FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming beta-fibrils in amyloid deposits. This theory does not explain the formation of beta-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to beta-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N(delta)-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4'-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40+/-9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.
Familial amyloidotic polyneuropathy is an autosomal dominant amyloidosis, characterized by the systemic deposition of amyloid with a particular involvement of the peripheral nerves. The disease generally manifests as a severe sensory, motor and autonomic neuropathy. Cardiomyopathy, nephropathy, vitreous opacities and carpal tunnel syndrome may occur in a variable association with the neuropathy. Trophic dermatological lesions are frequent in the more advanced stages of the disease. We examined the skin of 142 patients. The cutaneous manifestations more frequently observed were: xerosis (81.6%), seborrheic dermatitis (21.8%), traumatic and burn lesions (19.7%), acne (18.3%), neurotrophic ulcers (14%) and onychomycosis (10.5%). Among the hepatic transplanted patients (31%), seborrheic dermatitis and acne were the most frequent diagnoses.
SummaryFamilial amyloid polyneuropathy (FAP) is a hereditary disease which eventually causes serious ocular problems.Seven eyes from patients with F AP 1 were vitrectomised, and the insoluble pro teins from the vitreous were purified, the amyloid protein isolated, and the pre albumin characterised with a monoclonal antibody against amyloid fibril protein.Before surgery, visual acuity was very poor, due to abundant deposits in the vit reous, frequently attached to the posterior lens capsule. The pupil had peculiar indentations and the pupillary reflexes were abnormal. Intraocular pressure (lOP) was at the upper limit of normal. In the ocular fundus an intraretinal perifoveal gray ring was sometimes seen. Vitrectomy improved visual acuity, but the reappearance of vitreous deposits reduced it to 8.8/10 after 33.4 months, when treatment was needed for most of the eyes to control lOP. Amyloid and the mutant form of pre albumin characteristic of FAP 1, TTR Met 30, were shown to be present in the vitreous.
Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is a rare condition characterized by emotional and behavioral disturbances, dyskinesias, and extrapyramidal signs. It occurs in young women of reproductive age and is classically described as a paraneoplastic phenomenon. We present a 36-year-old, HIV-positive female who was admitted to the hospital in an acute confusional state, with a stiff posture, periods of motor agitation, and myoclonic jerks of the hands. Her mental state progressively deteriorated. Without evidence of infection, the presence of anti-NMDAR antibodies both in serum and cerebrospinal fluid clinched the diagnosis of autoimmune encephalitis. No evidence of neoplastic disease was found, and the beneficial response to immunosuppressive therapy was exceptional. This is the first report of anti-NMDAR encephalitis in an HIV-infected individual, reminding us that autoimmune encephalitis should be included in the differential diagnosis of a young patient presenting in an acute confusional state.
Transthyretin (TTR) is a homotetrameric protein involved in thyroid hormone transport in blood and in retinol binding in the central nervous system. More than 80 point mutations in this protein are known to be associated with the formation of amyloid deposits and systemic amyloidotic pathologies. Age at onset varies according to the mutation but considerable variations also occur for subjects carrying the same mutation. Moreover, wild-type TTR forms amyloid deposits in systemic senile amyloidosis, a geriatric disorder. An accurate diagnostic and the choice of therapeutic options depend on the identification of the specific mutation. Previous characterization of TTR variants by mass spectrometry required the use of antibodies for sample enrichment. We developed a novel assay based on ultra high-resolution mass spectrometry to identify human TTR variants. The method, requiring a very low sample amount, is based on SDS-PAGE fractionation of human serum, followed by peptide mass fingerprinting by MALDI-FTICR-MS (matrix assisted laser desorption ionization coupled to Fourier transform ion cyclotron resonance mass spectrometry). Moreover, it is possible to perform a relative quantification of wild type and mutant TTR forms by mass spectrometry. The method was tested and validated with the V30M mutant, involved in familial amyloidotic neuropathy of Portuguese type.
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