Amyloid Neuropathies: Disorders of the peripheral nervous system associated with the deposition of AMYLOID in nerve tissue. Familial, primary (nonfamilial), and secondary forms have been described. Some familial subtypes demonstrate an autosomal dominant pattern of inheritance. Clinical manifestations include sensory loss, mild weakness, autonomic dysfunction, and CARPAL TUNNEL SYNDROME. (Adams et al., Principles of Neurology, 6th ed, p1349)Amyloid Neuropathies, Familial: Inherited disorders of the peripheral nervous system associated with the deposition of AMYLOID in nerve tissue. The different clinical types based on symptoms correspond to the presence of a variety of mutations in several different proteins including transthyretin (PREALBUMIN); APOLIPOPROTEIN A-I; and GELSOLIN.Prealbumin: A tetrameric protein, molecular weight between 50,000 and 70,000, consisting of 4 equal chains, and migrating on electrophoresis in 3 fractions more mobile than serum albumin. Its concentration ranges from 7 to 33 per cent in the serum, but levels decrease in liver disease.Amyloidosis: A group of sporadic, familial and/or inherited, degenerative, and infectious disease processes, linked by the common theme of abnormal protein folding and deposition of AMYLOID. As the amyloid deposits enlarge they displace normal tissue structures, causing disruption of function. Various signs and symptoms depend on the location and size of the deposits.Amyloid: A fibrous protein complex that consists of proteins folded into a specific cross beta-pleated sheet structure. This fibrillar structure has been found as an alternative folding pattern for a variety of functional proteins. Deposits of amyloid in the form of AMYLOID PLAQUES are associated with a variety of degenerative diseases. The amyloid structure has also been found in a number of functional proteins that are unrelated to disease.Diabetic Neuropathies: Peripheral, autonomic, and cranial nerve disorders that are associated with DIABETES MELLITUS. These conditions usually result from diabetic microvascular injury involving small blood vessels that supply nerves (VASA NERVORUM). Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy (see OCULOMOTOR NERVE DISEASES); MONONEUROPATHY; mononeuropathy multiplex; diabetic amyotrophy; a painful POLYNEUROPATHY; autonomic neuropathy; and thoracoabdominal neuropathy. (From Adams et al., Principles of Neurology, 6th ed, p1325)Amyloid beta-Peptides: Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.Serum Amyloid A Protein: An ACUTE PHASE REACTION protein present in low concentrations in normal sera, but found at higher concentrations in sera of older persons and in patients with AMYLOIDOSIS. It is the circulating precusor of amyloid A protein, which is found deposited in AA type AMYLOID FIBRILS.Peripheral Nervous System Diseases: Diseases of the peripheral nerves external to the brain and spinal cord, which includes diseases of the nerve roots, ganglia, plexi, autonomic nerves, sensory nerves, and motor nerves.Amyloid beta-Protein Precursor: A single-pass type I membrane protein. It is cleaved by AMYLOID PRECURSOR PROTEIN SECRETASES to produce peptides of varying amino acid lengths. A 39-42 amino acid peptide, AMYLOID BETA-PEPTIDES is a principal component of the extracellular amyloid in SENILE PLAQUES.Plaque, Amyloid: Accumulations of extracellularly deposited AMYLOID FIBRILS within tissues.Hereditary Sensory and Motor Neuropathy: A group of slowly progressive inherited disorders affecting motor and sensory peripheral nerves. Subtypes include HMSNs I-VII. HMSN I and II both refer to CHARCOT-MARIE-TOOTH DISEASE. HMSN III refers to hypertrophic neuropathy of infancy. HMSN IV refers to REFSUM DISEASE. HMSN V refers to a condition marked by a hereditary motor and sensory neuropathy associated with spastic paraplegia (see SPASTIC PARAPLEGIA, HEREDITARY). HMSN VI refers to HMSN associated with an inherited optic atrophy (OPTIC ATROPHIES, HEREDITARY), and HMSN VII refers to HMSN associated with retinitis pigmentosa. (From Adams et al., Principles of Neurology, 6th ed, p1343)Islet Amyloid Polypeptide: A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.Cerebral Amyloid Angiopathy: A heterogeneous group of sporadic or familial disorders characterized by AMYLOID deposits in the walls of small and medium sized blood vessels of CEREBRAL CORTEX and MENINGES. Clinical features include multiple, small lobar CEREBRAL HEMORRHAGE; cerebral ischemia (BRAIN ISCHEMIA); and CEREBRAL INFARCTION. Cerebral amyloid angiopathy is unrelated to generalized AMYLOIDOSIS. Amyloidogenic peptides in this condition are nearly always the same ones found in ALZHEIMER DISEASE. (from Kumar: Robbins and Cotran: Pathologic Basis of Disease, 7th ed., 2005)Hereditary Sensory and Autonomic Neuropathies: A group of inherited disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and clinically by loss of sensation and autonomic dysfunction. There are five subtypes. Type I features autosomal dominant inheritance and distal sensory involvement. Type II is characterized by autosomal inheritance and distal and proximal sensory loss. Type III is DYSAUTONOMIA, FAMILIAL. Type IV features insensitivity to pain, heat intolerance, and mental deficiency. Type V is characterized by a selective loss of pain with intact light touch and vibratory sensation. (From Joynt, Clinical Neurology, 1995, Ch51, pp142-4)Optic Neuropathy, Ischemic: Ischemic injury to the OPTIC NERVE which usually affects the OPTIC DISK (optic neuropathy, anterior ischemic) and less frequently the retrobulbar portion of the nerve (optic neuropathy, posterior ischemic). The injury results from occlusion of arterial blood supply which may result from TEMPORAL ARTERITIS; ATHEROSCLEROSIS; COLLAGEN DISEASES; EMBOLISM; DIABETES MELLITUS; and other conditions. The disease primarily occurs in the sixth decade or later and presents with the sudden onset of painless and usually severe monocular visual loss. Anterior ischemic optic neuropathy also features optic disk edema with microhemorrhages. The optic disk appears normal in posterior ischemic optic neuropathy. (Glaser, Neuro-Ophthalmology, 2nd ed, p135)Serum Amyloid P-Component: Amyloid P component is a small, non-fibrillar glycoprotein found in normal serum and in all amyloid deposits. It has a pentagonal (pentaxin) structure. It is an acute phase protein, modulates immunologic responses, inhibits ELASTASE, and has been suggested as an indicator of LIVER DISEASE.Polyneuropathies: Diseases of multiple peripheral nerves simultaneously. Polyneuropathies usually are characterized by symmetrical, bilateral distal motor and sensory impairment with a graded increase in severity distally. The pathological processes affecting peripheral nerves include degeneration of the axon, myelin or both. The various forms of polyneuropathy are categorized by the type of nerve affected (e.g., sensory, motor, or autonomic), by the distribution of nerve injury (e.g., distal vs. proximal), by nerve component primarily affected (e.g., demyelinating vs. axonal), by etiology, or by pattern of inheritance.Sural Nerve: A branch of the tibial nerve which supplies sensory innervation to parts of the lower leg and foot.Amyloid Precursor Protein Secretases: Endopeptidases that are specific for AMYLOID PROTEIN PRECURSOR. Three secretase subtypes referred to as alpha, beta, and gamma have been identified based upon the region of amyloid protein precursor they cleave.Alzheimer Disease: A degenerative disease of the BRAIN characterized by the insidious onset of DEMENTIA. Impairment of MEMORY, judgment, attention span, and problem solving skills are followed by severe APRAXIAS and a global loss of cognitive abilities. The condition primarily occurs after age 60, and is marked pathologically by severe cortical atrophy and the triad of SENILE PLAQUES; NEUROFIBRILLARY TANGLES; and NEUROPIL THREADS. (From Adams et al., Principles of Neurology, 6th ed, pp1049-57)Diflunisal: A salicylate derivative and anti-inflammatory analgesic with actions and side effects similar to those of ASPIRIN.Liver Transplantation: The transference of a part of or an entire liver from one human or animal to another.Complicity: Association with or participation in an act that is, or is perceived to be, criminal or immoral. One is complicitous when one promotes or unduly benefits from practices or institutions that are morally or legally suspect.Erotica: Literary or artistic items having an erotic theme. It refers especially to books treating sexual love in a sensuous or voluptuous manner. (Webster, 3d ed)Oligonucleotides: Polymers made up of a few (2-20) nucleotides. In molecular genetics, they refer to a short sequence synthesized to match a region where a mutation is known to occur, and then used as a probe (OLIGONUCLEOTIDE PROBES). (Dorland, 28th ed)RNA: A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed)Molecular Sequence Data: Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Oligonucleotides, Antisense: Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize.Amyloidosis, Familial: Diseases in which there is a familial pattern of AMYLOIDOSIS.Histology, Comparative: The study of the similarities and differences in the structures of homologous tissues across various species.Cryptococcus gattii: A species of the fungus CRYPTOCOCCUS. Its teleomorph is Filobasidiella bacillispora.Mass Spectrometry: An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers.SwedenFaculty, Medical: The teaching staff and members of the administrative staff having academic rank in a medical school.Faculty: The teaching staff and members of the administrative staff having academic rank in an educational institution.Tandem Mass Spectrometry: A mass spectrometry technique using two (MS/MS) or more mass analyzers. With two in tandem, the precursor ions are mass-selected by a first mass analyzer, and focused into a collision region where they are then fragmented into product ions which are then characterized by a second mass analyzer. A variety of techniques are used to separate the compounds, ionize them, and introduce them to the first mass analyzer. For example, for in GC-MS/MS, GAS CHROMATOGRAPHY-MASS SPECTROMETRY is involved in separating relatively small compounds by GAS CHROMATOGRAPHY prior to injecting them into an ionization chamber for the mass selection.Paraphilias: Disorders that include recurrent, intense sexually arousing fantasies, sexual urges, or behaviors generally involving nonhuman objects, suffering of oneself or partners, or children or other nonconsenting partners. (from DSM-IV, 1994)Faculty, Dental: The teaching staff and members of the administrative staff having academic rank in a dental school.Complement Activation: The sequential activation of serum COMPLEMENT PROTEINS to create the COMPLEMENT MEMBRANE ATTACK COMPLEX. Factors initiating complement activation include ANTIGEN-ANTIBODY COMPLEXES, microbial ANTIGENS, or cell surface POLYSACCHARIDES.Complement Pathway, Classical: Complement activation initiated by the binding of COMPLEMENT C1 to ANTIGEN-ANTIBODY COMPLEXES at the COMPLEMENT C1Q subunit. This leads to the sequential activation of COMPLEMENT C1R and COMPLEMENT C1S subunits. Activated C1s cleaves COMPLEMENT C4 and COMPLEMENT C2 forming the membrane-bound classical C3 CONVERTASE (C4B2A) and the subsequent C5 CONVERTASE (C4B2A3B) leading to cleavage of COMPLEMENT C5 and the assembly of COMPLEMENT MEMBRANE ATTACK COMPLEX.Complement C3: A glycoprotein that is central in both the classical and the alternative pathway of COMPLEMENT ACTIVATION. C3 can be cleaved into COMPLEMENT C3A and COMPLEMENT C3B, spontaneously at low level or by C3 CONVERTASE at high level. The smaller fragment C3a is an ANAPHYLATOXIN and mediator of local inflammatory process. The larger fragment C3b binds with C3 convertase to form C5 convertase.Syncope, Vasovagal: Loss of consciousness due to a reduction in blood pressure that is associated with an increase in vagal tone and peripheral vasodilation.Tilt-Table Test: A standard and widely accepted diagnostic test used to identify patients who have a vasodepressive and/or cardioinhibitory response as a cause of syncope. (From Braunwald, Heart Disease, 7th ed)Syncope: A transient loss of consciousness and postural tone caused by diminished blood flow to the brain (i.e., BRAIN ISCHEMIA). Presyncope refers to the sensation of lightheadedness and loss of strength that precedes a syncopal event or accompanies an incomplete syncope. (From Adams et al., Principles of Neurology, 6th ed, pp367-9)Orthostatic Intolerance: Symptoms of cerebral hypoperfusion or autonomic overaction which develop while the subject is standing, but are relieved on recumbency. Types of this include NEUROCARDIOGENIC SYNCOPE; POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME; and neurogenic ORTHOSTATIC HYPOTENSION. (From Noseworthy, JH., Neurological Therapeutics Principles and Practice, 2007, p2575-2576)Atrial Natriuretic Factor: A potent natriuretic and vasodilatory peptide or mixture of different-sized low molecular weight PEPTIDES derived from a common precursor and secreted mainly by the HEART ATRIUM. All these peptides share a sequence of about 20 AMINO ACIDS.Chemistry, Analytic: The branch of chemistry dealing with detection (qualitative) and determination (quantitative) of substances. (Grant & Hackh's Chemical Dictionary, 5th ed)Hypotension, Orthostatic: A significant drop in BLOOD PRESSURE after assuming a standing position. Orthostatic hypotension is a finding, and defined as a 20-mm Hg decrease in systolic pressure or a 10-mm Hg decrease in diastolic pressure 3 minutes after the person has risen from supine to standing. Symptoms generally include DIZZINESS, blurred vision, and SYNCOPE.Flatulence: Production or presence of gas in the gastrointestinal tract which may be expelled through the anus.Institutionalization: The caring for individuals in institutions and their adaptation to routines characteristic of the institutional environment, and/or their loss of adaptation to life outside the institution.Heartburn: Substernal pain or burning sensation, usually associated with regurgitation of gastric juice into the esophagus.Drug-Related Side Effects and Adverse Reactions: Disorders that result from the intended use of PHARMACEUTICAL PREPARATIONS. Included in this heading are a broad variety of chemically-induced adverse conditions due to toxicity, DRUG INTERACTIONS, and metabolic effects of pharmaceuticals.Diagnostic Techniques and Procedures: Methods, procedures, and tests performed to diagnose disease, disordered function, or disability.Abbreviations as Topic: Shortened forms of written words or phrases used for brevity.Digestive System: A group of organs stretching from the MOUTH to the ANUS, serving to breakdown foods, assimilate nutrients, and eliminate waste. In humans, the digestive system includes the GASTROINTESTINAL TRACT and the accessory glands (LIVER; BILIARY TRACT; PANCREAS).

Capture of a dimeric intermediate during transthyretin amyloid formation. (1/93)

Point mutations in the human plasma protein transthyretin are associated with the neurological disorder familial amyloidosis with polyneuropathy type 1. The disease is characterized by amyloid fibril deposits causing damage at the site of deposition. Substitution of two amino acids in the hydrophobic core of transthyretin lead to a mutant that was very prone to form amyloid. In addition, this mutant has also been shown to induce a toxic response on a neuroblastoma cell line. Renaturation of the transthyretin mutant at low temperature facilitated the isolation of an amyloid-forming intermediate state having the apparent size of a dimer. Increasing the temperature effectively enhanced the rate of interconversion from a partly denatured protein to mature amyloid. Using circular dichroism the beta-sheet content of the formed mature fibrils was significantly lower than that of the native fold of transthyretin. Morphology studies using electron microscopy also indicated a temperature-dependent transformation from amorphous aggregates toward mature amyloid fibrils. In addition, 1-anilino-8-naphtalenesulfonate fluorescence studies suggested the loss of the thyroxin-binding channel within both the isolated intermediate and the mature fibrils.  (+info)

Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. (2/93)

Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by extracellular deposition of transthyretin (TTR) amyloid fibrils, particularly in the peripheral nervous system. No systematic immunohistochemical data exists relating TTR deposition with FAP progression. We assessed nerves from FAP patients in different stages of disease progression (FAP 0 to FAP 3) for TTR deposition by immunohistochemistry, and for the presence of amyloid fibrils by Congo Red staining. The nature of the deposited material was further studied by electron microscopy. We observed that early in FAP (FAP 0), TTR is already deposited in an aggregated nonfibrillar form, negative by Congo Red staining. This suggested that in vivo, preamyloidogenic forms of TTR exist in the nerve, in a stage before fibril formation. Cytotoxicity of nonfibrillar TTR was assessed in nerves of different FAP stages by immunohistochemistry for macrophage colony-stimulating factor. FAP 0 patients already presented increased axonal expression of macrophage colony-stimulating factor that was maintained in all other stages, in sites related to TTR deposition. Toxicity of synthetic TTR fibrils formed in vitro at physiological pH was studied on a Schwannoma cell line by caspase-3 activation assays and showed that early aggregates but not mature fibrils are toxic to cells. Taken together, these results show that nonfibrillar cytotoxic deposits occur in early stages of FAP.  (+info)

Myocardial muscarinic receptor upregulation and normal response to isoproterenol in denervated hearts by familial amyloid polyneuropathy. (3/93)

BACKGROUND: Patients with familial amyloid polyneuropathy, a rare hereditary form of amyloidosis, have progressive autonomic neuropathy. The disease usually does not induce heart failure but is associated with sudden death, conduction disturbances, and an increased risk of complications during anesthesia. Although cardiac sympathetic denervation has been clearly demonstrated, the postsynaptic status of the cardiac autonomic nervous system remains unelucidated. METHODS AND RESULTS: Twenty-one patients were studied (age, 39+/-11 years; normal coronary arteries; left ventricular ejection fraction 68+/-9%). To evaluate the density and affinity constants of myocardial muscarinic receptors, PET with (11)C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, was used. Cardiac beta-receptor functional efficiency was studied by the heart rate (HR) response to intravenous infusion of isoproterenol (5 minutes after 2 mg of atropine, 5, 10, and 15 ng/kg per minute during 5 minutes per step). The mean muscarinic receptor density was higher in patients than in control subjects (B'(max), 35.5+/-8.9 versus 26.1+/-6.7 pmol/mL, P=0.003), without change in receptor affinity. The increase in HR after injection of atropine as well as of MQNB was lower in patients compared with control subjects despite a similar basal HR (DeltaHR after atropine, 11+/-21% versus 62+/-17%; P<0.001), consistent with parasympathetic denervation. Incremental infusion of isoproterenol induced a similar increase in HR in patients and control subjects. CONCLUSIONS: Cardiac autonomic denervation in familial amyloid polyneuropathy results in an upregulation of myocardial muscarinic receptors but without change in cardiac beta-receptor responsiveness to catecholamines.  (+info)

Results of liver transplantation for familial amyloid polyneuropathy type I in Brazil. (4/93)

Familial amyloid polyneuropathy type I (FAP-I) is an inherited amyloidosis secondary to systemic deposition of amyloid fibrils containing mutant transthyretin (TTR) variants. The disease has a progressive clinical course and is usually fatal 10 years after its onset. TTR is mainly produced in hepatocytes, and liver transplantation (LT) has been proposed as an effective treatment for FAP-I. The aim of this study is to evaluate the results of LT for FAP-I in Brazil and analyze prognostic factors associated with survival after surgery. Twenty-four patients (median age, 36 years; range, 25 to 52 years) who underwent LT with the diagnosis of FAP-I were evaluated. Surgery was uneventful in all but six patients who died of complications of primary liver nonfunction (n = 1), cardiogenic shock (n = 1), sepsis (n = 3), and hepatic artery thrombosis (n = 3). Overall 1- and 5-year survival rates were 70% and 58%, respectively. Most patients had stabilization or improvement of symptoms after a median follow-up of 36 months (range, 14 to 82 months). Survivors had a shorter disease duration before LT (median, 6 years; range, 2 to 17 years v 9 years; range, 7 to 12 years; P =.02), greater albumin levels (median, 4 g/dL; range, 3 to 4.7 g/dL v 3.6 g/dL; range, 2.6 to 4.1 g/dL; P =.03), and greater modified body mass index scores (median, 735; range, 502 to 1,432 v 659; range, 411 to 803; P =.04) compared with nonsurvivors. However, only disease duration and albumin levels were independently associated with survival in multivariate analysis. In conclusion, LT is an effective therapy for FAP-I. Mortality after surgery is associated with poor nutritional status and long-standing disease before LT. Thus, LT should be performed as early as possible after the onset of FAP-I symptoms to avoid major disability and improve survival.  (+info)

Long-term follow-up of survival of liver transplant recipients with familial amyloid polyneuropathy (Portuguese type). (5/93)

Portuguese type familial amyloid polyneuropathy is a dominantly inherited neuropathic amyloidosis caused by a mutant transthyretin (TTR). Because TTR is produced mainly by the liver, liver transplantation (LT) abolishes production of the amyloidogenic variant TTR. To date, the procedure appears to halt the progress of the disease. However, long-term outcome is unknown. The aim of the present study is to evaluate the survival of our initial group of unselected liver transplant recipients with FAP. Seventy patients, 51 transplant recipients and a control group of 19 nontransplantation patients, with disease onset before the age of 55 years were included on the study. Transplant recipients were divided into two categories: (1) early series, with patients followed up for 5 years or longer, and (2) new series, with patients followed up for 1 to 5 years. Nonparametric statistical methods were used. Binary regression analyses were performed by stepwise logistic regression and Cox proportional hazard regression. Survival analysis was performed using Kaplan-Meier analysis, the Cox-Mantel test. Survival analyses and Cox proportional hazard regression analysis were performed from disease onset, not from LT. Significantly decreased survival was noted for transplant recipients with a modified body mass index (mBMI) less than 600 compared with the control group (P < .05). A significant difference in survival also was observed between transplant recipients with an mBMI greater than 600 at the time of LT compared with those with an mBMI less than 600 (P < .02). mBMI and age at LT had a significant impact on survival; whereas late deaths were related to age at LT, early deaths were related to mBMI. The cumulative 10-year survival rate after disease onset was 94% in the new series, with one early death (< 6 months) after LT, compared with a 78% survival rate and eight early deaths in the early series (P = .1).  (+info)

Effect of the intestinal flora on amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy. (6/93)

Familial amyloidotic polyneuropathy (FAP) is a hereditary disease characterized by the systemic accumulation of amyloid fibrils. A mutant transthyretin (TTR) gene is mainly responsible for the disease. However, the variable age of onset and low penetrance might be due to environmental factors, one of which is the intestinal flora. Three types of intestinal flora were introduced into a transgenic (Tg) mouse FAP model, 6.0-hMet30. The CV1 and CV2 group transgenic mice were transferred with the intestinal flora from two different mouse facilities housed under conventional conditions, and the SPF group transgenic mice were kept under specific pathogen free conditions in our facility. All the mice were maintained under controlled temperature, humidity and bacterial conditions. Over a period of 28 months, amyloid was not deposited in the SPF and CV1 groups. In contrast, amyloid was deposited in the esophagus and small intestine of two of the three CV2 mice at 18 months. Many neutrophils infiltrated the lesions. The numbers of tissue neutrophils were higher in the CV2 group than in the SPF and CV1 groups at 18 months. The CV2 flora included fewer gram-positive anaerobic cocci as well as higher proportions of yeasts, staphylococci and enterobacteriaceae compared with the SPF and CV1 flora. These findings suggest that the intestinal flora plays an important role in amyloid deposition.  (+info)

Evidence for early cytotoxic aggregates in transgenic mice for human transthyretin Leu55Pro. (7/93)

Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant disorder characterized by systemic extracellular deposition of transthyretin (TTR) amyloid fibrils. Several groups have generated transgenic mice carrying human TTR Val30Met, the most common mutation in FAP. To study amyloidogenicity and cytotoxicity of different TTRs, we produced transgenic mice expressing human TTR Leu55Pro, one of the most aggressive FAP-related mutations. TTR deposition and presence of amyloid fibrils was investigated and compared to animals carrying the human TTR Val30Met gene kept under the same conditions. Deposition in a C57BL/6J background (TTR-Leu55Pro mice) and in a TTR-null background [TTR-Leu55Pro X TTR-knockout (KO) mice] was compared. Animals in a C57BL/6J background presented early (1 to 3 months) nonfibrillar TTR deposition but amyloid was absent. In a TTR-null background, presence of amyloid fibrils was detected starting at 4 to 8 months with a particular involvement of the gastrointestinal tract and skin. This data suggested that TTR homotetramers are more prone to fibril formation than TTR murine wild-type/human mutant heterotetramers. The nature of the deposited material was further investigated by immunocytochemistry. Both amorphous aggregates and small TTR fibrils were present in TTR-Leu55Pro X TTR-KO transgenics. We observed that these TTR deposits mimic the toxic effect of TTR deposits in FAP: animals with TTR deposition, present approximately twofold increased levels of nitrotyrosine in sites related to deposition. The TTR-Leu55Pro X TTR-KO mice here described are an important tool for the dual purpose of investigating factors involved in amyloidogenesis and in cytotoxicity of deposited TTR.  (+info)

Familial ATTR amyloidosis: microalbuminuria as a predictor of symptomatic disease and clinical nephropathy. (8/93)

BACKGROUND: Portuguese type familial amyloid polyneuropathy (FAP) is a neuropathic amyloidosis caused by a mutant transthyretin (TTR). Varying degrees of renal involvement have been reported. Our aim was to assess the value of microalbuminuria (MA) for predicting clinical neurological disease and overt nephropathy in TTR-related amyloidosis. METHODS: All subjects had the TTR Val30Met mutation, and were recruited between 1993 and 1999. We have prospectively evaluated 22 asymptomatic gene carriers (7 male, 15 female; mean age 41.6+/-9.6 years) and 32 patients with neuropathy (14 male, 18 female; 36.8+/-8.8 years, on average, 33.0+/-9.3 years at the onset of neuropathy). We measured urinary albumin excretion every year, if asymptomatic, or every 6 months if already affected. Kidney biopsies were performed in patients with normal urinary albumin excretion, MA, and overt nephropathy, respectively. RESULTS: In asymptomatic carriers, persistent MA was detected in eight (36%) subjects. The presence of MA in asymptomatic gene carriers, compared with those having normal urinary albumin excretion, conferred a 4.8-fold risk of developing neuropathy, usually within the subsequent 3 years. Once neurological signs appeared, nephropathy, manifested as MA, progressed to overt nephropathy in one-half of subjects. In patients with neuropathy, 24 (75%) had MA during follow-up: evolution towards clinical renal disease occurred in 14 (58%) and renal failure occurred in five (21%), always after a course of MA. Proteinuria or renal failure without prior persistent MA were never observed in the present patient cohort. Histopathological evaluation did not reveal glomerular lesions other than amyloid deposits to explain abnormal urinary albumin excretion. The amount of mesangial and vascular-pole amyloid deposits was correlated with the degree of albuminuria. CONCLUSIONS: Microalbuminuria represents the first stage of clinical TTR amyloid nephropathy and is premonitory of neuropathy. Its presence identifies a subgroup of patients who are more prone to develop overt nephropathy. Screening of MA may be important to assess disease onset and to recommend liver transplantation in individuals at risk.  (+info)

  • The assessment and investigation of a possible neuropathy is one of the most common clinical problems facing the general neurologist. (
  • We examined the DNA analysis of familial amyloid polyneuropathy (FAP) patients and their families from Nagano and Hiroshima prefectures in Japan using recombinant DNA techniques and compared the results with the clinical features. (
  • Involvement of cranial nerves (for example, facial numbness or weakness, oculomotor disturbance) in an acute inflammatory neuropathy is helpful in excluding a cord lesion with a pseudo-lower motor neurone pattern of presentation, as may occur in acute myelopathies. (
  • Few peripheral neuropathies are associated with pure or predominantly small fiber involvement. (
  • A parallel focus in this laboratory is to use the previously described technique to diagnose human neuropathies involving small-diameter nociceptive nerves (small-fiber neuropathy). (