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     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Results of testing for anti-GM1 antibodies.

We used an ELISA technique to measure IgG and IgM antibodies to the ganglioside GM1, with the results expressed in arbitrary units. We tested 1007 sera from patients with peripheral neuropathy or muscle weakness. For IgG and IgM antibodies, the distribution of results differed significantly from a normal distribution. In the patient group, 81 of 1007 sera had elevated levels of IgG antibodies (> 10 units). Of these, 11 patients had very high levels (> 50 units). These 11 patients had diagnoses of GBS (4), motor neurone disease (3) or non-specific idiopathic neuropathy (4). For IgM antibodies, 115 of 1007 sera were positive (> 20 units). Of these, 18 patients had very high levels (> 50 units). These 18 patients had diagnoses of Guillain-Barré syndrome or Miller Fisher syndrome (4), multifocal motor neuropathy (4), motor neurone disease (2), non-specific neuropathy (2). We conclude that anti-GM1 antibodies in high titre are uncommon. Patients with multifocal motor neuropathy have high levels of antibody. However, patients with other disorders may also have high levels, so that anti-GM1 antibody levels alone are not a specific test for multifocal motor neuropathy. We found that antibodies to GM1 were present in the sera of patients with chronic idiopathic neuropathy, leading us to suggest that these antibodies may sometimes arise as a secondary response to disease.     

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.     

Comparing neuropathy in multiple myeloma and AL amyloidosis

Peripheral neuropathy (PN) is frequent in patients with monoclonal gammopathy due to plasma cell dyscrasia, but little is known about the comparative impact of nerve dysfunction in different disorders. We compared clinical and laboratory results between two diagnostic groups. We recruited 76 untreated multiple myeloma (MM) and 27 AL amyloidosis (ALA) patients for evaluation of symptoms, clinical findings and nerve conduction studies (NCS). We diagnosed significant PN using total neuropathy scores (TNS > 7) in 17.6% of MM and 48.1% of ALA patients and in 27.7% of MM and 35.7% of ALA patients using NCS findings. TNS score grades were significantly higher in the AL amyloidosis patients (Fisher's exact test: P = .02) but a NCS based PN diagnosis was not significantly different (Fisher's exact test: P = .13). A significantly higher TNS vibration (P = .04) and pin (P = .02) sensory sign and TNS reflex (P = .04) sign score was found in amyloidosis patients. Likewise, quantitative sensory thresholds for vibration was higher in amyloidosis patients (Welsh ANOVA: P = .01). NCS revealed signs of more frequent axonal tibial neuropathy with significantly lower motor response amplitudes (P = .02) and resulting higher TNS scores (P = .002), while sural nerve sensory response amplitudes were without significant difference (P = .86). We found more severe TNS grades of PN in AL amyloidosis patients compared with MM patients. We also found higher sensory symptoms scores and higher thresholds for vibration but similar sensory involvement using NCS. The NCS exclusively showed signs of an axonal neuropathy.     

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     

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.     

Low serum levels of nerve growth factor in diabetic neuropathy

Several structural and functional similarities between nerve growth factor and insulin have been described. Diabetes mellitus, a disease with absolute or relative deficiency of insulin is frequently associated with peripheral neuropathy whose physiopathological mechanisms are obscure. In this study, we measured serum levels of NGF in 18 patients with diabetic neuropathy and 9 healthy controls; patients with diabetic neuropathy had lower levels of NGF than controls (p less than 0.01). When patients were separated in two groups according to degree of impairment of motor nerve conduction velocity, those with more than 10% of impairment, had lower levels of NGF than those with less than 10% of impairment, or controls. It was found a correlation between NGF levels and decrease of motor nerve conduction velocity; then, diabetic neuropathy seems to be associated to low serum levels of NGF, pointing out a possible role of NGF in the pathology of diabetic neuropathy.     

Serum anti-GM1 and anti-GD1a antibodies in patients with motor neuron disease

Using an enzyme-linked immunosorbent assay (ELISA) sera from 100 individuals, 20 with motor neuron disease (MND), 25 with peripheral neuropathy (PN), 15 with degenerative dementia and 40 controls, were examined in order to detect serum IgM and IgG anti-GM1 and anti-GD1a antibodies. Patients with MND showed statistically significant higher levels of IgM anti-GM1 antibody compared to the control group. Three patients with peripheral neuropathy had very high levels of anti-GM1 and anti-GD1a antibodies. Antibody levels in patients with degenerative dementia showed no difference compared to the controls. These results suggest that a further inquiry into the role of serum anti-GM1 and anti-GD1a activity in motor neuron disease and peripheral neuropathy is necessary.     

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.     

HEAVY METAL LEVELS and DELTA-AMINO-LEVULINIC ACID DEHYDRASE LEVELS IN PERIPHERAL POLYNEUROPATHY

On the basis of assay of heavy metals in whole blood (lead, cadimum, chromium, copper, nickel and manganese) and delta-amino-levulinic-acid dehydrase (ALA-D) and ALA in urine in a normal Danish population, the levels of these clinco-chemical factors were assayed in 23 patients with peripheral neuropathy of unknown etiology. All patients studied showed electro-physiological sign of denervation and/or reduced motor or sensoric nerve conduction velocity. Cadmium and manganese were never found to be increased. In all but four patients, an increase of one or more heavy metals was found. Ten patients showed raised levels of two or more metals, the dominant metal being lead (10 cases), nine patients showed increased in chromium. A significant corrleation was found between increasing lead levels and decreasing ALA-D activity. Although normal concentrations of manganese were found, correlation analysis revealed a significant correlation between increased manganese and decreased ALA-D. The raised values of heavy metals could not be traced to occupational or other exposure to heavy metals and the increased values were not related to tobacco consumption. The findings are discussed in relation to known data on neuropathy and the results seem to indicate a multifactorial patholgenesis of the disease. Among factors contributing to the precipitation of the syndrome may be raised levels of heavy metals.     

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.     

Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy

OBJECTIVE: To determine the predictive value of plasma HIV RNA and CD4 lymphocytes for HIV-associated dementia and sensory neuropathy. METHODS: A total of 1,604 AIDS-free HIV seropositive men from the Multicenter AIDS Cohort Study were followed over a 10-year period (1985 to 1995). HIV-associated dementia and sensory neuropathy were diagnosed according to standard definitions. Baseline samples were used to measure plasma HIV RNA levels with a branched DNA assay and levels of beta2-microglobulin, CD4 lymphocyte counts, and hemoglobin levels. RESULTS: Seventy-seven patients with HIV-associated dementia and 213 patients with sensory neuropathy were identified. Baseline HIV RNA levels above 3,000 copies/mL and CD4 counts below 500 cells/mm3 were predictive of both neurologic outcomes, but neither hemoglobin, body mass index, nor beta2-microglobulin were independently predictive. After adjusting for age and level of education, individuals with baseline plasma HIV RNA >30,000 copies/mL had a relative hazard for dementia 8.5 times (p < 0.001) that of those with <3,000 copies/mL, and those with CD4 counts <200 cells/mm3 had a 3.5-fold (p = 0.003) greater hazard relative to those with CD4 counts >500 cells/mm3. Individuals with HIV RNA >10,000 copies/mL had a 2.3-fold (p = 0.008) greater hazard of sensory neuropathy than those with <500 copies/mL, and men with <750 CD4 cells/mm3 had a 1.4-fold (p = 0.03) greater hazard than those with >750 CD4 cells/mm3. CONCLUSIONS: High levels of systemic HIV replication may "drive" the initiation of neurologic disease; effective suppression of HIV may reduce the incidence of dementia and neuropathy. Levels of plasma HIV RNA and CD4 counts, determined before the initiation of antiretroviral therapy, were predictive of HIV-associated dementia and sensory neuropathy.