Acute intermittent porphyria with peripheral neuropathy: a follow-up study after hematin treatment

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.     

Porphyric neuropathy and hereditary delta-aminolevulinic acid dehydratase deficiency in an adult

A man without a history of porphyric attacks developed a subacute motor neuropathy at the age of 63. At the same time the first signs of a myeloproliferative disorder were found. He had a homozygous deficiency of erythrocyte delta-aminolevulinic acid dehydratase (ALA-D) with autosomal recessive inheritance. Treatment with parenteral glucose and with hematin had a beneficial influence on the plasma ALA levels. The finding of a motor neuropathy with increased plasma levels of ALA but not of porphobilinogen (PBG) supports the potential role of ALA in the pathogenesis of porphyric neuropathy.     

Porphyric neuropathies in an acute intermittent porphyria family

The objective of this study was to investigate two patients with porphyric neuropathy in a family with acute intermittent porphyria. Molecular analysis of the porphobilinogen deaminase (PBGD) gene was performed. We analyzed the clinical course of peripheral neuropathy and serial changes in nerve conduction studies (NCS) of the two patients. We also examined the pathological findings of sural nerve biopsy in one patient. Molecular analysis of the PBGD gene revealed a missense mutation (Arg26His) in exon 2 for two patients and their family members. Distal polyneuropathy was noted in the patients with chronic porphyric neuropathy. In the follow‐up NCS, recovery was relatively poor in the lower limb in one patient with severe polyneuropathy, and NCS evidence of deterioration was found following frequent hormone‐related porphyric attacks in another patient. The sural nerve biopsy showed marked loss of myelinated and unmyelinated fibers in one patient with chronic porphyric neuropathy. In contrast to radial and fibular motor nerves in acute porphyric neuropathy, the sural nerve is vulnerable to involvement in chronic porphyric neuropathy following repeated porphyric attack as seen in the NCS.     

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.     

Electromyogram and nerve conduction in patients with acute intermittent porphyria

Summary Diminished activity of uroporphyrinogen I-synthetase in the liver and other tissues may be regarded to be the primary genetic deficiency of acute intermittent porphyria (AIP). Increased production and renal excretion of delta-aminolevulinic acid (ALA) und porphobilinogen (PBG) are secondary phenomena. The neuropsychiatric symptomatology of AIP consists of neuropathy, vegetative crises and exogenous psychoses.In this study electromyographic and neurographic investigations were performed on 20 persons with AIP. 16 patients had experienced attacks of AIP, 10 of them including neuropathy. 4 persons showed the biochemical findings of AIP but had not yet had symptoms.In cases with persistent pareses following porphyric neuropathy denervation signs or sequelae were still present. In patients without clinical symptoms and in latent cases there were normal or borderline findings. Motor nerve conduction velocity was mostly decreased in combination with denervation signs and in a range that indicated a primarily axonal nerve lesion and consequent myelin damage rather than primary demyelinization. The mean motor conduction velocity of n. tibialis was somewhat lower in patients with porphyric crises without neuropathy than in latent cases without any clinical crises. The differences were not significant in other nerves. The findings are discussed under consideration of the electrodiagnostic results of other investigations and of neuropathological and clinical data.Herrn Prof. Dr. Richard Jung zum 65. Geburtstag gewidmet     

Severe ptosis without ophthalmoplegia due to porphyric neuropathy

In this case report, we present a patient with severe ptosis without ophthalmoplegia due to porphyric neuropathy. This could be explained only by selective involvement of oculomotor nuclei.     

Acute intermittent porphyria presenting as a diffuse encephalopathy

Although acute intermittent porphyria presents with dramatic neurological findings, the diagnosis is difficult. An 18-year-old woman had a clinical picture of porphyric encephalopathy. Magnetic resonance (MR) imaging demonstrated multiple large contrast-enhancing subcortical white matter lesions, which regressed with glucose and hematin infusions. Diffusion-weighted MR imaging was normal, and MR spectroscopy excluded acute demyelination or tissue necrosis. MR findings of acute intermittent porphyria can differ from those in posterior reversible encephalopathy syndrome by virtue of intense contrast enhancement. Because diffusion-weighted MR imaging and spectroscopy were normal, the lesions are likely caused by reversible vasogenic edema and transient breakdown of the blood-brain barrier.     

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.     

Peripheral nerve changes in porphyric neuropathy: Findings in a sural nerve biopsy

Summary The changes in a sural nerve biopsy of a patient with porphyric neuropathy were studied by light and electron microscopy. Linear arrays of myelin ovoids constituted the most common abnormality in whole mounts of teased-fiber preparations. Round or irregular formations of variable osmiophilia were the most frequent finding in thick-section preparations examined by phase contrast microscopy. Lamellar whorls represented the most prevalent lesion in thinsections studied under the electron microscope. In addition, along the teased fibers, segmental demyelination was definitely detected, although rarely; in thick sections, the true extent of the nerve fiber loss was fully appreciated; in thin sections, a variety of axon and myelin changes of a distinct character were discovered. The studies demonstrate that in peripheral nerves of porphyric neuropathy, axonand myelin changes generally run together and proceed pari passu in the same segment of nerve fiber. Furthermore, among the pathogenetic mechanisms invoked to account for the neuropathic changes none are favored to the exclusion of others by these studies. Therefore, a primary axonaland myelinic disorder on the basis of a deranged porphyrin metabolism is as good a possibility as any hitherto advanced explanation of the pathogenesis of the neuropathic changes. The secondary lesions of Wallerian degeneration and segmental demylination may simple be grafted upon the primary lesions evoked by the metabolic abnormality.     

Peripheral nerve findings in hereditary coproporphyria

Summary In spite of several cases reported in the literature, the exact pathogenetic mechanism of neuropathic changes in porphyric neuropathy remains uncertain. Various authors have ascribed the neuropathologic findings to either a dying-back axonal degeneration or segmental demyelination. In recent years, the hypothesis of an axonal and myelinic disorder has received support by the demonstration of a combined and simultaneous involvement of both these structures. Such different opinions are also a consequence of the reduced number of detailed bioptic observations in the different forms of acute porphyria not only during acute phases but also between attacks. In this paper we report the results of light- and electronmicroscopic examination of two sural nerve biopsies from subjects with hereditary coproporphyria. The first was performed 6 months after an acute attack, the second specimen was obtained from a patient without acute attacks, who had clinical and electrophysiologic signs of a chronic progressive neuropathy. In both cases a dying-back axonal degeneration is considered the primary change. The pathogenetic mechanism of peripheral nerve lesions in porphyric neuropathy will be discussed finally.     

An autopsy case of acute porphyria with a decrease of both uroporphyrinogen I synthetase and ferrochelatase activities

Summary 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.     

Polyneuropathies in teenagers: a clinicopathological study of 45 cases

The aim of the present study was to investigate the causes of polyneuropathy in teenagers and to describe some characteristic clinical, laboratory, electrophysiological and pathological features. Forty-five patients with peripheral nervous disorders aged 13-19 were studied. Hereditary polyneuropathy of different types was diagnosed in 28 patients (62%); nine showed chronic inflammatory demyelinating polyneuropathy (CIDP) and two showed vasculitic neuropathy. In two more cases polyneuropathy was attributed to toxic agents, while among the rest, one was diagnosed as metachromatic leucodystrophy (juvenile type), one as adrenoleucodystrophy, one as porphyric neuropathy and one as Fabry disease. The high incidence of hereditary neuropathies in teenagers differs from that in adults, but is similar to that encountered in children. In our study, CIDP appears to be a frequent cause of neuropathy in teenagers, while the other causes are broadly similar to those found in studies concerning children rather than adults.     

Corneal confocal microscopy for the diagnosis of diabetic autonomic neuropathy

Introduction: A case series of acute intermittent porphyria (AIP) is described that focuses on the clinical course of the disease with regard to neurological manifestations of the peripheral nervous system. Methods: Eight patients were diagnosed with AIP on the basis of characteristic clinical findings, erythrocyte porphobilinogendeaminase activity, neuropathic patterns, serial changes in nerve conduction studies (NCS), and temporal relationship of central nervous system involvement. Results: Six patients diagnosed with AIP <2 months after symptom onset had neuropathy that was predominantly upper extremity, motor, and proximal. NCS recovery rates were slower in the lower than the upper limbs. Two patients diagnosed >2 months after symptom onset had distal sensorimotor polyneuropathy. Conclusions: The findings from this case series suggest that the peripheral nerves may be differentially and selectively involved in different diagnostic stages of porphyric neuropathy. Muscle Nerve 51 : 363–369, 2015     

Posttraumatic epilepsy and acute intermittent porphyria: effects of phenytoin, carbamazepine, and clonazepam.

A patient with uncontrolled posttraumatic epilepsy and acute intermittent prophyria was subjected to successive therapeutic trials with phenytoin, carbamazepine, and clonazepam, while eating an adequate diet. Both phenytoin and carbamazepine treatments caused significant increases in porphobilinogen excretion and appeared to induce acute porphyric attacks. In contrast, treatment with clonazepam under rigid dietary control for 10 days caused no increase in porphilbinogen excretion. During the subsequent 7 months of treatment with clonazepam, neither seizures nor porphyric attacks recurred. These findings suggest that clonazepam may be a safe and effective treatment for chronic or severe generalized seizure disorders in patients with acute intermittent porphyria.     

Autonomic involvement in inherited neuropathies

The inherited peripheral neuropathies constitute a large group of disorders, in some of which the causative metabolic defect has been identified whereas in the majority it is still unknown. Amongst the former, autonomic involvement is an important component in porphyric neuropathy, in the familial amyloid polyneuropathies, in Fabry's disease and in dopamine-hydroxylase deficiency. The latter group includes the hereditary sensory and autonomic neuropathies in some of which, such as the Riley-Day syndrome, autonomic disturbances are prominent, whereas in others they constitute only a minor component of the symptomatology. Autonomic dysfunction is an important component of the neurological manifestations in multiple endocrine neoplasia type IIB.     

Experimental porphyric neuropathy: a preliminary report

An experimental model for the study of porphyric neuropathy is presented. Injection of either tetraphenyl-porphinesulfonate (TPPS), hematoporphyrin derivative (HpD), or delta-amino-levulinic acid (ALA) into mice resulted in markedly decreased motor nerve conduction velocity (MNCV). THe MNCV returned to normal within one week following the injection of large doses of ALA, and within three weeks following the injection of close to lethal doses of HpD, but there was no recovery of nerve function within 50 days following injection of substantially smaller doses of TPPS. Ultrastructural examination of motor nerves at various times following TPPS injection revealed the gradual development of structural abnormalities. Ultrastructural examination of the same nerves after a single dose of either ALA or HpD failed to demonstrate any abnormalities. The present observations call for precaution as to the use of TPPS as photosensitizer in human cancer treatment.     

The interaction of the factor VIII/von Willebrand factor complex with hematin

Intravenous infusion of hematin, used in the treatment of acute porphyria, induces a decline in the plasma factor VIII/von Willebrand factor complex (VIII/vWF) and thrombocytopenia. We investigated this problem by studying the interaction between hematin, purified VIII/vWF, and platelets in vitro. Hematin was labeled with either 59Fe or 3H and characterized by gel chromatography. Hematin self-aggregated, forming a complex with an average molecular weight of approximately 10,000 daltons. When incubated with VIII/vWF for 30 min at 37 degrees C and applied to Sepharose CL-4B, the hematin eluted with the VIII/vWF in the void volume. Hematin inhibited the dissociation of factor VIII antigen (VIII:Ag) from the von Willebrand antigen (vWF:Ag) in 0.25 M CaCl2, and reversed the aggregation of VIII:Ag induced by 0.1 M 6-aminocaproic acid. Both hematin and the hematin-VIII/vWF complex bound to washed normal platelets and to platelets from a patient with Bernard-Soulier syndrome. Thrombasthenic platelets were not aggregatable by hematin, and bound significantly less hematin-VIII/vWF than normal platelets suggesting that hematin-induced platelet activation was required for binding. Likewise, binding was inhibited by PGE1 which also prevented aggregation. We conclude that hematin forms complexes with VIII/vWF, alters the functional activity and dissociation of this compound, and participates in the binding of VIII/vWF to platelets.     

Hematin and propranolol in acute intermittent porphyria. Full recovery from quadriplegic coma and respiratory failure

The authors present a case of acute intermittent porphyria (AIP) in an almost fatal relapse with quadriplegia, bulbar paralysis and coma. Intravenous hematin produced an immediate arousal from coma and allowed a gradual resumption of bulbar and autonomic functions. Persistent tachycardia and hypertension necessitated huge doses of intravenous propranolol. Both hematin and propranolol administrations were followed by a remarkable decrease in urinary amino-levulinic acid and porphobilinogen excretion. Nevertheless, after the acute stage, the patient was left with a severe generalized muscle wasting. After 7 months of intensive physical therapy, complete recovery of all neuromuscular functions was achieved. The modern aspects of the management of AIP are presented; the efficacy and the limits of hematin and propranolol therapy are discussed.     

Neurotoxicity of δ-aminolevulinic acid and porphobilinogen

Rats were injected with δ-aminolevulinic acid (ALA) and with porphobilinogen (PBG) into the lateral ventricle of the brain. An ataxia- and catatonia-like state, followed by jumping seizures, occurred dose dependently and without significant differences between ALA and PBG. The relatively high amount required and the clinical observation that seizures are not typically seen in patients with a porphyric attack make these substances not likely causative agents for the porphyric symptomatology.