Purple pigments: The pathophysiology of acute porphyric neuropathy

The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.     

Excretion of porphyrins and porphyrin precursors during neuromuscular paralysis produced by dithiobiuret

Urinary excretion of porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) and total porphyrins was measured during intoxication of rats with 2,4-dithiobiuret (DTB), a chemical which produces delayed-onset neuromuscular weakness, in an attempt to ascertain whether or not DTB poisoning in the rat would serve as an animal model of the neurologic symptoms of acute intermittent porphyria. Daily administration of DTB (1 mg/kg/day, i.p.) produced flaccid skeletal muscle weakness first detected after 4 to 5 days of treatment. Onset of skeletal muscle weakness was associated with a significant increase in urinary excretion of ALA. The excretion of PBG and total porphyrin was also increased; however, the increase was not significant. The increase in porphyrins and porphyrin precursors was due to increased urine output which coincided with the onset of neuromuscular weakness; urinary concentrations of ALA, PBG, and porphyrins were not increased by DTB. Measurements of free-erythrocyte protoporphyrin, taken after 7 days of DTB treatment, indicated a significant elevation of free erythrocyte protoporphyrin concentration. The pattern of alterations in the heme precursors associated with DTB-induced paralysis in rats is quite different from that observed in humans afflicted with acute intermittent porphyria. Therefore, we conclude that DTB-induced paralysis in the rat does not represent an accurate animal model of acute intermittent porphyria.     

Intrastriatal administration of 5-aminolevulinic acid induces convulsions and body asymmetry through glutamatergic mechanisms

The involvement of glutamatergic and GABAergic mechanisms in the behavioral effects induced by the intrastriatal injection of 5-aminolevulinic acid (ALA) (1-8 mgr;mol/2 mgr;l), a metabolite that accumulates in porphyrias, was evaluated. ALA administration to adult female rats increased locomotor activity, induced clonic convulsions and elicited dose-dependent body asymmetry assessed by the elevated body swing test. ALA-induced convulsions were prevented by intrastriatal preadministration of the glutamate antagonists, 6, 7-dinitroquinoxaline-2,3-dione (8 nmol/0.5 microl) or dizocilpine (2. 5 nmol/0.5 microl), but not by the GABA agonist, muscimol (46 pmol/0. 5 microl). Body asymmetry was prevented only by 6, 7-dinitroquinoxaline-2,3-dione pretreatment. A higher dose of muscimol (92 pmol/0.5 microl) prevented both ALA-induced convulsions and body asymmetry. However, this dose of muscimol induced motor biases, which make difficult to ascertain the involvement of GABA(A) receptors in ALA-induced behavioral effects. This study suggests that glutamatergic mechanisms underlie the ALA-induced convulsions and body asymmetry. The present results may be of value in understanding the physiopathology of the neurological dysfunction occurring in acute porphyrias.     

Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias

BACKGROUND: Acute intermittent porphyria (AIP), due to half-normal hydroxymethylbilane synthase activity,is characterized by acute life-threatening neurologic attacks whose etiology remains unclear. To date, only 3 patients confirmed to have homozygous dominant AIP (HD-AIP) have been described (hydroxymethylbilane synthase genotypes R167Q/R167Q and R167W/R173Q). OBJECTIVE: To investigate the genetic, biochemical, clinical, and neuroradiologic features of a severely affected infant with HD-AIP. DESIGN: Clinical, imaging, and genotype/phenotype studies were performed. RESULTS: The proband, homoallelic for hydroxymethylbilane synthase mutation R167W, had approximately 1% of normal hydroxymethylbilane synthase activity, elevated porphyrins and porphyrin precursors, severe psychomotor delay, and central and peripheral neurologic manifestations. When expressed in vitro, the R167W mutant enzyme had less than 2% of normal activity but was markedly unstable, consistent with the proband's severe phenotype. Mitochondrial respiratory chain enzymes were normal. Neuroradiologic studies revealed a unique pattern of deep cerebral white matter injury, with relative preservation of the corpus callosum, anterior limb of the internal capsule, cerebral gray matter, and infratentorial structures. CONCLUSIONS: This severely affected patient with HD-AIP expanded the phenotypic spectrum of HD-AIP. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement in HD-AIP, whereas most structures developed prenatally were intact. These findings indicate that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency and suggest that porphyrin precursor toxicity is primarily responsible for the acute neurologic attacks in heterozygous AIP and other porphyrias.     

Neurological and neuropsychiatric manifestations of porphyria

Abstract

Porphyrias are inherited disorders of the heme biosynthetic pathway, usually characterized by dermatological changes due to the accumulation of byproducts in the pathway. Select porphyrias also affect the nervous system, namely hereditary coproporphyria, acute intermittent porphyria and variegate porphyria. Complications include paralysis, hyponatremia which can risk central pontine myelinolysis, seizures and coma. Neurological complications usually result from severe episodes of acute attacks. Acute attacks may also elicit neuropsychiatric symptoms such as confusion, hallucinations, anxiety and psychosis. However, these manifestations are generally self-limiting. Due to the generally low incidence of porphyria and full knowledge the associated neurological and psychiatric manifestations, we review the relevant porphyrias along with their clinical manifestations, evaluation, and management to raise its awareness in the clinical picture and to prevent misdiagnosis. Porphyria should be considered within the differential diagnosis for unexplained neurological symptoms.     

Akute intermittierende Porphyrie

Acute porphyrias are rare, but often misdiagnosed and may take a dramatic clinical course. The combination of various internal, psychiatric and neurological symptoms can mimic different other diseases. We report a 40-year-old female patient who was admitted with a subacute tetraparesis. During the last 2 months the patient was treated several times because of abdominal pain and just before admission to our clinic in a psychiatric hospital because of acute mental changes and hallucinations. The typical combination of abdominal pain, motor neuropathy and psychiatric symptoms confirmed by increased amounts of porphyrins and their precursors, led us to promptly diagnose acute intermittent porphyria. Better knowledge about the pathogenesis has clearly improved the prognosis of acute porphyria. In remission, measurement of enzyme activities or mutation screening can be the only diagnostic verification. A mutation screening for family members should be conducted to identify symptom-free carriers, especially in cases of a positive family history.     

Porphyric neuropathy

The hepatic porphyrias are a group of rare metabolic disorders characterized by enzymatic defects in the biosynthesis of heme, a metalloporphyrin that is the principal product of porphyrin metabolism. The hepatic porphyrias are genetically transmitted as autosomal-dominant disorders with variable expression that produce a particularly severe form of neuropathy. Most medical students readily recognize acute attacks of porphyria when the classic triad of abdominal pain, psychosis, and neuropathy is present. Yet, porphyric neuropathy is a source of confusion in practice, and patients with porphyria rarely receive the correct diagnosis early in the course of the illness. Porphyric neuropathy is manifest by symptoms, signs, and cerebrospinal fluid abnormalities resembling acute Guillain-Barré syndrome. However, accompanying psychological features, a proximal predilection of asymmetric weakness, and electrodiagnostic findings indicative of an axonal polyradiculopathy or neuronopathy all suggest the diagnosis of porphyria. Confirmation of the diagnosis depends on use of appropriate laboratory studies. The underlying pathophysiology of porphyric neuropathy has not been established, but it may be related to direct neurotoxicity of elevated levels of delta-aminolevulinic acid. The severity of the neuropathy and the availability of potential treatments, including avoidance of provocative factors, make identification important.     

Transport of 5-aminolevulinic acid between blood and brain

Little is known about the movement of 5-aminolevulinic acid (delta-aminolevulinic acid; ALA) between blood and brain. This is despite the fact that increases in brain ALA may be involved in generating the neuropsychiatric symptoms in porphyrias and that systemic administration of ALA is currently being used to delineate the borders of malignant gliomas. The current study examines the mechanisms involved in the movement of [(14)C]ALA across the blood-brain and blood-CSF barriers in the rat. In the adult rat, the influx rate constant (K(i)) for [(14)C]ALA movement into brain was low ( approximately 0.2 microl/g per min), was unaffected by increasing plasma concentrations of non-radioactive ALA or probenecid (an organic anion transport inhibitor) and, therefore, appears to be a diffusional process. The K(i) for [(14)C]ALA was 3-fold less than that for [(14)C]mannitol, a molecule of similar size. This difference appears to result from a lower lipid solubility rather than saturable [(14)C]ALA transport from brain to blood. The K(i) for [(14)C]ALA for uptake into the neonatal brain was 7-fold higher than in the adult. However, again, this was unaffected by increasing plasma ALA concentrations suggesting a diffusional process. In contrast, at the blood-CSF barrier, there was evidence of carrier-mediated [(14)C]ALA transport from blood to choroid plexus and blood to CSF. Both processes were inhibited by administration of non-radioactive ALA and probenecid. However, experiments in choroid plexus epithelial cell primary cultures indicated that transport in these cells was polarized with [(14)C]ALA uptake from the apical (CSF) side being about 7-fold greater than uptake from the basolateral (blood) side. In total, these results suggest that the brain is normally fairly well protected from changes in plasma ALA concentration by the very low blood-brain barrier permeability of this compound and by a saturable efflux mechanism present at the choroid plexus.     

Studies on porphyrin-heme biosynthesis in organotypic cultures of chick dorsal root ganglion. I. Observations on neuronal and non-neuronal elements

Living, mature organotypic cultures of chick dorsal root ganglion maintained in culture for 3 weeks were incubated in medium containing various levels of a precursor of porphyrin and heme formation, delta-aminolevulinic acid (ALA), (0.5 mM to 10 mM) or a combination of ALA (10 MM) and a metal chelator, CaMg-EDTA (5 mM) for up to 48 hours. Although no morphologic changes occurred in the cultures incubated with these compounds as observed by bright-field or dark-field microscopy, fluorescence microscopic study at 12, 24, and 48 hours demonstrated an intense red fluorescence with in the non-neuronal cells of the cultures (Schwann cells, fibroblasts, and macrophages) but not in the nerve cells. Spectrofluorometric analysis of perchloric acid-methanol extracts of the cultures revealed an emission spectrum characteristic of porphyrins. Autoradiographic studies, using 14C-labelled ALA, indicated that ALA was taken up by all cells (nerve cells as well as non-neuronal cells) in the cultures. The cultures incubated with ALA plus the metal chelator CaMg-EDTA showed the same distribution of porphyrin fluorescence, but a 2-fold increase in the amount of porphyrins was generated, when compared to cultures incubated with ALA alone. This observation suggests that a considerable fraction of porphyrins may be utilized to form heme in these cells since CaMa-EDTA blocks ferrochelatase activity, the terminal enzyme in the heme biosynthetic pathway. This is the first demonstration of active porphyrin-heme biosynthesis from ALA in cultured nervous system cells. Our results indicate that this biosynthetic pathway remains active in 3-week old cultures of chick dorsal root ganglion, and further, that the pathway appears to be predominantly present in the non-neuronal cellular elements of the ganglion rather than in nerve cells.     

Is screening for urinary porphobilinogen useful among patients with acute polyneuropathy or encephalopathy?

Acute porphyrias are a group of inherited metabolic disorders representing overproduction syndromes with the formation of neurotoxic haem precursors. Clinical manifestations consist of acute attacks, which include abdominal pain, dysautonomia, mental symptoms, polyneuropathy and seizures mimicking many other acute neurological disorders.Porphyrin metabolites were screened in 108 patients with acute polyneuropathy or encephalopathy associated with pain and/or dysautonomia, who attended neurological wards, in order to evaluate the number of patients with acute porphyria.Urinary porphyrins and their precursors were increased in 21% of the cases. Surprisingly many patients (11%) had previously undiagnosed acute porphyria. Half of these patients had had mild to moderate symptoms of acute porphyria previously. Secondary porphyrinuria, which was mainly transient coproporphyrinuria because of hepatopathy, was also common (10%). Of the 108 patients studied, the levels of urinary porphyrins or their precursors were normal in the majority (79%) of the cases, who commonly had Guillain-Barré syndrome (40%). Epileptic seizures were also frequent (18%), but none of the patients with acute porphyria had solely epileptic seizures without prolonged confusion (>or= 1 day).Based on our findings, acute inherited porphyria is not infrequent among the selected group of neurological patients and screening of urinary PBG is cost-beneficial. Since the correct diagnosis of a hereditary disease is essential, genetic screening should be performed whenever possible for patients with clinically and biochemically confirmed acute porphyria.     

Brainstem dysfunction in variegate porphyria

Introduction: Variegate porphyria (VP) is a rare metabolic disorder that may present as an acute predominantly motor neuropathy. Cranial nerves and brainstem functions have been only scarcely studied. Methods: Brainstem reflexes were examined in symptomatic and non-symptomatic VP mutation carriers of a single family. Results: Similar results were found in the 2 patients with a history of porphyric crises. The blink reflex showed an absence of late responses (R2 and R2c) to stimulation of both sides. The masseter inhibitory reflex showed reduced inhibition of the second phase. The jaw jerk was normal. The asymptomatic carriers did not show any of the abnormalities just noted. Conclusions: Our results are compatible with a central lower pons-upper medulla disorder in the brainstem. We hypothesize that brainstem dysfunction in VP patients with a history of porphyric crises may be due to neurotoxic effects of porphyrin precursors as well as subclinical osmolarity changes due to hyponatremia. Muscle Nerve 46: 426-433, 2012.     

Acute intermittent porphyria presenting as acute pancreatitis and posterior reversible encephalopathy syndrome

Acute intermittent porphyria (AIP) is an inherited metabolic disease that can affect the autonomic, peripheral and central nervous systems. Pancreatic diseases assocated with AIP is rarely reported. We report here a 60-year-old non-alcoholic male who had typical manifestations of AIP, including abdominal pain, constipation, tachycardia, hypertension, mental disturbances, psychiatric manifestations, seizures, peripheral neuropathy, and excessive excretion of porphyrin precursors in urine. Increases of serum amylase and lipase, as well as mild pancreatic edema on ultrasonography, were noted during the acute attack of AIP, suggesting concomitant acute pancreatitis. In this patient, brain magnetic resonance imaging revealed reversible multifocal cerebral lesions resembling a posterior reversible encephalopathy syndrome (PRES) during the acute attack of AIP. Because the clinical manifestations of acute pancreatitis could be present with an acute attack of AIP, early confirmation of diagnosis is mandatory to effectively manage the attack and avoid inappropriate treatment.     

5-Aminolevulinate and 4, 5-dioxovalerate ions decrease GABA(A) receptor density in neuronal cells, synaptosomes and rat brain

Porphyrias are heme-associated metabolic disorders such as intermittent acute porphyria (IAP) and lead poisoning, where 5-aminolevulinate (ALA) accumulates. Effects of ALA on the CNS have been explained by ALA binding to GABA(A) receptors, followed by receptor lesions from oxyradicals and 4, 5-dioxovalerate (DOVA) generated from metal-catalyzed ALA oxidation by oxygen. We have characterized the effects of ALA and DOVA on GABA(A) receptor density in synaptosomes and neurons in vitro and also in brains of rats treated with ALA or succinylacetone methyl ester (SAME), a tyrosine catabolite derivative able to induce ALA accumulation. Radiolabeling assays revealed that following exposure to DOVA the concentration of synaptosomal GABAergic sites decreased by approximately 50%. Pretreatment with DOVA resulted in less GABA(A) receptor density in P19 and WERI cells and altered cell morphology. Furthermore, exposure to DOVA also induced a 5-fold increase in WERI cell mortality rate. Treatment with ALA resulted in loss of neuronal morphology and decrease of GABA(A) density in P19 neuronal cells. ALA and SAME treatment diminished the density of GABAergic receptors in the habenular complex and the parabigeminal nucleus of rat brain as studied by immunohistochemical procedures. Our results strongly suggest that ALA- and DOVA-promoted damage to GABA(A) receptors may contribute to the neurological manifestations of AIP and plumbism.     

delta-Aminolevulinic acid: influences on synaptic GABA receptor binding may explain CNS symptoms of porphyria.

Symptoms of acute porphyria have been attributed to effects of delta-aminolevulinic acid (ALA). We report that ALA selectively competes for the binding of tritiated gamma-aminobutyric acid ([3H]GABA) associated with synaptic GABA receptors in central nervous system membranes. Concentrations of ALA that inhibit GABA receptor binding are consistent with levels of ALA thought to exist in the central nervous system of porphyric patients. Some of the symptoms of acute porphyria resemble those elicited by muscimol, a potent GABA agonist drug. Barbiturates, which exacerbate porphyric symptoms, are potent facilitators of the synaptic actions of GABA. The results suggest that some symptoms of acute porphyria might be attributable to a mimicking by ALA of GABA at its central nervous system receptor sites.     

血卟啉病的神经系统表现分析

为了探讨血卟啉病神经系统表现规律,增加对本病的认识,并给临床医生提供一个实用的临床诊断和治疗方法。笔者报道了2例,加上国内近10年报道的13例,本文对此15例进行了全面的分析,对该病的发病机制、分类、临床表现、诊断、治疗及预后进行了系统的讨论。结果发现血卟啉病神经系统表现为周围感觉运动神经病4例、内脏自主神经病9例、抽搐发作4例及精神症状6例。我们报道的例2中有枕叶梗塞所致的皮层盲,国外少见,国内未见报道。血、尿中尿卟啉、粪卟啉及前体的测定是诊断有关键,避免诱因、静脉滴注血红素及葡萄糖是主要的治疗手段。     

Effect of hematin in porphyric neuropathy.

Early, intravenous administration of hematin in a patient with acute intermittent porphyria and severe quadriparesis may have produced partial but remarkable improvement of neuropathy, and resulted in simultaneous decline of porphyrin precursors in the blood. Intermittent, biweekly hematin infusions given 1 month after the onset of the porphyric relapse had no effect on recovery of the residual neuropathy. We believe hematin may be effective in the treatment of porphyric neuropathy, if administered before irreversible neuronal damage has occured.     

Acute neuropathy mimicking porphyria induced by aminolevulinic acid during photodynamic therapy

An 82-year-old man developed severe, acute, predominantly motor polyneuropathy, signs of autonomic involvement, and skin changes following aminolevulinic acid (ALA) administration. The compound was used as a prodrug for photodynamic therapy of Barrett's esophagitis. Changes were observed in various parameters of the heme pathway. The case reported represents a rare response to ALA treatment, resembling an acute attack of hepatic porphyria with neurological features.     

Inhibition of the evoked release of acetylcholine by the porphyrin precursor delta-aminolevulinic acid.

The effect of delta-aminolevulinic acid (ALA) on neuromuscular transmission were studied. High concentrations (0.6 to 18 mM) of ALA caused significant reductions in the amplitudes of curarized end-plate potentials (epps). Changing the ratio of calcium to magnesium in the bathing solution allowed the quantal content of the epps to be directly measured. Under these conditions, ALA reduced the quantal content of epps without affecting the depolarization produced by a single quantum of acetylcholine. It was concluded that ALA, in high concentrations, inhibits the release of acetylcholine evoked by a nerve impulse but is unlikely to be the cause of the neurological defects of acute porphyria.     

Diagnosis of motor neuropathy

Motor neuropathy is a clinical entity which leads to consideration of a wide spectrum of peripheral nerve disorders. Firstly, it may be distinguished from other causes of peripheral motor involvement such as muscle diseases and disorders of the neuromuscular junction. Secondly, it may be discussed in two different forms: acute and chronic. Acute chronic neuropathies are mainly observed in Guillain-Barré syndrome, in which electrophysiological studies allow us to recognize the classical demyelinating form and the axonal form. The other causes of acute motor neuropathy are mainly poliomyelitis and porphyrias. Chronic motor neuropathies are mainly observed in motor neuron diseases, mainly amyotrophic lateral sclerosis, but also Kennedy's disease and other lower motor neuron diseases which may be inherited or acquired. The other causes are multifocal motor neuropathy and the predominantly motor forms of chronic inflammatory demyelinating polyneuropathy. The characterization of these different types of chronic neuropathy is of major importance because of the therapeutic consequences which may lead to the proposal of specific treatments.