Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0152025 (polyneuropathy)
 7,862 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Portuguese-type amyloidosis (transthyretin amyloidosis, ATTR V30M) is the most common form of systemic hereditary amyloidosis, inherited in autosomal dominant mode. The disease, also called familial amyloid polyneuropathy type I (FAP-I), is caused by a mutant transthyretin (TTR) protein, which is synthesized by the liver. A single amino acid substitution of methionine for valine at position 30 of the TTR molecule (TTR V30M) was found in Portuguese patients. The clinical disease usually manifests as a peripheral sensory, motor and autonomic neuropathy starting in the 3rd or 4th decade of life. Renal manifestations of ATTR V30M, like other amyloidoses, are different levels of proteinuria and renal insufficiency. In ATTR V30M a large amyloid deposition in the medullary zone of the kidney and tubules is characteristic. A more extensive glomerular and vascular involvement is present only in patients with renal manifestations. A prospective survey in the north of Portugal showed that a stage of microalbuminuria (MA) could precede nephropathy and neurological disease. Nephropathy in FAP-I is present in one-third of affected patients and tends to aggregate in families. The progression towards end-stage renal disease (ESRD) affects 10% of the patients, and the survival after initiation of dialysis is a mean of 21 months. Patients who progress to ESRD have a late onset of neuropathy and lower prevalence of clinical disease in their families. Liver transplantation is a widely accepted treatment for FAP-I, and combined liver-kidney transplantation is also an option for selected patients with FAP-I and ESRD.
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PMID:Portuguese-type amyloidosis (transthyretin amyloidosis, ATTR V30M). 1283 49

Type I (transthyretin Val30Met) familial amyloid polyneuropathy (FAP ATTR Val30Met) has been reported in relation to two endemic foci in Japan. These cases are characterized by a relatively young age at onset, between the second and third decade, high penetrance rate, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction, and atrioventricular nodal block requiring pacemaker implantation. In contrast to these endemic cases, because of advances in DNA diagnosis, late-onset cases of FAP ATTR Val30Met with symptoms appearing at or over 50 years of age are now recognized to occur widely throughout Japan. These cases have a male preponderance, low penetrance rate, no relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms. This type of FAP ATTR Val30Met has been overlooked because its clinical and genetic features differ from those of "typical" early-onset cases. Anticipation of age at onset is known to occur in pedigrees from the two endemic foci in Japan, with age at onset becoming younger in patients of successive generations. On the other hand, age at onset of patients in late-onset families seems to be uniformly late among the patient siblings when family history is present. Pathologic findings of the peripheral nervous system also differ in accordance with differences of clinical features. Loss of dorsal root and sympathetic ganglion neurons was severe in the early-onset cases, whereas it was only mild to moderate in the late-onset cases. Unmyelinated fibers in the biopsied sural nerve specimens of late-onset cases seemed to be relatively well preserved compared to those of previously reported early-onset cases.
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PMID:Clinicopathologic and genetic features of early- and late-onset FAP type I (FAP ATTR Val30Met) in Japan. 1464 40

Classical familial amyloid polyneuropathy may have a course with progressive renal impairment. We studied 62 patients (24 males, 38 females) with FAP, transthyretin variant V30M, and end-stage renal disease (ESRD) treated with hemodialysis, all referred to a single center over a period of 11 years. Clinical course, morbidity and survival after dialysis were analyzed. Patient's mean age at first dialysis was 51.5 +/- 10.7 years, and mean duration of neuropathy was 10.2 +/- 3.8 years. The most frequent form of presentation of FAP nephropathy was nephrotic proteinuria with renal dysfunction. In the year prior to dialysis, renal function declined rapidly, and fluid overload was the main indication to initiate treatment. The presence of decubitus ulcers, significant disability, venous catheter for definitive vascular access for long-term treatment, and permanent bladder catheter, were related to death during the first year of dialysis. The mean duration of renal replacement therapy was 21 months, with a 54.5% one year, and 38.4% two year treatment survival. However, when the duration of neurological symptoms at first dialysis exceeded 10 years, survival was significantly lower. Infections, (41% were decubitus ulcers with sepsis) were the cause of early, as well as late mortality. Early creation of vascular access for hemodialysis, surveillance of skin wounds, and intervention on neurogenic bladder are essential to improve the prognosis of ESRD in FAP.
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PMID:End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M: presentation, survival and prognostic factors. 1518 96

FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming beta-fibrils in amyloid deposits. This theory does not explain the formation of beta-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to beta-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N(delta)-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4'-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40+/-9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.
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PMID:Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy. 1528 12

Three brothers in a family with Val30Met transthyretin (TTR) amyloid polyneuropathy (FAP) in Iiyama, Japan were studied pathologically. In this family, affected members have been reported to show typical clinical features of FAP, and some have been documented to exhibit symptoms and signs of central nervous system (CNS) involvement consisting of cerebellar ataxia and pyramidal tract signs. After the original description, this family was regarded as a unique phenotype of this form of FAP; however, subsequent molecular genetic studies revealed that some patients and asymptomatic members in the family had Val30Met TTR and/or spinocerebellar ataxia type 1 (SCA1) gene mutations. In this study, pathological examination of two patients with both FAP and CNS symptoms showed (1) TTR-immunoreactive leptomeningeal and cerebrovascular amyloid deposition compatible with Val30Met TTR FAP, and (2) neuronal loss and gliosis mainly in the Purkinje cell layer, spinocerebellar system, olivo-ponto-cerebellar system, dentato-rubral system, gracile nuclei, cuneate nuclei, and various nuclei of cranial nerves, accompanied by anti-expanded polyglutamine tract antibody positive neuronal intranuclear inclusions, all of which were compatible with the pathological findings of SCA1. On the other hand, the remaining patient with FAP symptoms only showed the former pathological finding alone. The present study demonstrates, at the pathological level, that Val30Met TTR FAP and SCA1 coexist in the same family members, and that the CNS dysfunction seen in the patients in this family is ascribable to SCA1 pathology but not to CNS amyloidosis.
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PMID:Coexistence of familial transthyretin amyloidosis ATTR Val30Met and spinocerebellar ataxia type 1 in a Japanese family--a follow-up autopsy report. 1552 22

In transthyretin familial amyloid polyneuropathy (TTR-FAP), single clinical features rarely remain isolated and are usually accompanied by other symptoms. We describe a patient with TTR-FAP, who had recurrent episodes of syncope for 4 years as an overt and isolated symptom. Later, he experienced paresthesia in the hands, and impotence. Molecular analysis of the TTR gene revealed a Thr49Ala mutation. The unusual clinical presentation presents a diagnostic challenge.
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PMID:Recurrent syncope as persistently isolated feature of transthyretin amyloidotic polyneuropathy. 1572 88

Machado-Joseph disease [MJD, also spinocerebellar ataxia type 3 (SCA3)] and familial amyloid polyneuropathy type I (FAP-I or ATTR V30M) are neurodegenerative disorders, inherited in an autosomal dominant fashion, which have a high prevalence in Portugal, probably due to a founder effect. MJD and FAP-I are late-onset diseases, with symptoms emerging usually during adulthood. CGPP, which is the national reference centre for these disorders, has a genetic lab that offers diagnostic, pre-symptomatic and prenatal testing and an outpatient clinic to counsel and follow relatives at risk for hereditary ataxias, FAP-I and Huntington disease (HD). The present work is a review of our 10-year experience with psychological counselling of individuals at risk for MJD and FAP-I. Persons at risk for FAP-I may show a better response to pre-symptomatic testing than those who are at risk for MJD and HD because of the availability of liver transplantation, which may improve their health and life expectancy. Psychological well-being and specific distress of MJD and FAP-I test applicants, before undergoing genetic testing (baseline level) and 3 to 6 months after disclosure of test results, have shown a low level of change, both in identified carriers and non-carriers. A major goal of psychological characterization of at-risk individuals for MJD and FAP-I is to determine the factors that influence the uptake of genetic testing.
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PMID:Psychological aspects of pre-symptomatic testing for Machado-Joseph disease and familial amyloid polyneuropathy type I. 1663 Jan 62

FAP is characterized by progressive polyneuropathy and autonomic dysfunction and the latter consists of marked orthostatic hypotension, disturbed bowel movement, impotence and urinary incontinence. All these autonomic symptoms severely affect patient's daily activity. The precursor protein of amyloid fibrils in this disease is a variant form of transthyretin (TTR) in serum. Since TTR is produced mainly in the liver, liver transplantation has been employed for FAP patients as only one curative treatment. During the past 12 years more than 50 FAP patients underwent liver transplantation in Japan and the five-year survival rate of them was 77%. Early intervention (less than 5 years after onset) can provide a better chance of improving patients' condition after transplantation and gastrointestinal autonomic symptoms that include severe episodic nausea, vomiting, and alternating constipation and diarrhea significantly relieve shortly after operation. Preoperative clinical severity and the nutritional status of patients are correlated with their outcome after liver transplantation. Among them the presence of an autonomic failure in FAP patients seems to be contraindication for this challenging operation.
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PMID:[Autonomic dysfunction in FAP: its therapeutic effect by liver transplantation]. 1743 6

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.
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PMID:Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). 1842 77

Presymptomatic genetic testing of an untreatable disease raises clinical, ethical, legal and psychosocial questions. Investigations in specific disorders are needed to help in understanding the motivation for and the impact of genetic testing in the lives of persons at risk for these diseases. Here, we performed a longitudinal study to investigate the psychological consequences of presymptomatic genetic testing on people at risk for transthyretin-related familial amyloidotic polyneuropathy (TTR-FAP). The aim of the present study was to provide possible guidelines for genetic counselling and psychosocial support. Impact of Event Scale Revised (IES-R), Hospital Anxiety and Depression Scale (HADS) and SF-36 questionnaires were administered to 18 asymptomatic subjects before, immediately after communication of the genetic test result and after 3, 6 and 26 months. Our findings showed evidence of anxiety, depression, avoidance of the disease, and psychological distress, especially for women, including those with a negative genetic test result ("survivor guilt"). A psychological support has to be provided before and continued at long term after presymptomatic genetic testing for TTR-FAP in people with positive result as well as in those with negative result.
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PMID:Psychosocial impact of presymptomatic genetic testing for transthyretin amyloidotic polyneuropathy. 1908 1


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