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)
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Amyloidosis45
- The familial amyloid neuropathies (or familial amyloidotic neuropathies, neuropathic heredofamilial amyloidosis, familial amyloid polyneuropathy) are a rare group of autosomal dominant diseases wherein the autonomic nervous system and/or other nerves are compromised by protein aggregation and/or amyloid fibril formation. (wikipedia.org)
- Fibrinogen, apolipoprotein A1, and lysozyme are associated with a closely related condition, familial visceral amyloidosis. (wikipedia.org)
- Liver transplantation has proven to be effective for ATTR familial amyloidosis due to Val30Met mutation. (wikipedia.org)
- Familial amyloid neuropathy is a slowly progressive condition characterized by the buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body's organs and tissues. (marktforschung.de)
- The neuropathic form of transthyretin amyloidosis primarily affects the peripheral and autonomic nervous systems, resulting in peripheral neuropathy and difficulty controlling bodily functions. (medlineplus.gov)
- Occasionally, people with the cardiac form of transthyretin amyloidosis have mild peripheral neuropathy. (medlineplus.gov)
- In AL amyloidosis, amyloid protein is derived from immunoglobulin light chains, and most often involves the kidneys and the heart. (nih.gov)
- Amyloidosis can affect peripheral sensory, motor or autonomic nerves and deposition of amyloid lead to degeneration and dysfunction in these nerves. (hopkinsmedicine.org)
- In cases of familial amyloidosis, genetic testing in the blood may be useful. (hopkinsmedicine.org)
- Frequencies and geographic distributions of genetic mutations in transthyretin- and non-transthyretin-related familial amyloidosis. (medscape.com)
- CONCLUSION A diagnosis of amyloidosis type V (familial amyloidosis, Finnish type, FAF/Meretoja syndrome/gelsolin related amyloidosis) was made. (bmj.com)
- 1-4 Type II LCD is associated with systemic amyloidosis as amyloidosis type V/Meretoja syndrome/familial amyloidosis, Finnish type (FAF)/gelsolin related amyloidosis (OMIM No 105120). (bmj.com)
- Autosomal-dominant transthyretin (TTR)-related amyloidosis usually manifests in the second to over sixth decade with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure. (springer.com)
- Transthyretin (ATTR) amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of amyloid fibrils composed of transthyretin (TTR). (nih.gov)
- TTR protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into amyloid fibrils, resulting in autosomal dominant hereditary amyloidosis, including familial amyloid polyneuropathy, familial amyloid cardiomyopathy and familial leptomeningeal amyloidosis. (nih.gov)
- Analogous misfolding of wild-type TTR results in senile systemic amyloidosis, now termed wild-type ATTR amyloidosis, characterised by acquired amyloid disease in the elderly. (nih.gov)
- Background: Gastrointestinal complications are common in hereditary transthyretin amyloid (ATTRm) amyloidosis. (diva-portal.org)
- 53 The Finnish type of systemic amyloidosis is characterized clinically by a unique constellation of features including corneal lattice dystrophy, and cranial neuropathy, bulbar signs, and skin changes. (malacards.org)
- Amyloidosis, Finnish Type, also known as finnish type amyloidosis , is related to amyloidosis, familial visceral and hereditary amyloidosis , and has symptoms including renal insufficiency , cardiomyopathy and nephrotic syndrome . (malacards.org)
- 71 Amyloidosis 5: A hereditary generalized amyloidosis due to gelsolin amyloid deposition. (malacards.org)
- The condition was first described in 1969, by the Finnish ophthalmologist Jouko Meretoja, and is also known as Familial amyloid neuropathy type IV, Meretoja syndrome, Hereditary amyloidosis, Finnish type. (wikipedia.org)
- It is a form of amyloidosis, where the amyloid complexes are formed from fragments of the protein gelsolin in the plasma, due to a mutation in the GSN gene (c.654G>A or c.654G>T). Wrinkly skin syndrome List of cutaneous conditions Finnish heritage disease Rapini, Ronald P. (wikipedia.org)
- Transthyretin (TTR) amyloidosis is a rare disorder in which the TTR protein forms amyloid fibrils that accumulate in peripheral nerves, the heart, and other organs throughout the body. (alzforum.org)
- PNP caused by AL-amyloidosis there are also hereditary amyloidotic neuropathies. (centerwatch.com)
- Report covers products from therapy areas Metabolic Disorders, Central Nervous System and Cardiovascular which include indications Familial Amyloid Neuropathies, Amyloidosis, Amyloid Cardiomyopathy, Familial Amyloid Cardiomyopathy, Alzheimer's Disease, Cardiomyopathy and Neuropathy. (reportsnreports.com)
- Autonomic description in patients with very early TTR amyloidosis (Familial Amyloid Polyneuropathy). (neurology.org)
- Thirty-three patients were selected from a cohort of patients with TTR amyloidosis that fulfilled the diagnostic criteria: a positive amyloid mutation, stage 0 or I in Coutinho's classification, and abnormal neurophysiologic or cardiologic tests that would show initiation of the disease. (neurology.org)
- Hereditary (also called familial) transthyretin amyloidosis is a rare disease due to an anomaly (mutation) of part of your DNA (gene). (amyloidosisalliance.org)
- TTR amyloidosis mainly affects the nerves (neuropathy), the heart, but also, more rarely, the eyes and the kidneys. (amyloidosisalliance.org)
- The systemic amyloidosis types are all very different from each other with respect to the biochemical nature of the amyloid deposit. (bu.edu)
- The amyloid fibrils in this type of amyloidosis are made up of immunoglobulin light chain proteins (kappa or lambda). (bu.edu)
- Secondary amyloidosis is caused by a chronic infection or an inflammatory disease such as rheumatoid arthritis, familial Mediterranean fever, osteomyelitis, or granulomatous ileitis. (bu.edu)
- The abnormal TTR protein deposits as amyloid fibrils: thus, it is termed ATTR amyloidosis. (bu.edu)
- Familial amyloid polyneuropathy (FAP), also called transthyretin-related hereditary amyloidosis , transthyretin amyloidosis abbreviated also as ATTR ( hereditary form), or Corino de Andrade's disease , is an autosomal dominant neurodegenerative disease. (pharmaceuticalintelligence.com)
- The differential diagnosis should include diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy (see this term), and light chain (AL), gelsolin and apolipoprotein A1 amyloidosis (see these terms). (pharmaceuticalintelligence.com)
- Amyloid deposition in inflammatory syndromes is amplified by the underlying inflammatory state, significantly increasing morbidity and mortality, especially in the case of renal amyloidosis. (medscape.com)
- In a pathology review of 124 patients undergoing carpal tunnel release without a previous diagnosis or clinical signs of amyloidosis, 82% had amyloid deposition. (medscape.com)
- At 10-year follow-up, only 2 patients had systemic amyloidosis diagnosed after amyloid was discovered in their tenosynovium. (medscape.com)
- Kishida D, Okuda Y, Onishi M, Takebayashi M, Matoba K, Jouyama K. Successful tocilizumab treatment in a patient with adult-onset Still's disease complicated by chronic active hepatitis B and amyloid A amyloidosis. (medscape.com)
- In our body, the metabolic inborn error , Familial Amyloidosis , a familial pattern of the amyloidosis , is a dis-ease processes of an abnormal protein folding and amyloid deposits. (wellnessadvocate.com)
- RESULTS: Among the 24 patients, 20 (83.3%) had amyloidosis light chain (AL), three (12.5%) had amyloid A, and one (4.2%) had transthyretin-related type amyloidosis. (bvsalud.org)
- The cause of organ damage in amyloidosis is unclear but most likely due to the direct toxic effects of amyloid. (medreviews.com)
- Autosomal dominant amyloid polyneuropathy, associated with familial amyloidosis and most commonly involving a mutant form of the protein transthyretin (a-globulin secreted by the liver that transports retinol-binding protein and thyroxine in the blood . (lymphedemapeople.com)
- Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin. (moldiag.com)
- Tafamidis ( INN , or Fx-1006A , trade name Vyndaqel ) is a drug for the amelioration of transthyretin-related hereditary amyloidosis (also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease. (drugapprovalsint.com)
Fibrils14
- TTR gene mutations lead to decreased stability of the TTR tetramer, resulting in misfolded proteins that form amyloid fibrils and subsequent extracellular deposition of amyloid in several tissues (from peripheral and autonomic nerves to myocardium and intestine). (neurology.org)
- Familial amyloid polyneuropathy (FAP) or transthyretin (TTR) amyloid neuropathy is a rare group of autosomal dominant diseases caused by the deposition of protein and/or amyloid fibrils around the peripheral nerves and in various tissues, including the heart muscle. (researchandmarkets.com)
- Mutations of the transthyretin (TTR) gene can result in the production of unstable TTR proteins which can accumulate as amyloid fibrils. (pfizer.com)
- Amyloid fibrils can deposit in a variety of organs including the nerves, heart and kidneys, interfering with normal function. (pfizer.com)
- Subsequently, it was learned that amyloid deposits contain extremely insoluble protein fibrils that share similar morphological features (80- to 150-Å fibrils) but comprise many different proteins with no obvious sequence similarity. (pnas.org)
- Amyloid isolated from AD brain tissue consists predominantly of a family of polypeptides designated Aβ to indicate their source (amyloid plaque) and their secondary structure within the plaque-derived fibrils (β-sheet). (pnas.org)
- Specifically, supersaturated solution of amyloid peptides were metastable, but immediate fibril formation could be "seeded" by addition of a small amount of preformed amyloid fibrils comprising the identical peptide ( 3 ). (pnas.org)
- Albany, NY -- ( SBWIRE ) -- 06/22/2018 -- Familial amyloid polyneuropathy (FAP) or transthyretin (TTR) amyloid neuropathy is a genetic disorder caused by the deposition of insoluble amyloid fibrils around the peripheral nerves and in various tissues, including the heart muscle. (sbwire.com)
- Infection or inflammation causes elevation of an acute phase protein, SAA, a portion of which (AA protein) deposits as amyloid fibrils. (bu.edu)
- The tetramer has to dissociate into misfolded monomers to aggregate into a variety of structures including amyloid fibrils. (pharmaceuticalintelligence.com)
- [ 86 ] Whether causal or just associated, various autoimmune diseases can also predispose to the deposition of amyloid fibrils. (medscape.com)
- Synovial fluid may contain amyloid fibrils, although it is not particularly inflammatory, with white blood cell counts on average less than 2000 cells/µL. (medscape.com)
- Fandrich M, Meinhardt J, Grigorieff N. Structural polymorphism of Alzheimer Abeta and other amyloid fibrils. (medscape.com)
- Fandrich M. On the structural definition of amyloid fibrils and other polypeptide aggregates. (medscape.com)
Autonomic neuropathy11
- Symptoms for the disorder include limb weakness, and loss of sensation in case of peripheral neuropathy, bowel disturbance and sexual dysfunction in case of autonomic neuropathy. (researchandmarkets.com)
- In addition to the acquired causes, inherited disorders like hereditary sensory-autonomic neuropathy (HSAN), familial amyloid polyneuropathy (FAP), Tangier disease, and Fabry disease also exist. (medscape.com)
- Transthyretin (TTR) related Familial Amyloid Polyneuropathy presents as a severe sensory, motor and autonomic neuropathy. (biomedcentral.com)
- Diabetic autonomic neuropathy affects each tissue, organ and system in the whole body and is strongly involved in the development of foot ulceration. (scielo.org.za)
- Familial amyloid polyneuropathy (FAP) or transthyretin (TTR) amyloid polyneuropathy is a progressive sensorimotor and autonomic neuropathy of adulthood onset. (pharmaceuticalintelligence.com)
- hereditary sensory and autonomic neuropathy (HSAN) any of several inherited neuropathies that involve slow ascendance of lesions of the sensory nerves, resulting in pain, distal trophic ulcers, and a variety of autonomic disturbances. (thefreedictionary.com)
- Diabetes is the most common cause of autonomic neuropathy in more developed countries. (wackbag.com)
- The full APOLLO results showed improvement with patisiran relative to placebo in the primary endpoint of modified Neuropathy Impairment Score +7 (mNIS+7) and additional secondary endpoints encompassing sensory, motor, and autonomic neuropathy symptoms, as well as in exploratory cardiac endpoints, at 18 months. (huginonline.com)
- Out of the amyloid variants that affect the nervous tissue, autonomic neuropathy is common. (explainmedicine.com)
- This is due to gastroparesis as a result of the autonomic neuropathy. (explainmedicine.com)
- In one study, gastric retention was present in one third of the patients with autonomic neuropathy due to familial amiloidosis. (explainmedicine.com)
Deposits21
- Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant progressive disorder characterized by a length-dependent sensorimotor polyneuropathy with variable autonomic dysfunction and extraneurologic multisystemic manifestations (including gastrointestinal dysfunction, cardiomyopathy, nephropathy, and ocular and leptomeningeal involvement) resulting from focal deposits of amyloid. (neurology.org)
- Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). (medlineplus.gov)
- Familial amyloid polyneuropathy (FAP) is a severe hereditary disease, due to production by the liver of a genetic variant transthyretin (TTR) resulting in tissue amyloid deposits. (biomedcentral.com)
- 3,4 Vyndaqel is a novel specific transthyretin stabilizer designed to prevent the formation of these misfolded proteins and the subsequent amyloid deposits that induce neurodegeneration and decline of neurologic function. (pfizer.com)
- Complement activation products were detected on and around amyloid deposits within peripheral nerves. (elsevier.com)
- The detection of C5b-9 neoantigen on amyloid deposits demonstrated that the full complement cascade was activated. (elsevier.com)
- Complement activation on amyloid deposits and the generation of C5b-9 in vivo may contribute to bystander injury of axons in the vicinity of amyloid deposits. (elsevier.com)
- Many of these deposits were originally identified by their histochemical staining property, hence their designation as amyloid (starch-like). (pnas.org)
- Initial rectal and fat biopsies did not show amyloid deposits. (diva-portal.org)
- Only then was a repeated fat biopsy positive for amyloid deposits. (diva-portal.org)
- There are several types of eye condition which depend on where the amyloid deposits are situated in the eye and vary considerably from one patient to another. (amyloidosisalliance.org)
- Glaucoma is secondary to amyloid deposits in the evacuation mechanism of the aqueous humour. (amyloidosisalliance.org)
- Amyloid deposits are made of the beta-2 microglobulin protein that accumulated in tissues, particularly around joints, when it cannot be excreted by the kidney because of renal failure. (bu.edu)
- Localized amyloid deposits in the airway (trachea or bronchus), eye, or urinary bladder are often caused by local production of immunoglobulin light chains, not originating in the bone marrow. (bu.edu)
- Clinical observation and tissue biopsy (from the nerve or kidney, labial salivary glands, subcutaneous fat tissue or rectal mucosa) are required for a definitive diagnosis: amyloid deposits are characterized by Congo red staining on light microscopy and green birefringence on polarized light microscopy. (pharmaceuticalintelligence.com)
- The classic "shoulder-pad" sign denotes end-stage amyloid deposits in the shoulder synovium and periarticular structures, but is rarely seen. (medscape.com)
- Carpal tunnel syndrome can be the presenting sign of primary or secondary forms of amyloid, as only minimal deposits are required to impair nerve conduction. (medscape.com)
- The spherical amyloid deposits have a characteristic MRI appearance that differs from common pituitary adenomas. (medscape.com)
- Journal Article] Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. (nii.ac.jp)
- These findings suggest that amyloid deposits could infiltrate the various anatomical structures of the inner ear. (cepia.team)
- This study aimed to explore the potential of skin nerve pathologies as early and disease‐progression biomarkers and their relationship with skin amyloid deposits. (myneuronews.com)
Sensory19
- Where sensory symptoms are present with few clinical signs, the classical features of a lower motor neurone disorder may be absent and a transverse myelitis, myelopathy, or other central nervous system disorder can masquerade as a neuropathy. (bmj.com)
- A common co-occurrence, particularly in the elderly, is the combined presence of cervical spondylotic myelopathy and late onset predominantly sensory axonal neuropathy. (bmj.com)
- The typical symptoms of amyloid neuropathy are due to sensory and autonomic dysfunction. (hopkinsmedicine.org)
- Early diagnosis is pivotal for effective therapeutic options, but it is hampered by the heterogeneity of the clinical spectrum which can lead to misdiagnosis with other neurological condition/disorder such as axonal sensory-motor neuropathy (CMT2) as described in literature. (springer.com)
- The aim of our study was to search for TTR mutations in a large cohort of selected undiagnosed axonal sensory-motor neuropathy patients to establish if misdiagnosis is frequent or rare in the Italian population. (springer.com)
- The aim of our study was to search for TTR mutations in a large cohort of selected undiagnosed axonal sensory-motor neuropathy patients, classified as CMT2, to establish if CMT could occasionally mimic TTR-FAP. (springer.com)
- Painful burning feet is caused by a sensory neuropathy with small fiber involvement in more than 90% of cases. (medscape.com)
- Elderly patients who lack sural sensory responses can still be diagnosed with small fiber neuropathy. (medscape.com)
- We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. (uzh.ch)
- Diabetes mellitus Tabes dorsalis (neuropathy caused by syphilis Hansen's Disease (Leprosy) Tumors from the spinal cord Degenerative change of the spinal cord or peripheral nerve Amyloid Familial-hereditary neuropathies including Charcot-Marie Toothe Disease, Hereditary sensory neuropathy and Dejerine-Sottas Condition Pernicious Anemia. (omex3.com)
- Our results suggest that urinary liver-type fatty acid binding protein, quantitative sensory testing(QST), serum or urinary Glycer-glyceraldehyde-derived advanced glycation end product (Glycer-AGEs), small-fiber pain threshold values, and amount of the deposition of alpha-synuclein in peripheral nerves are the most useful methods to diagnose the aging-related peripheral neuropathy. (nii.ac.jp)
- Denny-Brown's sensory neuropathy hereditary sensory radicular neuropathy . (thefreedictionary.com)
- diabetic neuropathy a complication of diabetes mellitus consisting of chronic symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves. (thefreedictionary.com)
- hereditary motor and sensory neuropathy (HMSN) any of a group of hereditary polyneuropathies involving muscle weakness, atrophy, sensory deficits, and vasomotor changes in the lower limbs. (thefreedictionary.com)
- Types include hereditary sensory radicular neuropathy and familial dysautonomia . (thefreedictionary.com)
- Called also hereditary sensory neuropathy and Denny-Brown's sensory neuropathy or syndrome . (thefreedictionary.com)
- serum neuropathy a neurologic disorder, usually involving the cervical nerves or brachial plexus, occurring two to eight days after the injection of foreign protein, as in immunization or serotherapy for tetanus, diphtheria, or scarlet fever, and characterized by local pain followed by sensory disturbances and paralysis. (thefreedictionary.com)
- It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. (pubmedcentralcanada.ca)
- Small‐fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. (myneuronews.com)
Cardiac4
- Patients suffer progressive neuropathy, lose their ability to move (referred to as FAP when those are the primary symptoms) and can develop cardiac myopathy (called familial amyloid cardiomyopathy or FAC when cardiac symptoms predominate). (alzforum.org)
- Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. (diva-portal.org)
- Hypertrophic cardiomyopathy (HCM) is a heterogeneous, often familial disease, characterized by cardiac hypertrophy, predominantly affecting the interventricular septum. (diva-portal.org)
- Journal Article] Dominant cardiac type of familial amyloidotic polyneuropathy associated with a novel transthyretin variant Thr59Arg. (nii.ac.jp)
Cardiomyopathy3
- Most patients have modest involvement of internal organs, but severe systemic disease can develop in some individuals causing peripheral polyneuropathy, amyloid cardiomyopathy, and nephrotic syndrome leading to renal failure. (malacards.org)
- Amyloid heart disease mimicking hypertrophic cardiomyopathy. (diva-portal.org)
- Symptoms of disease are usually neuropathy and cardiomyopathy and occur in mid to late life. (bu.edu)
Diagnosis6
- Diagnosis is based on clinical presentation, amyloid deposition on tissue biopsy, and the diagnostic hallmark TTR mutation on genetic testing. (neurology.org)
- Diagnosis of amyloid neuropathies is based on history, clinical examination and supporting laboratory investigations. (hopkinsmedicine.org)
- While the diagnosis of the amyloidotic neuropathy can be conducted histologically, a molecular genetic approach is necessary to diagnose TTR-FAP. (centerwatch.com)
- It is very important to define the amyloid type immediately when the diagnosis is made as treatments are different. (bu.edu)
- Detection of amyloid-associated TTR mutations is required for diagnosis. (pharmaceuticalintelligence.com)
- Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. (pubmedcentralcanada.ca)
Polyneuropathies1
- Familial amyloid polyneuropathies (also known as FAPs) are a group of life-threatening multisystem amyloid disorders that are transmitted as an autosomal dominant trait, and is due to mutations of the transthyretin (TTR) gene. (explainmedicine.com)
Treatment of familial amyloid polyne2
- Globally, development of new drugs for treatment of familial amyloid polyneuropathy, and rise in the prevalence of familial amyloid polyneuropathy are the prime growth drivers of global familial amyloid polyneuropathy market. (researchandmarkets.com)
- But with long waiting periods for liver transplants, there is a need for effective treatment of familial amyloid polyneuropathy. (sbwire.com)
Corneal dystrophy1
- It is typically characterized by cranial neuropathy and lattice corneal dystrophy. (malacards.org)
Diabetic Neuropathy4
- The Norfolk QoL-DN questionnaire is a standardized 35-item patient-reported outcomes measure that is sensitive to the different features of diabetic neuropathy - small fiber, large fiber, and autonomic nerve function. (clinicaltrials.gov)
- Neuropathy impairment score (NIS), the Norfolk Quality of life (QoL) - diabetic neuropathy total score (Norfolk), this last only at baseline, 12 and 24M. (biomedcentral.com)
- Co-primary endpoints were changes in baseline scores of the modified Neuropathy Impairment Score +7 (mNIMS+7) and the Norfolk Quality of Life Diabetic Neuropathy questionnaire. (alzforum.org)
- Abstract Paranodal demyelination has been discussed as a potential mechanism of nerve fiber damage in diabetic neuropathy (DNP). (myneuronews.com)
Genetic6
- Both patients were confirmed to have transthyretin-related familial amyloid polyneuropathy (TTR-FAP) by genetic testing. (neurology.org)
- Familial hypercholesterolemia is a frequent genetic disease associated with a high lifetime risk of cardiovascular disease (CVD). (bioportfolio.com)
- Familial hypercholesterolemia is a genetic lipoprotein disorder characterized by elevated plasma low-density lipoprotein cholesterol level, (tendinous xanthomas, xanthelasmas, and premature arcus corn. (bioportfolio.com)
- Prediction of subtle left ventricular systolic dysfunction in homozygous and heterozygous familial hypercholesterolemia: Genetic analyses and speckle tracking echocardiography study. (bioportfolio.com)
- Forty-six patients were recruited for the genetic studies (21 women), 11 familial and 35 sporadic cases. (diva-portal.org)
- Distributon and genetic heterogeneity of famillial amyloid polyneuropathy in the east Asian area. (nii.ac.jp)
Systemic4
- Transthyretin (TTR)-related familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant, systemic disease. (springer.com)
- First symptoms usually occur from the second to over sixth decade of life with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure. (springer.com)
- Journal Article] Changes in pathological and biochemical findings of systemic tissue sites in familial amyloidotic polyneuropathy more than 10 years after liver transplantation. (nii.ac.jp)
- The other type consists of vasculitic neuropathy (systemic or nonsystemic), which is caused by inflammatory vasculopathy affecting small- and medium-diameter epineurial and perineurial vessels that leads to nerve ischemia or infarcts. (lymphedemapeople.com)
Autosomal3
- An autosomal recessive disorder affecting DIHYDROPYRIMIDINE DEHYDROGENASE and causing familial pyrimidinemia. (bioportfolio.com)
- Objective: To study anxiety as a variable of the mid- and long-term psychological impact of pre-symptomatic testing for three autosomal dominant late-onset disorders - Huntington's disease (HD), Machado-Joseph disease (MJD) and familial amyloid polyneuropathy (FAP) TTR V30M - in a Portuguese sample. (bvsalud.org)
- There are several familial autonomic neuropathies with autosomal dominant, autosomal recessive, or X-linked patterns of inheritance. (wackbag.com)
Gelsolin1
- The most common form of the hereditary familial amyloidotic neuropathy (FAP) is the Transthyretin-related FAP, however two other amyloidogenic proteins have been described: Apolipoprotein A-I and Gelsolin. (centerwatch.com)
Mutations2
- Familial Amyloid Polyneuropathy (FAP) is a rare, hereditary disease caused by mutations in the transthyretin (TTR) protein. (clinicaltrials.gov)
- In AD and Parkinson's disease as well, rare, early-onset forms have been linked to mutations in the fibril-forming proteins [amyloid β-protein (Aβ, see below) or its precursor, amyloid precursor protein and α-synuclein, respectively]. (pnas.org)
Disorders14
- Global Markets Direct's latest Pharmaceutical and Healthcare disease pipeline guide Familial Amyloid Neuropathies - Pipeline Review, H2 2016, provides an overview of the Familial Amyloid Neuropathies (Metabolic Disorders) pipeline landscape. (marktforschung.de)
- Global Markets Direct's Pharmaceutical and Healthcare latest pipeline guide Familial Amyloid Neuropathies - Pipeline Review, H2 2016, provides comprehensive information on the therapeutics under development for Familial Amyloid Neuropathies (Metabolic Disorders), complete with analysis by stage of development, drug target, mechanism of action (MoA), route of administration (RoA) and molecule type. (marktforschung.de)
- The Familial Amyloid Neuropathies (Metabolic Disorders) pipeline guide also reviews of key players involved in therapeutic development for Familial Amyloid Neuropathies and features dormant and discontinued projects. (marktforschung.de)
- Familial Amyloid Neuropathies (Metabolic Disorders) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. (marktforschung.de)
- The pipeline guide provides a snapshot of the global therapeutic landscape of Familial Amyloid Neuropathies (Metabolic Disorders). (marktforschung.de)
- The pipeline guide reviews pipeline therapeutics for Familial Amyloid Neuropathies (Metabolic Disorders) by companies and universities/research institutes based on information derived from company and industry-specific sources. (marktforschung.de)
- The pipeline guide reviews key companies involved in Familial Amyloid Neuropathies (Metabolic Disorders) therapeutics and enlists all their major and minor projects. (marktforschung.de)
- The pipeline guide evaluates Familial Amyloid Neuropathies (Metabolic Disorders) therapeutics based on mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. (marktforschung.de)
- The term peripheral neuropathy encompasses a wide range of disorders in which the nerves outside of the brain and spinal cord - peripheral nerves - have been damaged. (encyclopedia.com)
- For example, peripheral neuropathy is only one symptom of diseases such as amyloid neuropathy, certain cancers, or inherited neurologic disorders. (encyclopedia.com)
- Indeed, abnormal protein aggregation characterizes many, if not all, neurodegenerative disorders, not just AD and Parkinson's disease, but also Creutzfeldt-Jakob disease, motor neuron diseases, the large group of polyglutamine disorders, including Huntington's disease ( 1 ), as well as diseases of peripheral tissue like familial amyloid polyneuropathy (FAP). (pnas.org)
- The autonomic neuropathies are a group of disorders in which the small, lightly myelinated and unmyelinated autonomic nerve fibres are selectively targeted. (wackbag.com)
- One type, the immune-mediated demyelinating neuropathies, includes Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and related disorders. (lymphedemapeople.com)
- In TTR-related disorders such as transthyretin familial amyloid polyneuropathy (TTR-FAP), tetramer dissociation is accelerated that results in unregulated amyloidogenesis and amyloid fibril formation. (drugapprovalsint.com)
Prevalence4
- Studies of the prevalence of neuropathy in the community are rare but suggest a figure of between 2-8%, 1 making peripheral neuropathy at least as common as stroke. (bmj.com)
- Despite this high prevalence of neuropathy, it is only a small proportion of patients with neuropathies who are referred for detailed evaluation, principally those individuals with disabling disease, or with none of the obvious risk factors such as diabetes or alcoholism. (bmj.com)
- In Portugal and Sweden where Transthyretin Related Familial Amyloid Polyneuropathy (TTR-FAP) is endemic, disease prevalence ranges from 1 in 1.000 to 1 in 10.000 people. (springer.com)
- The prevalence of familial amyloid polyneuropathy is very low across the globe. (sbwire.com)
Syndrome4
- On March 6, Ionis reported that dangerously low platelet counts forced five patients out of the company's Phase 3 trial of volanesorsen, an ASO that targets the AOEC-III gene for treatment of familial chylomicronemia syndrome, but claimed that was due to reduced levels of triglycerides. (alzforum.org)
- 10 Primary vasculitic neuropathy includes Churg-Strauss syndrome, microscopic polyangiitis, classic polyarteritis nodosa and Wegener granulomatosis. (scielo.org.za)
- entrapment neuropathy any of a group of neuropathies, such as carpal tunnel syndrome , caused by mechanical pressure on a peripheral nerve. (thefreedictionary.com)
- Autonomic neuropathies can also occur as a result of amyloid deposition, after acute infection, as part of a paraneoplastic syndrome, and after exposure to neurotoxins including therapeutic drugs. (wackbag.com)
Proteins2
- Familial amyloid polyneuropathy (FAP) is a life-threatening disease that can be caused by a mutation in the transthyretin ( TTR ) gene, one of the precursor proteins of amyloid. (neurology.org)
- Currently over 30 different proteins are found to cause amyloid deposition. (sbwire.com)
Symptoms2
- Treatment of amyloid neuropathies is directed at both preventing further deposition of amyloid in peripheral nerves and treating painful symptoms. (hopkinsmedicine.org)
- Symptoms can occur in any organ of the body and include heart failure, protein in the urine or kidney failure, enlarged liver, neuropathy or enlarged tongue. (bu.edu)
Disease16
- Certain neuropathies co-exist with CNS disease, such as vitamin B12 deficiency, adrenomyeloneuropathy, neuroacanthocytosis, spinocerebellar syndromes, to name but a few of many. (bmj.com)
- Predicting cardiovascular disease in familial hypercholesterolemia. (bioportfolio.com)
- Estimated costs of hospitalization due to coronary artery disease attributable to familial hypercholesterolemia in the Brazilian public health system. (bioportfolio.com)
- A few studies examined association between familial hypercholesterolemia (FH) and atherosclerotic cardiovascular disease (ASCVD) in Asians with low levels of serum cholesterol. (bioportfolio.com)
- The most common of the inherited peripheral neuropathies in the United States is Charcot-Marie-Tooth disease, which affects approximately 125,000 persons. (encyclopedia.com)
- Peripheral neuropathy may develop as a primary symptom, or it may be due to another disease. (encyclopedia.com)
- The NEURO-TTR trial is testing the antisense oligonucleotide therapy IONIS-TTR Rx in people with familial amyloid neuropathy (FAP), a fatal disease caused by aggregation of the transthyretin protein. (alzforum.org)
- Medical or surgical treatment of the underlying chronic infection or inflammatory disease can slow down or stop the progression of this type of amyloid. (bu.edu)
- Amyloid and Alzheimer's disease: inside and out. (medscape.com)
- Some diseases in this group have been numbered: types I and II are varieties of Charcot-Marie-Tooth disease and type III is progressive hypertrophic neuropathy . (thefreedictionary.com)
- progressive hypertrophic neuropathy a slowly progressive familial disease beginning in early life, marked by hyperplasia of interstitial connective tissue, causing thickening of peripheral nerve trunks and posterior roots, and by sclerosis of the posterior columns of the spinal cord, with atrophy of distal parts of the legs and diminution of tendon reflexes and sensation. (thefreedictionary.com)
- Differential difficulties exist in diagnosing the disorder, and familial amyloid polyneuropathy directly mimics the disease. (medreviews.com)
- Without early therapy, however, the disease has a dismal prognosis, and peripheral neuropathy usually persists or worsens despite therapy and improvement in other organs. (medreviews.com)
- Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. (drugapprovalsint.com)
- Abstract Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer's disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). (myneuronews.com)
- Abstract BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). (myneuronews.com)
Amyloidotic neuropathies2
- Aside from acquired amyloidotic neuropathies (e.g. (centerwatch.com)
- More recent studies provided evidence for the presence of hereditary amyloidotic neuropathies amongst the German population and that they are currently underdiagnosed. (centerwatch.com)
Clinical2
- The assessment and investigation of a possible neuropathy is one of the most common clinical problems facing the general neurologist. (bmj.com)
- 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. (elsevier.com)
Protein called amyloid1
- an illness where a protein called amyloid is deposited in tissues and organs. (hopkinsmedicine.org)
Vasculitic2
- The primary pathology of vasculitic neuropathies is a vasculitis of the small and medium-sized vessels in the peripheral nervous system 9 with an area of infarction in the nerve. (scielo.org.za)
- Vasculitic neuropathies are classified into primary and secondary vasculitides. (scielo.org.za)
Fibril protein2
- Saraiva MJ, Birken S, Costa PP. Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. (medscape.com)
- Amino acid sequence homology between the amyloid fibril protein and human plasma gelsoline. (moldiag.com)
Involvement2
- 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. (bmj.com)
- Few peripheral neuropathies are associated with pure or predominantly small fiber involvement. (medscape.com)
Mutation1
- Patients with familial amyloid polyneuropathy are born with a mutation in the TTR gene which leads to the disorder. (sbwire.com)
Precursor3
- The aggregation of one precursor protein leads to peripheral neuropathy and/or autonomic nervous system dysfunction. (wikipedia.org)
- The importance of the Aβ42 form was confirmed by the finding that selective elevation of Aβ42 level occurs in all three early-onset FAD genes identified to date: amyloid precursor protein, presenilin-1, and presenilin-2 ( 4 ). (pnas.org)
- Single strand conformation polymorphism analysis and direct DNA sequencing revealed a variant AGC (serine) codon at amino acid position 84 of the amyloid precursor protein, transthyretin (TTR). (elsevier.com)
Renal2
- Some patients may develop peripheral neuropathy and renal failure. (malacards.org)
- Ultimately, many patients die from waning organ functions, including renal failure due to amyloid accumulation in the kidneys, he told Alzforum. (alzforum.org)
Patients15
- We identified 2 unrelated patients with atypical features of tongue atrophy and fasciculations in the setting of a severe neuropathy. (neurology.org)
- Medical records were reviewed from patients suspected of having amyloid polyneuropathy seen in the Neuromuscular Clinic at the University of California, Irvine, between 2010 and 2015. (neurology.org)
- This is an open-label, single-arm study to assess the reduction of low-density lipoprotein cholesterol (LDL-C) by REGN1500 in patients with homozygous familial hypercholesterolemia (HoFH). (bioportfolio.com)
- Depending on the type of amyloid protein, patients may benefit from liver or bone marrow transplant. (hopkinsmedicine.org)
- Genotypic-phenotypic variations in a series of 65 patients with familial amyloid polyneuropathy. (medscape.com)
- BUSINESS WIRE )--Pfizer announced today that the European Commission has approved Vyndaqel ® (tafamidis) for the treatment of Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) in adult patients with stage 1 symptomatic polyneuropathy. (pfizer.com)
- Tafamidis, an oral drug that stabilizes TTR preventing amyloid deposition, was recently introduced in Europe to delay neuropathy progression in ambulatory patients. (biomedcentral.com)
- In 2014, GlaxoSmithKline paid U.S. based Isis Pharmaceuticals USD 1 million for the advancement of the Phase III study of ISIS-TTRRx in patients with familial amyloid polyneuropathy. (sbwire.com)
- Even at a very early stage of somatic neuropathy the patients showed important alterations in all autonomic tests. (neurology.org)
- [ 87 ] However, autopsy study shows that amyloid arthropathy in RA is often undiagnosed in patients with long-standing severe RA. (medscape.com)
- The Query Amyloid Late Enhancement (QALE) score, myocardial native T2, T1 and extra cellular volume fraction (ECV) were calculated for all patients. (cepia.team)
- Tafamidiswas approved by the European Medicines Agency (EMA) in 2011 under the market name Vyndaqel for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adult patients with early-stage symptomatic polyneuropathy to delay peripheral neurologic impairment. (drugapprovalsint.com)
- Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy . (drugapprovalsint.com)
- In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system ( neurodegeneration ) initially and later failure of the heart. (drugapprovalsint.com)
- Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 [SGII(PGP9.5)] and peptidergic vasoactive intestinal peptide [SGII(VIP)], and cutaneous amyloid index. (myneuronews.com)
Small-fiber neuropathy1
- 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). (ntu.edu.tw)
Neuropathic1
- Neuropathic pain due to amyloid neuropathy can be treated with anti-seizure medications, antidepressants, or analgesics including opiate drugs. (hopkinsmedicine.org)
Progression1
- Alternatively, a European Medicines Agency approved drug Tafamidis or Vyndaqel now exists which stabilizes transthyretin tetramers comprising wild type and different mutant subunits against amyloidogenesis halting the progression of peripheral neuropathy and autonomic nervous system dysfunction. (wikipedia.org)
Liver1
- The course and prognostic factors of familial amyloid polyneuropathy after liver transplantation. (medscape.com)
Tissue1
- It is a heterogenous form of amyloid deposition, mostly localized to one tissue. (explainmedicine.com)
Entrapment1
- In the same context, spondylotic radiculopathies may co-occur with upper limb entrapment neuropathies. (bmj.com)
Dysfunction2
- Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). (medscape.com)
- Familial amyloid polyneuropathy is characterized by slowly progressive, peripheral sensorimotor polyneuropathy and autonomic dysfunction. (sbwire.com)