Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031117 (peripheral neuropathy)
 10,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial amyloidotic polyneuropathy (FAP) with a mutation in position 30 of transthyretin (TTR) (previously called prealbumin) is an autosomal dominant inherited disorder characterized by varying degrees of peripheral neuropathy, nephropathy, gastrointestinal problems, and vitreous amyloid. We have earlier diagnosed homozygosity for the TTR-Met30-gene using Southern analysis in four Swedish individuals. We have found it possible to detect homozygosity for the Met-30 mutation by amplifying discrete regions of the TTR-gene using polymerase chain reaction (PCR), and the amplification products restricted with NsiI analysed by gel electrophoresis. Clinical data on seven homozygous individuals, including three new cases, are presented.
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PMID:Homozygosity for the transthyretin-Met30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences. 135 8

The autosomal dominant prealbumin amyloidoses are late-onset disorders characterized by varying degrees of peripheral neuropathy, nephropathy and cardiomyopathy. To date, seven different single amino acid mutations in the plasma protein prealbumin (transthyretin) have been found to be associated with amyloidosis and each is the result of a single nucleotide change in the prealbumin gene. By virtue of the restriction endonuclease sites created by the point mutations which give rise to the protein variants, direct DNA tests using Southern analysis have already been developed for detection of the Met-30, Ile-33, Ala-60, Tyr-77 and Ser-84 prealbumin genes. As an alternative to Southern analysis, we have amplified discrete regions of the prealbumin gene using polymerase chain reaction (PCR) and used restriction enzyme analysis of the PCR products to detect the Met-30, Ala-60, Tyr-77 and Ser-84 prealbumin genes after agarose gel electrophoresis and staining with ethidium bromide. In comparison to Southern analysis these alternative tests yield results much more quickly and avoid the use and handling of radioactively labeled probes.
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PMID:Hereditary amyloidosis: detection of variant prealbumin genes by restriction enzyme analysis of amplified genomic DNA sequences. 215 45

The slow axonal transport of proteins radiolabeled by incorporation of [35S]methionine was studied in motor nerves of rats subjected to chronic hypoxia. The conditions involved exposure to an atmosphere of 8-10% oxygen for periods of 3, 5, or 10 weeks. An experimentally verified computer model predicted a drop in mean endoneurial oxygen tension from 30.5 to 19 mm Hg, despite a measured increase in circulating hemoglobin from 16 to 22 g%. Nerve conduction velocity was unaffected during the early stages of hypoxia. After 10 weeks of hypoxia, conduction velocity still appeared normal in the sciatic nerve but was reduced in the caudal nerve by 2.5-4.5 m/s. At no time, however, was there evidence of impaired slow axonal transport, which proceeded with a mean velocity between 1 and 2 mm/day. Another set of experiments was performed to evaluate slow axonal transport in motor nerves of rats with peripheral neuropathy induced by the toxicant, p-bromophenylacetylurea. The results suggested a lower transport velocity in rats showing total hind-limb paralysis as compared with rats showing only mild to moderate motor dysfunction. The difference, however, could have reflected accelerated transport in mild neuropathy. In our view, the observations in experimental hypoxia- and toxicant-induced neuropathy are noteworthy for the resistance of slow transport to perturbation of the neuronal environment.
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PMID:Slow axonal transport in experimental hypoxia and in neuropathy induced by p-bromophenylacetylurea. 244 41

To elucidate the pathogenesis of the peripheral neuropathy associated with hypoglycemia the anterograde fast component (aFC) of axonal transport was studied in nondiabetic rats during acute and prolonged insulin-induced hypoglycemia and in streptozocin-diabetic (STZ-D) rats with acute hypoglycemia. [35S]methionine and [3H]fucose were injected into the dorsal root ganglion (L5) to label protein and glycoprotein, respectively. During the 4 h of transport, thigh temperature was maintained constant. Acute severe hypoglycemia (1.5 +/- 0.2 mM) was associated with a 36% decrease in the amount of aFC (2.3 +/- 0.7% in the test group vs. 3.6 +/- 0.8% in the controls), whereas transport velocity was unaffected. Prolonged hypoglycemia, obtained by pretreatment with insulin for 3 days, prevented the decrease in amount of aFC. In STZ-D rats, acute severe hypoglycemia (1.5 +/- 0.6 mM) produced a similar but less-pronounced decrease of aFC. We conclude that hypoglycemia is associated with alterations in axonal transport that could play a role in development of neuropathy. Prolonged hypoglycemia protects axonal transport against the effects of glucopenia, and an untreated diabetic state maintained for several days has a partially protective effect against episodes of hypoglycemia.
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PMID:Anterograde fast component of axonal transport during insulin-induced hypoglycemia in nondiabetic and diabetic rats. 355 82

The first instance of familial amyloidotic polyneuropathy affecting a Jewish family is reported. Vitreous opacities were its presenting feature in the father at age 30 and the son at 25. Severe autonomic dysfunction and progressive peripheral neuropathy affecting initially the lower extremities soon followed. Death, suicidal in the son, occurred after seven and four years of illness. Their amyloid contained three proteins-an entire variant monomer of prealbumin, glycine replacing threonine as residue 49, and both products of its cleavage at the point of substitution. Lower limb familial amyloidotic polyneuropathy has been recorded in many families in Portugal, Sweden and Japan and occasionally in families of various ethnic stocks. This ethnic diversity prompts consideration of genetic heterogeneity. Differentiation on a genetic basis is forestalled since all pedigrees are compatible with autosomal dominant transmission and clinical data are marred by observer variance, even regarding vitreous opacities. Notwithstanding, an isolated British family is unique in the frequent occurrence of intractable peptic ulceration, cataracts, deafness and renal disease not attributable to amyloidosis and a striking predominance of males afflicted. Biochemically, monomeric prealbumin has been demonstrated by electrophoretic and immunologic techniques as the single protein constituent of amyloids isolated from Portuguese, Japanese and Swedish patients. The variant prealbumin of Japanese amyloid is characterised by methionine replacing valine as residue 30 and is identical to that found in plasma (but not as yet in amyloid) of affected Swedes. These limited data suggest that: (a) derivation of their amyloids from prealbumin is the biochemical common denominator of lower limb familial amyloidotic neuropathies regardless of the ethnic derivation of the afflicted; (b) to the extent that ethnic diversity reflects genetic heterogeneity, this will be demonstrable in the amyloid (and hopefully in the plasma) of the afflicted as entity-specific variant prealbumin monomers distinguished by different single amino acid substitutions; (c) on clinical and biochemical grounds, lower limb familial amyloidotic neuropathies include at least three genetic entities. In the upper limb and facial forms of familial amyloidotic polyneuropathy first recorded in Swiss and Finns respectively, the differences in their patterns of neurological disease and ocular lesions could be the result of their amyloids deriving from proteins other than prealbumin.
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PMID:Amyloidotic polyneuropathy in a Jewish family. Evidence for the genetic heterogeneity of the lower limb familial amyloidotic neuropathies. 385 86

The accumulation of 3H-fucose labelled glycoprotein and 35S-methionine labelled protein carried by the retrograde axonal transport in the sensory fibres of the sciatic nerve was examined on the day after injection of streptozotocin in rats. The accumulation of fucose-label was reduced (2.8 +/- 0.4 (SD) versus 2.1 +/- 0.5 (arbitrary units), 2p = 0.0044) indicating a decreased retrograde flux of glycoproteins. This early transport abnormality could have a key role in the development of peripheral neuropathy in diabetes.
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PMID:Retrograde axonal transport. A possible role in the development of neuropathy. 616 98

This review focuses on the biochemical and clinical aspects of methylation in neuropsychiatric disorders and the clinical potential of their treatment with ademetionine (S-adenosylmethionine; SAMe). SAMe is required in numerous transmethylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAMe is intimately linked with folate and vitamin B12 (cyanocobalamin) metabolism, and deficiencies of both these vitamins have been found to reduce CNS SAMe concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, myelopathy and peripheral neuropathy. SAMe has a variety of pharmacological effects in the CNS, especially on monoamine neurotransmitter metabolism and receptor systems. SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-1 (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders.
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PMID:The clinical potential of ademetionine (S-adenosylmethionine) in neurological disorders. 752 20

Familial amyloidotic polyneuropathy (FAP) is an autosomal inherited disease, characterized by extracellular amyloid deposits and by peripheral neuropathy. Amyloid fibrils derived from most types of FAP consist of variant transthyretin (TTR) with single amino acid substitutions, and methionine 30 TTR is the most common variant TTR. TTR is mainly produced in the liver and the choroid plexus. Biochemical and molecular biological techniques have been revealing the amyloidogenicity of variant TTR in vitro and in vivo using the transgenic mouse as a model. It will be important for the development of effective therapy to find out the factors, other than variant TTR, which affect amyloid deposition and define the tissue specificity of amyloid.
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PMID:Genetic abnormalities and pathogenesis of familial amyloidotic polyneuropathy. 770 38

Familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant disorder. Progressive peripheral and autonomic neuropathy are associated with neural and visceral deposition of amyloid, derived most commonly from the Met-30 variant of the plasma protein transthyretin. We have reported previously that orthotopic liver transplantation causes prompt replacement of variant transthyretin by the donor wild-type in the plasma. We now report clinical outcome 1-2 years after transplantation. Three of the first four patients have improved general wellbeing, walking ability, and bowel function, and one of them has regained normal bladder and bowel function. There has been little objective improvement in peripheral neuropathy. The fourth patient, who had the most severe neurological deficits and a complicated postoperative course, has not improved but there has been no further deterioration in contrast to the inexorable progression before transplantation. Quantitative scintigraphy with radiolabelled serum amyloid P component showed visceral amyloid deposits in all three patients studied; in two who were followed serially the deposits regressed after transplantation in association with the clinical improvement. Another FAP patient who was also monitored prospectively for 2 years but who did not undergo transplantation, showed, as expected, progression of neuropathy and increased visceral amyloid deposition. Liver transplantation does therefore have important benefits in FAP during the first 2 years after surgery. Neurological decline is halted and amyloid deposits can be mobilised. The best timing and long-term results of the procedure must now be established.
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PMID:Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. 809 3

The literature on folate related neuropathy has been reviewed. Twenty patients fulfilled the following criteria (a) they presented with neurological findings for which no other cause could be found (b) the serum or red cell and/or the CSF folate was low (c) the serum vitamin B12 or vitamin B12 absorption was normal and (d) they showed a significant response to folic acid. Ten presented with a peripheral neuropathy, eight with subacute combined degeneration of the cord and two with a myelopathy. In two patients the neuropathy occurred when treatment for congenital malabsorption of folate--an isolated lesion affecting folate alone--lapsed. Two patients with subacute combined degeneration died and posterio-lateral sclerosis of the cord was confirmed at autopsy. Three patients were mentally retarded and nine showed mental changes which also responded to folate in addition to the neurological disorder. A single biochemical reaction, the methionine synthetase reaction, is suggested as the basis for the neurological as well as the haematological consequences of both vitamin B12 and folate deficiency. The pitfalls in diagnosis are discussed and a greater awareness of the condition urged.
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PMID:Folate responsive neuropathy. 817 46


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