Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.61 (porphobilinogen deaminase)
637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An autopsy case of a 37-year-old woman with acute porphyria is reported. The patient began to complain of severe menstrual pains, and later developed serious peripheral neuropathy and various autonomic nervous symptoms. The autopsy revealed a marked loss and degeneration of axons and myelin sheaths in the peripheral nervous system (PNS), and prominent central chromatolysis of the spinal anterior horn cells. The predominant process of the peripheral neuropathy appeared to be axonal degeneration. Biochemical analysis showed a marked increase of delta-aminolevulinic acid (ALA), porphobilinogen, uroporphyrin, and coproporphyrin in the urine, and an increase of coproporphyrin and protoporphyrin in the stools and blood. In the analysis of the enzymatic activities of the liver and bone narrow, the activity of ALA synthetase (ALA-S) was markedly increased, and the activities of both uroporphyrinogen I synthetase (URO-S) and ferrochelatase were decreased. It was characteristic in this case that the enzymatic abnormalities found in both acute intermittent porphyria (AIP) and variegate porphyria (VP) coexisted. Biochemical analysis of the sciatic nerve showed an increase of ALA-S activity and a decrease of both URO-S and ALA dehydrase activities. This was the first report that indicated the presence of abnormal activities of the heme biosynthetic enzymes in the peripheral nerves of porphyric patients. The possibility was discussed that these enzymatic abnormalities of the heme biosynthesis in the peripheral nerve itself might be strongly related to the pathogenesis of the porphyric neuropathy.
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PMID:An autopsy case of acute porphyria with a decrease of both uroporphyrinogen I synthetase and ferrochelatase activities. 608 95

Acute intermittent porphyria (AIP) is a human disease resulting from a dominantly inherited partial deficiency of the heme biosynthetic enzyme, porphobilinogen deaminase (PBGD). The frequency of the trait for AIP is 1/10,000 in most populations, but may be markedly higher (1/500) in psychiatric patients. The clinical expression of the disease is characterized by acute, life-threatening attacks of 'porphyric neuropathy' that include abdominal pain, motor and sensory neurological deficits and psychiatric symptoms. Attacks are frequently precipitated by drugs, alcohol and low caloric intake. Identical symptoms occur in other hepatic porphyrias. To study the pathogenesis of the neurologic symptoms of AIP we have generated Pbgd-deficient mice by gene targeting. These mice exhibit the typical biochemical characteristics of human AIP, notably, decreased hepatic Pbgd activity, increased delta-aminolevulinic acid synthase activity and massively increased urinary excretion of the heme precursor, delta-aminolevulinic acid after treatment with drugs such as phenobarbital. Behavioural tests reveal decreased motor function and histopathological findings include axonal neuropathy and neurologic muscle atrophy.
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PMID:Porphobilinogen deaminase deficiency in mice causes a neuropathy resembling that of human hepatic porphyria. 856 60

Acute intermittent porphyria mimics a variety of commonly occurring disorders and thus poses a diagnostic quagmire. Psychiatric manifestations include hysteria, anxiety, depression, phobias, psychosis, organic disorders, agitation, delirium, and altered consciousness ranging from somnolence to coma. Some patients develop psychosis similar to schizophrenia. Psychiatric hospitals have a disproportionate number of patients with this disorder as only difficult and resistant patients accumulate there. Presence of photosensitive porphyrins in the urine is diagnostic. When porphyrins are absent, excess of alpha aminolevulinic acid and porphobilinogen are present in the urine. The definitive test is to measure monopyrrole porphobilinogen deaminase in RBCs. This diagnosis should be entertained in the following situations: (a) unexplained leukocytosis; (b) unexplained neuropathy; (c) etiologically obscure neurosis or psychosis; (d) 'idiopathic' seizure disorder; (e) unexplained abdominal pain; (f) conversion hysteria, and (g) susceptibility to stress. Porphyria is important in psychiatry as it may present with only psychiatric symptoms; it may masquerade as a psychosis and the patient may be treated as a schizophrenic person for years; the only manifestation may be histrionic personality disorder which may not receive much attention. Diagnosis is based on a high index of suspicion and appropriate investigation. Various psychotropic drugs exacerbate acute attacks. While it is important not to use the unsafe drugs in porphyric patients, it is also imperative to look for this diagnosis in cases where these drugs produce unprecedented drug reactions.
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PMID:Porphyria: reexamination of psychiatric implications. 865 42

Acute porphyrias are inherited disorders caused by partial deficiency of specific heme biosynthesis enzymes. Clinically, porphyrias are manifested by a neuropsychiatric syndrome that includes peripheral neuropathy. Although much is known about the porphyrias' enzyme defects and their biochemical consequences, the cause of the neurological manifestations remains unresolved. We have studied porphyric neuropathy in mice with a partial deficiency of porphobilinogen deaminase (PBGD). PBGD-deficient mice (PBGD-/-) imitate acute porphyria through massive induction of hepatic delta-aminolevulinic acid synthase by drugs such as phenobarbital. Here we show that PBGD-/- mice develop impairment of motor coordination and muscle weakness. Histologically femoral nerves of PBGD-/- mice exhibit a marked decrease in large-caliber (>8 microm) axons and ultrastructural changes consistent with primary motor axon degeneration, secondary Schwann cell reactions, and axonal regeneration. These findings resemble those found in studies of affected nerves of patients with acute porphyria and thus provide strong evidence that PBGD deficiency causes degeneration of motor axons without signs of primary demyelination, thereby resolving a long-standing controversy. Interestingly, the neuropathy in PBGD-/- mice developed chronically and progressively and in the presence of normal or only slightly (twofold) increased plasma and urinary levels of the putative neurotoxic heme precursor delta-aminolevulinic acid. These data suggest that heme deficiency and consequent dysfunction of hemeproteins can cause porphyric neuropathy.
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PMID:Motor neuropathy in porphobilinogen deaminase-deficient mice imitates the peripheral neuropathy of human acute porphyria. 1020 64

The authors identified a novel mutation of the porphobilinogen deaminase (PBG-D) gene in a patient with acute intermittent porphyria presenting with severe and bilateral axonal radial motor neuropathy. Electrophysiologic studies revealed prominent involvement of distal radial nerves in the setting of mild polyneuropathy. Analysis of the PBG-D gene revealed a single base-pair insertion (887insA) in exon 14.
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PMID:Porphyria presenting with bilateral radial motor neuropathy: evidence of a novel gene mutation. 1194 Jul 7

Acute intermittent porphyria (AIP), an inborn error of metabolism, results from the deficient activity of the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD). Clinical symptoms of this autosomal dominant hepatic porphyria include episodic acute attacks of abdominal pain, neuropathy, and psychiatric disturbances. Current therapy based on intravenous heme administration is palliative and there is no way to prevent the attacks. Thus, efforts are focused on methods to replace the deficient activity in the liver to prevent the acute attacks of this hepatic porphyria. Here we explore the efficiency of a non-viral gene delivery to obtain PBGD expression in the liver of AIP transgenic mice. Four vectors were evaluated: naked DNA and DNA complexed to liposomes, polyethylenimine (PEI), and PEI-galactose, using a luciferase construct as reporter gene. The vectors were administered intravenously or directly into the portal vein with transient blood flow blockage. After tail vein injection of the DNA complexes, the liposome vector had the highest luciferase expression in lung and less in liver. When injected into the portal vein, the naked DNA had considerably higher hepatic reporter gene expression; 100 microg of naked DNA had the highest hepatic luciferase expression 24h after portal vein injection. When these vectors were used to deliver the PBGD gene into the AIP mouse model no enhancement of the endogenous PBGD activity in liver was detectable, despite the presence of the PBGD-plasmids as verified by PCR. Thus, more efficient non-viral vectors are needed to express sufficient PBGD activity over the endogenous hepatic level (approximately 30% of normal) in this murine system.
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PMID:Non-viral delivery of the porphobilinogen deaminase cDNA into a mouse model of acute intermittent porphyria. 1511 Mar 17

We report a patient with acute intermittent porphyria who presented with progressive motor neuropathy, particularly in the upper limbs. The electrophysiological studies showed an asymmetric motor neuropathy with a prominent involvement of both the radial and left peroneal nerves. During the 1-year follow-up period, 6 courses of hematin infusion, with 150 mg daily for 4 consecutive days every month, were administrated. The motor neuropathy showed a steady and gradual improvement following the hematin treatment. Molecular analysis of the porphobilinogen deaminase gene revealed a short segment deletion (1008-1019delCAGCCTGGCCAA) resulting in a truncated protein. The findings suggest that early hematin treatment is temporally associated with interval improvement of the patient's porphyric motor neuropathy.
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PMID:Acute intermittent porphyria with peripheral neuropathy: a follow-up study after hematin treatment. 1745 18

Acute intermittent porphyria (AIP) is a rare metabolic disorder characterized by mutations of the porphobilinogen deaminase gene. Clinical manifestations of AIP are caused by the neurotoxic effects of increased porphyrin precursors, although the underlying pathophysiology of porphyric neuropathy remains unclear. To further investigate the neurotoxic effect of porphyrins, excitability measurements (stimulus-response, threshold electrotonus, current-threshold relationship and recovery cycle) of peripheral motor axons were undertaken in 20 AIP subjects combined with the results of genetic screening, biochemical and conventional nerve conduction studies. Compared with controls, excitability measurements from five latent AIP patients were normal, while 13 patients who experienced acute porphyric episodes without clinical neuropathy (AIPWN) showed clear differences in their responses to hyperpolarizing currents (e.g. reduced hyperpolarizing I/V slope, P < 0.01). Subsequent mathematical simulation using a model of human axons indicated that this change could be modelled by a reduction in the hyperpolarization-activated, cyclic nucleotide-dependent current (I(H)). In contrast, in one patient tested during an acute neuropathic episode, axons of high threshold with reduced superexcitability, consistent with membrane depolarization and reminiscent of ischemic changes. It is proposed that porphyrin neurotoxicity causes a subclinical reduction in I(H) in AIPWN axons, whereas porphyric neuropathy may develop when reduced activity of the Na(+)/K(+) pump results in membrane depolarization.
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PMID:Nerve function and dysfunction in acute intermittent porphyria. 1866 8

A 45-year-old man with end-stage renal disease due to polycystic kidney disease was admitted to the hospital because of recurrent abdominal pain, progressive peripheral motor neuron neuropathy, and respiratory failure. The diagnosis of acute intermittent porphyria was confirmed by an elevated porphyrin concentration in the urine and the presence of an R167Q mutation in the porphobilinogen deaminase gene. Use of hydroxyzine, weight loss, and/or a mild upper respiratory viral infection might have been the provoking factor of the acute intermittent porphyria. Treatment with intravenous hemin (3 mg/kg) and a high-carbohydrate diet (3000 kcal/d) had no clinical effect. Tetraplegia and chronic respiratory insufficiency developed, and the patient needed a pacemaker because of a symptomatic sinus bradycardia due to autonomic dysfunction. The patient died 10 months after the first manifestation of acute intermittent porphyria.
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PMID:Acute intermittent porphyria as a cause of respiratory failure: case report. 1925 9

Acute intermittent porphyria (AIP) is an inherited metabolic disease due to a deficiency of the hydroxymethylbilane synthase in the haem biosynthesis. It manifests with occasional neurovisceral crises due to overproduction of porphyrin precursors such as aminolaevulinic acid (ALA) which is released from the liver to the circulation. The majority of the acute attacks manifest as a combination of abdominal pain, mild mental symptoms and autonomic dysfunction mainly due to vagal insufficiency. However, both acute peripheral neuropathy and encephalopathy may develop if an acute attack proceeds especially due to administration of porphyrinogenic drugs. Acute porphyric neuropathy is predominantly motor and associates with a history of abdominal pain and dysautonomia, CNS involvement and mild hepatopathy. Other features include preservation of achilles reflexes while global hyporeflexia and neuropathic or myalgic pain. The pathogenesis of porphyric neuropathy is complex but overproduction of ALA via direct neurotoxicity, oxidative damage, and modification of glutamatergic release may initiate the neuronal damage. Acute encephalopathy manifests as a combination of mental symptoms, seizures, SIADH, but rarely focal CNS deficits. Posterior reversible encephalopathy syndrome (PRES), which has been found in patients' MRI during an acute attack with severe encephalopathy, could explain the pathogenesis of encephalopathy and seizures in AIP. Neurological manifestations are unspecific and careful interpretation of abnormal excretion of porphyrin precursors should be done before the symptoms can be related to inherited acute porphyrias and not to secondary porphyrinuria. Currently the prognosis of neuropathy and encephalopathy in AIP is good even in severe attacks, but physicians should be aware of a potentially fatal outcome of the disease.
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PMID:Neurological manifestations of acute intermittent porphyria. 1926 5


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