How does porphyria affect the nervous system

In those clinically affected, acute episodes usually manifest after puberty, more commonly in females. AIP symptoms comprise a variety of neurological severe pain, sensory loss, motor weakness, convulsions and more general manifestations fever, tachycardia, nausea, vomiting, constipation , as well as respiratory failure that can lead to coma and death Kauppinen, Symptoms of AIP do not generally develop unless a person with the enzymatic deficiency encounters a trigger such as hormonal substances, medications, sun exposure or dietary factors Herrick and McColl, Porphyric neuropathy PN typically presents as a motor neuropathy of the axonal type Albers and Fink, The pathophysiology underlying axonal dysfunction in AIP remains unknown.

Heme is an essential component of the mitochondrial electron transport chain and critical to aerobic metabolism and ATP production. Fast axonal transport is highly energy dependent, and diminished ATP availability would disrupt this process. Changes in axonal ion channel function and membrane potential may now be investigated in vivo using novel nerve excitability methods, recently adapted for clinical use Kiernan et al. In the present study, multiple excitability parameters were recorded to investigate axonal properties in patients with AIP, and also in asymptomatic carriers of genetic mutations linked to AIP.

The aim was to test the hypothesis that the development of porphyric neuropathy may be linked to axonal membrane depolarization. Clinical assessment and neurophysiological investigations including nerve conduction studies NCS and nerve excitability studies were undertaken in 15 AIP patients 10 with previous clinical episodes and confirmed genetic mutations; 5 with previously confirmed clinical episodes without detected mutation and 5 asymptomatic latent gene carriers.

The clinical and biochemical characteristics of this cohort are summarized in Table 1. Clinical diagnosis was confirmed through assessment of serum biochemistry indices, enzyme activity and mutation screening of patients and their families. The studies were performed in accordance with the Declaration of Helsinki. Summary of clinical and biochemical data from AIP patients either clinically affected or latent gene carrier.

Patient 14 was excluded from the subsequent data analysis due to presence of co-existent diabetes mellitus DM. Patient 20 developed acute porphyric neuropathy. Routine nerve conduction studies used conventional techniques Kimura, Excitability studies were undertaken on the median and peroneal nerves. Compound muscle action potentials CMAPs were recorded using surface electrodes from the abductor pollicis brevis APB and tibialis anterior TA with the active electrode at the motor point and the reference electrode 4 cm distal Eduardo and Burke, Stimulus current was applied via non-polarizable electrodes with the cathode over the median nerve at the wrist and the anode 10 cm proximal over muscle.

These stimuli were combined with suprathreshold conditioning stimuli or subthreshold polarizing currents. The amplitude of the CMAP was measured from baseline to the negative peak. The automated excitability protocols incorporated the following measures:. The slope of this curve may be used to provide an estimate of the threshold analog of input conductance Kiernan and Bostock, Prolonged subthreshold currents were used to alter the potential difference across the internodal axonal membrane.

Threshold was tested at different time points during and after the ms polarizing currents. The final part of the protocol measured the recovery of axonal excitability following delivery of a supramaximal conditioning stimulus with conditioning-test intervals from 2 to ms. This was followed by a period of superexcitability due to the depolarizing afterpotential Barrett and Barrett, ; Blight, ; Bowe et al.

To model the excitability changes in human motor axons induced by porphyria, mathematical simulations were undertaken using a model of the human axon Bostock et al. The equations for a single node and internode, representing a spatially uniform axon, were evaluated by integration over successive small time steps Van Euler's method, Press et al.

At times corresponding to those in human nerve excitability recordings, the excitability of the model nerve was tested repeatedly to determine threshold with an accuracy of 0. The weights were the same for all threshold measurements of the same type e. The standard model was obtained by minimizing the discrepancy between the model and the normal control data with an iterative least squares procedure, so that alteration of any of the above parameters would make the discrepancy worse.

Values obtained in this study were compared to established normative data for NCS for this unit Burke et al. For the excitability studies, a separate group of normal Taiwanese controls 11 healthy females, 2 males was recruited to match the gender ratio of the AIP patients ages: AIPWN 19—54 years, mean Recordings were compared using the Student's t test.

Demographic, biochemical and genetic data for the 20 subjects are detailed in Table 1. After clinical and excitability testing, one patient was found to be diabetic and his data were excluded from the analysis given that diabetes mellitus may affect axonal excitability Kitano et al. None of the other subjects had a history of other medical conditions known to affect nerve function other than AIP. The results presented in this study were categorized according to three groups: i 13 patients with AIP without neuropathy AIPWN ; the diagnosis of porphyria was confirmed by elevated ALA levels, positive porphyrin urine tests and in 10 cases a confirmed PBGD mutation; however, each of these patients had normal NCS, further confirming that they did not have neuropathy; ii five asymptomatic latent AIP gene carriers; iii one patient with AIP who developed clinical neuropathy AIPN was studied during an acute neuropathic relapse.

Comparison of mean data from AIPWN patients with control subjects established no significant difference in the stimulus—response curves Fig. During threshold electrotonus Fig. The steeper the curve i. In contrast, the steepening of the curve towards the bottom represents inward rectification, an accommodation to the hyperpolarizing current due to an increase in the hyperpolarization-activated conductance, I H Pape, No difference was shown in the depolarizing direction, in contrast to the significant difference established with greater hyperpolarization.

To investigate whether these changes in nerve excitability occurred independently of clinical episodes, excitability studies were also undertaken in a group of asymptomatic subjects who expressed PBGD genetic mutations linked to the development of porphyria. To investigate the reproducibility of these excitability changes, repeat testing was undertaken on patient 1 on seven different occasions.

This series of studies confirmed that excitability parameters were highly repeatable, with small variability between multiple sessions of testing Fig. The stimulus—response curve of this patient was consistently normal Fig. The consistency of the repeated superexcitability measurements in patient 1 Fig. Previous data on intra-individual variation in superexcitability in normal subjects Kiernan et al.

Patient 20, a previously undiagnosed year-old female, presented acutely with a 3-day history of generalized weakness, manifested by difficulty in walking up stairs and also in raising her arms. In addition, the patient complained of intermittent abdominal pain and change in urine colour Fig.

Cranial nerve examination revealed a lower motor neuron pattern of facial weakness bilaterally. Deep tendon reflexes remained symmetrically normal and plantar responses were flexor. Sensory examination was normal. Urine sample obtained from patient 20 during the porphyric attack, with dark port wine colour evident after the sample was left standing in sunlight, in comparison to a control sample.

In this acutely symptomatic patient, nerve conduction studies demonstrated reductions in compound motor action potential CMAP amplitudes, with relative preservation of conduction velocities, consistent with a motor neuropathy of the axonal type Table 2.

Sensory values were within normal limits as were proximal H-reflex and F-wave parameters. Electromyography demonstrated widespread reduction in interference patterns in upper and lower limb muscles, with minor evidence of spontaneous activity, limited to the right deltoid.

Nerve conduction parameters from patient 20, who presented with acute neuropathy. Sensory amplitudes were within normal limits as were proximal H-reflex and F-wave parameters. Treatment with a high glucose diet g daily and infusions of heme arginate mg daily led to reduction in plasma porphyrin indices, associated with gradual clinical improvement.

In this symptomatic acute porphyric neuropathy patient, excitability studies established that axons were of high threshold in both upper median nerve and lower limb peroneal nerve recordings, with stimulus—response curves shifted to the right, and rheobase increased median nerve 6.

Recordings on this patient were repeated 4 months after the initial presentation when the patient had clinically improved and demonstrated significant improvement in stimulus—response measures. Furthermore, superexcitability, a sensitive marker of membrane potential Kiernan and Bostock, , demonstrated marked improvement and had increased from Although the value of In light of the established reduction of superexcitability with membrane depolarization e.

Kiernan and Bostock, , the results in Fig. Recovery cycles of acute phase of the illness open circle and after glucose and heme treatment filled circle demonstrated improvement after treatment, particularly an increase in superexcitability block arrow. Porphyria cutanea tarda PCT is the most common type of all the porphyrias. Many signs and symptoms of porphyria are similar to those of other, more common conditions. This can make it difficult to know if you're having an attack of porphyria.

If you have any of the above symptoms, seek medical attention. In an autosomal dominant disorder, the mutated gene is a dominant gene located on one of the nonsex chromosomes autosomes. You need only one mutated gene to be affected by this type of disorder. To have an autosomal recessive disorder, you inherit two mutated genes, one from each parent.

These disorders are usually passed on by two carriers. Their health is rarely affected, but they have one mutated gene recessive gene and one normal gene dominant gene for the condition. All types of porphyria involve a problem in the production of heme. Heme is a component of hemoglobin, the protein in red blood cells that carries oxygen from your lungs to all parts of your body.

Heme production, which occurs in the bone marrow and liver, involves eight different enzymes — a shortage deficiency of a specific enzyme determines the type of porphyria. In cutaneous porphyria, the porphyrins build up in the skin, and when exposed to sunlight, cause symptoms.

In acute porphyrias, the buildup damages the nervous system. Just because you inherit a gene or genes that can cause porphyria doesn't mean that you'll have signs and symptoms. You might have what's called latent porphyria, and never have symptoms.

This is the case for most carriers of the abnormal genes. Porphyria cutanea tarda PCT typically is acquired rather than inherited, although the enzyme deficiency may be inherited. Certain triggers that impact enzyme production — such as too much iron in the body, liver disease, estrogen medication, smoking or excessive alcohol use — can cause symptoms. In addition to genetic risks, environmental factors may trigger the development of signs and symptoms in porphyria.

When exposed to the trigger, your body's demand for heme production increases. This overwhelms the deficient enzyme, setting in motion a process that causes a buildup of porphyrins. Although there's no way to prevent porphyria, if you have the disease, avoid triggers to help prevent symptoms.

Because porphyria is usually an inherited disorder, your siblings and other family members may want to consider genetic testing to determine if they have the disease, and get genetic counseling if needed. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission.

If you have a type of acute porphyria that causes skin symptoms, treatment may include protecting your skin from sunlight. If you have any type of cutaneous porphyria, your doctor will recommend steps to protect your skin from sunlight.

Doctors may prescribe different treatments for different types of cutaneous porphyria. Depending on the type of porphyria you have, your doctor may recommend steps to prevent or treat complications. Porphyria cutanea tarda and acute porphyria can increase the risk of developing liver cancer. Depending on your risk, your doctor may recommend blood tests and an ultrasound or another type of imaging test to check for liver cancer.

Finding cancer at an early stage improves the chance of curing the cancer. In people with protoporphyria, doctors may recommend protecting the liver by avoiding alcohol and getting hepatitis A and hepatitis B vaccines.

If protoporphyria leads to liver failure, you may need a liver transplant. In some cases, doctors may also recommend a bone marrow transplant, which can cure protoporphyria and keep the disease from damaging the new liver. If protoporphyria leads to gallstones, treatment typically involves surgery to remove the gallbladder. People with congenital erythropoietic porphyria or hepatoerythropoietic porphyria who develop severe anemia may require treatment with blood transfusions.

In some cases, doctors may also recommend surgery to remove an enlarged spleen, which can help treat anemia. If you have acute porphyria, your doctor may check for complications such as high blood pressure and chronic kidney disease, which may lead to kidney failure. Your doctor may prescribe medicines to lower blood pressure and recommend steps to manage chronic kidney disease or treatments for kidney failure.

If you have acute porphyria, your doctor may recommend a balanced diet in which 60 to 70 percent of your calories come from carbohydrates. Talk with your doctor or a dietitian before changing your diet to try to lose weight.

They can help you plan a safe diet to lose weight gradually. People with cutaneous porphyrias who need to avoid sunlight may have lower levels of vitamin D. Doctors may recommend vitamin D supplements to treat low vitamin D levels. The NIDDK conducts and supports clinical trials in many diseases and conditions, including liver diseases. The trials look to find new ways to prevent, detect, or treat disease and improve quality of life.

Clinical trials—and other types of clinical studies —are part of medical research and involve people like you. When you volunteer to take part in a clinical study, you help doctors and researchers learn more about disease and improve health care for people in the future. Researchers are studying many aspects of porphyria, such as new treatments to prevent acute porphyria attacks or relieve symptoms of cutaneous porphyria.

Find out if clinical studies are right for you. You can find clinical studies on porphyria at www. In addition to searching for federally funded studies, you can expand or narrow your search to include clinical studies from industry, universities, and individuals; however, the NIH does not review these studies and cannot ensure they are safe.

Always talk with your health care provider before you participate in a clinical study. The Porphyrias Consortium conducts research to advance our understanding of porphyrias and to improve diagnosis and treatment. The NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Bonkovsky, M. What are the types of porphyria? How common are porphyrias? Who is more likely to get porphyria?

What are the complications of porphyrias? What are the symptoms of porphyria? What causes porphyrias? How do doctors diagnose porphyrias? How do doctors treat porphyrias? How do doctors prevent and treat complications of porphyria?