To describe abnormalities in choroidal and retinal vasculature associated with Val30Met familial transthyretin amyloidosis (V30M-FTA) using fluorescein and indocyanine green (ICG) angiography.
...Prospective, cross-sectional study.
This study was conducted at the French National Reference Center for FTA. We included 18 consecutive genetically confirmed V30M-FTA patients (36 eyes) who underwent complete neurologic examination, including staging with polyneuropathy disability (PND) score, and complete ophthalmic evaluation, including staging of intraocular amyloid deposits and fluorescein and ICG angiograms (ICG-A). The grading of choroidal and retinal angiopathy, and their association with neurologic functional impairment, were the main outcome measures.
Eleven men and 7 women, mean age 61.6 ± 12.1 years, were included. Retinal amyloid angiopathy (RAA) was detected in 24 eyes (92%) of 13 patients, with microaneurysms, retinal hemorrhages, and retinal ischemia of variable extent. Three patients (5 eyes) had neovascular glaucoma and 2 (2 eyes) had preretinal neovascularization. ICG-A indicated choroidal amyloid angiopathy (CAA) in all patients, with 3 distinct patterns—diffuse (9/18 patients), focal (5/18 patients), or punctiform (4/18 patients)—based on the extent of late hypercyanescence along the choroidal arteries. PND scores were significantly higher in patients with diffuse CAA (firework pattern) compared to those with limited CAA (focal and punctiform patterns) (2.89 vs 1.78, P = .045).
RAA is a frequent and severe complication of V30M-FTA that may lead to anterior and posterior segment neovascularization. CAA was detected in all patients, with a late hypercyanescent delineation of the choroidal arterial vasculature, which was more extensive with increased disease severity.
We describe a kindred with slowly progressive gastrointestinal symptoms and autonomic neuropathy caused by autosomal dominant, hereditary systemic amyloidosis. The amyloid consists of Asp76Asn ...variant β(2)-microglobulin. Unlike patients with dialysis-related amyloidosis caused by sustained high plasma concentrations of wild-type β(2)-microglobulin, the affected members of this kindred had normal renal function and normal circulating β(2)-microglobulin values. The Asp76Asn β(2)-microglobulin variant was thermodynamically unstable and remarkably fibrillogenic in vitro under physiological conditions. Previous studies of β(2)-microglobulin aggregation have not shown such amyloidogenicity for single-residue substitutions. Comprehensive biophysical characterization of the β(2)-microglobulin variant, including its 1.40-Å, three-dimensional structure, should allow further elucidation of fibrillogenesis and protein misfolding.
Apolipoprotein A1 amyloidosis (ApoAI) results from specific mutations in the APOA1 gene causing abnormal accumulation of amyloid fibrils in diverse tissues. The kidney is a prominent target tissue in ...ApoAI amyloidosis with a remarkable selectivity for the renal medulla. Here, we investigated six French families with ApoAI Glu34Lys, p.His179Profs∗47, and a novel p.Thr185Alafs∗41 variant revealing unprecedented clinical association of a glomerular with a retinal disease. Comprehensive clinicopathological, molecular and proteomics studies of numerous affected tissues ensured the correlation between clinical manifestations, including novel unrecognized phenotypes, and apoA-I amyloid deposition. These ophthalmic manifestations stemmed from apoA-I amyloid deposition, highlighting that the retina is a previously unrecognized tissue affected by ApoAI amyloidosis. Our study provides the first molecular evidence that a significant fraction of ApoAI amyloidosis cases with no family history result from spontaneous neomutations rather than variable disease penetrance. Finally, successful hepatorenal transplantation resulted in a life- and vision-saving measure for a 32-year-old man with a hitherto unreported severe ApoAI amyloidosis caused by the very rare Glu34Lys variant. Our findings reveal new modes of occurrence and expand the clinical spectrum of ApoAI amyloidosis. The awareness of glomerular and ocular manifestations in ApoAI amyloidosis should enable earlier diagnosis and avoid misdiagnosis with other forms of renal amyloidosis. Thus, documented apoA-I amyloid deposition in the retina offers new biological information about this disease and may change organ transplantation practice to reduce retinal damage in patients with ApoAI amyloidosis.
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Congo red-positive material was described in normal and diseased parathyroids (adenoma and hyperplasia) 50 years ago. However, the incidence and the clinical significance of such observation are ...unknown, and the causal fibril protein has never been convincingly demonstrated.
We conducted the present study including an exceptional case report accompanied with a retrospective study of 105 parathyroid adenomas. We used histopathological, immunohistochemical, ultrastructural, mass spectrometry-based proteomic analysis of parathyroid adenoma tissue samples, and genetic analysis.
We describe a 57-year-old man with mild hypercalcemia and elevated parathyroid hormone (PTH) level for whom histopathological analysis revealed a parathyroid adenoma associated with nodular typical amyloid deposits. Tandem mass spectrometry after laser microdissection (LMD-MS) of amyloid adenoma identified PTH as the fibril protein, and no germline mutation in the PTH gene was detected. Congo red-positive PTH-deposits were further observed in 6.6% of the parathyroid adenomas analyzed, and were associated with complete/incomplete or absent universal amyloid signature, but with fibrillar morphology at ultrastructural level.
Inappropriate PTH production leads to progressive disease-amyloid aggregation of PTH in a subset of parathyroid adenomas, providing new insights into the pathophysiology of this condition and adding PTH to the list of amyloid protein derived from hormones.
The study describes organic producers’ perceptions of organic livestock production, product commercialisation, use of contentious inputs such as allopathic antibiotics, antiparasitics and vitamins ...and bedding materials availability in Mediterranean (MED) and North/Western European (NWE) countries. A total of 426 MED (46.2%) and NWE (53.8%) responses were analysed revealing more difficulty finding information on alternatives to antiparasitics and antibiotics than on bedding materials. They identified ‘feeding/nutrition’, ‘animal health’ and ‘welfare’ as the most relevant topics in their farms. Whereas ruminants and monogastrics farmers in the NWE region also indicated ‘organic regulation’ as relevant, farmers rearing ruminant species in the MED region identified farm profitability and commercialisation. Farmers still mainly relied in conventional treatments but they often applied phytotherapy, although >61% of the participants did not treat their animals in the last year. If treated, most of them administered on average one course of antibiotic treatment per animal (>62%). In the MED region, the main sources of information on alternative treatments were veterinarians (>60%) and the Internet (>32%). In the NWE region, it was other farmers for producers including ruminant species (>63%) and veterinarians (>77%) for monogastric farmers. In the NWE region, direct commercialisation and through a cooperative and/or food industry were the most frequent channel used; while, in the MED region, they were the food industry and/or direct commercialisation. In conclusion, this survey provides novel cross-European insights into organic livestock producers' concerns. A particular value of the survey is that MED countries, which are often underrepresented, were well sampled.
To compare different clinical and Spectral-Domain Optical Coherence Tomography (SD-OCT) features of high myopic eyes with Stickler syndrome (STL) with matched controls.
Patients with genetically ...confirmed STL with axial length ≥ 26 mm and controls matched for axial length were included. The following data were obtained from SD-OCT scans and fundus photography: choroidal and retinal thickness (respectively, CT and RT), peripapillary atrophy area (PAA), presence of posterior staphyloma (PS).
Twenty-six eyes of 17 patients with STL and 25 eyes of 19 controls were evaluated. Compared with controls, patients with STL showed a greater CT subfoveally, at 1000 μm from the fovea at both nasal and temporal location, and at 2000 and 3000 μm from the fovea in nasal location (respectively, 188.7±72.8 vs 126.0±88.7 μm, 172.5±77.7 vs 119.3±80.6 μm, 190.1±71.9 vs 134.9±79.7 μm, 141.3±56.0 vs 98.1±68.5 μm, and 110.9±51.0 vs 67.6±50.7 μm, always P< 0.05). Furthermore, patients with STL showed a lower prevalence of PS (11.5% vs 68%, P< 0.001) and a lower PAA (2.2±2.1 vs 5.4±5.8 mm
, P=0.03), compared with controls.
This study shows that high myopic patients with STL show a greater CT, a lower PAA and a lower prevalence of PS, compared with controls matched for axial length. These findings could be relevant for the development and progression of myopic maculopathy in patients with STL.
Congenital primary aphakia (CPA) is a rare developmental disorder characterized by the absence of lens, the development of which is normally induced during the 4th–5th wk of human embryogenesis. This ...original failure leads, in turn, to complete aplasia of the anterior segment of the eye, which is the diagnostic histological criterion for CPA. So far, the genetic basis for this human condition has remained unclear. Here, we present the analysis of a consanguineous family with three siblings who had bilateral aphakia, microphthalmia, and complete agenesis of the ocular anterior segment. We show that a null mutation in the
FOXE3 gene segregates and, in the homozygous state, produces the mutant phenotype in this family. Therefore, this study identifies—to our knowledge, for the first time—a causative gene for CPA in humans. Furthermore, it indicates a possible critical role for
FOXE3 very early in the lens developmental program, perhaps earlier than any role recognized elsewhere for this gene.
•• A novel Vcan mouse allele, VcanAA, has ADAMTS protease-resistant versican.•• VcanAA/AA mice are viable and develop soft tissue-syndactyly (STS)•• VcanAA/AA STS is rendered more severe in ...combination with Adamts20Bt/Bt.•• Mice lacking the versican GAGβ domain, but not the GAGα domain, also have STS.•• The versican GAGβ proteolytic fragment versikine is necessary for web regression.
Two inherent challenges in the mechanistic interpretation of protease-deficient phenotypes are defining the specific substrate cleavages whose reduction generates the phenotypes and determining whether the phenotypes result from loss of substrate function, substrate accumulation, or loss of a function(s) embodied in the substrate fragments. Hence, recapitulation of a protease-deficient phenotype by a cleavage-resistant substrate would stringently validate the importance of a proteolytic event and clarify the underlying mechanisms. Versican is a large proteoglycan required for development of the circulatory system and proper limb development, and is cleaved by ADAMTS proteases at the Glu441-Ala442 peptide bond located in its alternatively spliced GAGβ domain. Specific ADAMTS protease mutants have impaired interdigit web regression leading to soft tissue syndactyly that is associated with reduced versican proteolysis. Versikine, the N-terminal proteolytic fragment generated by this cleavage, restores interdigit apoptosis in ADAMTS mutant webs. Here, we report a new mouse transgene, VcanAA, with validated mutations in the GAGβ domain that specifically abolish this proteolytic event. VcanAA/AA mice have partially penetrant hindlimb soft tissue syndactyly. However, Adamts20 inactivation in VcanAA/AA mice leads to fully penetrant, more severe syndactyly affecting all limbs, suggesting that ADAMTS20 cleavage of versican at other sites or of other substrates is an additional requirement for web regression. Indeed, immunostaining with a neoepitope antibody against a cleavage site in the versican GAGα domain demonstrated reduced staining in the absence of ADAMTS20. Significantly, mice with deletion of Vcan exon 8, encoding the GAGβ domain, consistently developed soft tissue syndactyly, whereas mice unable to include exon 7, encoding the GAGα domain in Vcan transcripts, consistently had fully separated digits. These findings suggest that versican is cleaved within each GAG-bearing domain during web regression, and affirms that proteolysis in the GAGβ domain, via generation of versikine, has an essential role in interdigital web regression.
Hereditary renal amyloidosis caused by a new variant lysozyme in a French family.
The number of proteins with mutations resulting in amyloidosis has continued to increase. Five ...proteins—transthyretin, fibrinogen α-A chain, apolipoprotein AI, lysozyme, apolipoprotein AII, cystatin C and gelsolin—can be associated with hereditary amyloidosis involving the kidney.
A French family with a history of autosomal dominant hereditary amyloidosis with early sicca syndrome and nephropathy leading to renal failure after the fifth to, the seventh decade was studied. Several tissue specimens obtained from the proband and his relatives were examined. Immunohistochemistry was performed on paraffin embedded sections using the indirect immunoperoxidase technique. We searched for mutations in the five exons and flanking introns of the lysozyme gene.
Amyloid deposits from the bowel, labial salivary gland and kidney were intensively stained by anti-lysozyme antibody. Sequence analysis of lysozyme exon 2 from the affected individuals revealed a nucleotide substitution predicting a substitution of the amino acid at position 64 in the mature protein from tryptophane, an aromatic residue to the cationic residue arginine (W64R).
We report a novel mutation (W64R) of the lysozyme that is associated with hereditary amyloidosis and prominent nephropathy. Since the treatment of hereditary amyloidosis greatly varies with the nature of the amyloid protein, thorough characterization of the latter is crucial for the management of the disease.
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