alternative splicing that introduces a 57-nucleotide (nt) intronic sequence to the alpha-Gal A transcript from intron 4 of the gene has been identified. In addition, a novel midintronic base substitution that results in substantially increased alternative splicing has been identified in a patient with Fabry disease who has the cardiac variant phenotype. The sequence of the patient's intron 4 contains a single G-->A transversion at genomic nt 9331 (IVS4+919 G-->A ), located at the minus sign4 position of the 3' end of the intronic insertion (nts 9278--9334 in the genomic sequence). Minigene constructs containing the entire intron 4 sequence with G, A, C, or T at nt 9331 within an alpha-Gal A complementary DNA expression vector were prepared and expressed in COS-1 cells. Whereas transfection of the G or T minigenes transcribed predominantly normal-sized transcripts, the transfection of the A or C minigenes produced a large amount of the alternatively spliced transcript. These results suggest that the G-->A mutation, within an A/C-rich domain, results in increased recognition of the alternative splicing by an A/C-rich enhancer-type exonic splicing enhancer. The intronic mutation was not observed in 100 unrelated unaffected men but was present in 6 unrelated patients with cardiac Fabry disease. Reverse-transcriptase polymerase chain reaction of total RNA of various normal human tissues revealed that the alternatively spliced transcript was present in all of the samples, and especially at a higher ratio in the lung and muscle. The normal transcript was present in the patients' lymphoblasts and resulted in approximately 10% residual enzyme activity, leading to a cardiac phenotype of Fabry disease.