Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Porphyrias are a group of metabolic disorders, usually genetic in origin, secondary to deficiencies of various enzymes involved in the heme biosynthesis. Each deficiency is associated with a characteristic increase in heme precursors that allows accurate diagnosis. Porphyrias typically affect nervous system and skin. Potentially life-threatening neurovisceral attacks in patients with porphyria are often precipitated by drugs, fasting, hormonal changes, or infectious diseases. There may be four categories of neuropsychiatric manifestations: seizures, polyneuropathy, transient sensory-motor symptoms, and cognitive or behavioral abnormalities. Many psychiatric manifestations are also seen in patients with acute porphyria. Hyponatremia and hypomagnesemia are common electrolyte abnormalities seen in acute attacks. Both the electrolyte changes are risk factors for the development of seizures. Acute inherited porphyria should always be considered in patients with acute polyneuropathy or encephalopathy. In several patients, a posterior reversible encephalopathy syndrome and cerebral vasospasm have been described. Porphyric neuropathy resembles acute Guillain-Barré syndrome. Electrodiagnostic findings indicate an axonal neuropathy. Axonal dysfunction is, possibly, linked to the effects of neural energy deficits acquired through haem deficiency along with the neurotoxic effects of porphyrin precursors. Treatment of seizures is particularly problematic as many of the commonly used anticonvulsants are contraindicated in porphyria. Heme therapy can induce a definite remission if given early in an attack. Givosiran is a new drug as of 2022 that has shown promising results in alleviating recurrent attacks of acute intermittent porphyria. A placebo-controlled, randomized trial has demonstrated that the patients with acute intermittent porphyria who received givosiran have a fewer number of porphyria attacks. Givosiran was most effective when administered early in the course of the disease. Recurrent attacks of porphyria predispose to hypertension, chronic renal failure, and liver malignancy. In this article, the author discusses the history, clinical features, pathophysiology, classification, and treatment of porphyria.
• Porphyrias are a group of genetic disorders caused by mutations in enzymes of the heme biosynthesis pathway.
• Porphyrias present acutely in attacks, consisting of severe abdominal pain, nausea, constipation, confusion, and seizure, and can be life-threatening.
• The precipitating factors include drugs, steroid hormones, anesthetic agents, severe fasting, stress, infections, smoking, and alcohol.
• Porphyric neuropathy is manifest by symptoms, signs, and cerebrospinal fluid abnormalities resembling acute Guillain-Barré syndrome.
• A high index of suspicion is required to make the diagnosis.
• Heme therapy is effective when given early in the course of an attack.
• Gene therapy and liver transplantation are exciting future treatment possibilities.
The word “porphyria” derives from the Greek word “porphyrus,” which means red or purple. Stokvis reported the first case of porphyria in 1889, and Campbell described its pathology in 1898 (67; 16). Early in the twentieth century, Waldenstrom called this disease a little imitator in distinction to the more common manifestations of neurosyphilis. Clinical observations by Waldenstrom (Sweden) and Watson (United States) served to better define the condition (76; 77; 79). In 1969, it was proposed that the episodic madness suffered by King George III (1738 to 1820) resulted from an acute hereditary porphyria, variegate porphyria. Even episodic psychiatric illness of Vincent van Gogh was considered to be because of porphyria. Archibald Cochrane, one of the founders of evidence-based medicine, also suffered from porphyria. Various studies have greatly advanced the molecular genetic basis of the disease (34; 75).
Porphyrias are a group of genetic disorders caused by mutations in enzymes of the heme biosynthesis pathway. Each of the seven types of porphyria is caused by partial deficiency of a different enzyme. Porphyrias are usually classified into hepatic and erythropoietic types based on the major sites of the porphyrin production. They are also classified clinically as acute or cutaneous on the basis of their major clinical manifestations. Of the five hepatic porphyrias, four can present with life-threatening acute neurovisceral attacks. These include acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare 5-aminolevulinic acid dehydratase porphyria. Porphyria cutanea tarda is the most common hepatic porphyria, which presents with skin photosensitivity. Neurologic manifestations are not observed in this variety of porphyria. Two erythropoietic porphyrias, congenital erythropoietic porphyria and erythropoietic protoporphyria, present with skin photosensitivity. Neuropathy is rarely seen in erythropoietic protoporphyria (47; 35).
Porphyria is characterized by genetic heterogeneity and highly variable expression (25; 09; 34). There are a variety of hydroxymethylbilane synthase gene mutations in every ethnic group. More than 1000 mutations in the heme biosynthetic genes causing porphyrias have been identified so far. Many are low-expression alleles. Certain genotype/phenotypes can predict clinical severity of porphyrias (87). Different ethnic groups may have different kinds of genetic mutations and may have different triggers for the disease (23; 27; 45).
The clinical manifestations of porphyria are distinctive and include recurrent attacks of acute abdominal pain with gastrointestinal symptoms (so-called neurovisceral episodes); there may be one of four neuropsychiatric symptoms: seizures, polyneuropathy, transient sensory-motor symptoms, and cognitive or behavioral abnormalities (63; 70).
Typically, periods of clinical latency are interrupted by acute symptomatic episodes. Many people with latent porphyria (about 90% of those with the gene defect) never have acute attacks but may intermittently excrete excess porphyrins. It is recognized that a variety of environmental stressors (drugs, hormonal influences, a calorie-deficient diet, intercurrent infection, and surgery) may initiate these exacerbations. Long airline flights have also triggered attacks of acute intermittent porphyria, although the cause is unknown. Porphyric attacks are rare before puberty; in adult life they are most frequent in women during the luteal phase of the menstrual cycle. It has been estimated that acute porphyria, in females, is usually diagnosed around the age of 26 years, commonly after the onset of acute symptoms. Attack risk is diminished after 35 years of age (08).
The neurovisceral attacks are characterized by the acute onset of severe neuropathic abdominal pain that can mimic the presentation of “acute abdomen.” The pain is poorly localized and usually steady but may include cramping and is often associated with nausea and vomiting, paralytic ileus, and constipation, although hyperactive bowel sounds and diarrhea may occur.
Overactivity of the sympathetic nervous system, reflecting either a secondary response to pain or the result of associated dysautonomia, produces tachycardia and hypertension and may produce urinary retention, hyperhidrosis, and tremor. Tachycardia and systemic arterial hypertension may correlate with increased catecholamine production. Persistent hypertension and renal dysfunction may occur. Hyponatremia may be due to hypothalamic involvement and inappropriate antidiuretic hormone secretion or excess gastrointestinal or renal sodium loss.
Together with the abdominal symptoms, the patient may develop a range of neuropsychiatric manifestations. Delirium and confusion can complicate an acute attack, and psychiatric symptoms occur in as many as 50% of cases in the major published series. Neuropsychiatric manifestations are often self-limiting (69). The pathogenesis of the neuropsychiatric manifestations remains unclear and poorly understood, but multiple hypotheses have been proposed, including central nervous system metabolic abnormalities, ischemia, demyelination, oxidative stress, free radical damage, aminolevulinic acid direct neurotoxicity, and nervous tissue heme deficiency (28).
Generalized seizures may occur in approximately 15% of adults, often in association with low serum sodium (the result of the syndrome of inappropriate diuretic hormone or gastrointestinal salt loss). Seizures are difficult to manage as many of the anticonvulsants are contraindicated in porphyria. One report suggested that porphyria may even be an etiologic factor in some cases of chronic refractory partial or generalized epilepsy (82). Porphyria should also be considered if the addition of a new antiepileptic medication causes a major deterioration in epilepsy. Involvement of the central nervous system has not been as well-documented, but a posterior reversible encephalopathy syndrome has been described. This is a proposed clinico-neuroradiological entity characterized by headache, altered mental status, cortical blindness, seizures, and other focal neurologic signs, and a characteristic magnetic resonance imaging picture. Mullin and coworkers described a porphyric crisis in a woman with previously undiagnosed hereditary coproporphyria (triggered by rifampicin), leading to vasospasm and stroke (48).
Many psychiatric manifestations are seen in acute porphyria. The spectrum of psychiatric manifestations includes anxiety, affective alterations, behavioral changes, and personality and psychotic symptoms. These patients may also have adjustment disorder and substance use disorders. Psychiatric symptoms can arise at any time during the course of the disease. These symptoms are often difficult to identify (19).
A variety of electrolyte abnormities are frequently encountered in these patients. Hyponatremia is the most common electrolyte abnormality during acute attacks. Another electrolyte abnormality, hypomagnesemia is also common. Both the electrolyte changes are risk factors for the development of seizures (10).
Porphyric neuropathy is manifest in symptoms, signs, and cerebrospinal fluid abnormalities resembling acute Guillain-Barré syndrome. Electro-diagnostic findings indicate an axonal neuropathy. The polyneuropathy usually follows a neurovisceral attack by 2 to 3 days but may occur independently. Neuropathy occurs in about 50% of attacks. Back pain typically precedes the onset of weakness, which is rapid, with worsening usually over a few days and recovery over weeks to months, depending on the extent of axonal injury. Prominent weakness is often seen in proximal muscles (the upper limbs), in cranial nerve-innervated muscles (bulbar weakness), and (in some cases) extraocular muscle paresis. Weakness may rarely be focal and asymmetrical. The extensors of the wrists and fingers may also be particularly affected. An ascending pattern of weakness is unusual and may serve to differentiate porphyric neuropathy from the more typically length-dependent neuropathies. Muscle wasting occurs early, reflecting axonal injury. Deep tendon reflexes tend to be depressed in proportion to the muscle wasting and are not lost early like the acute demyelinating polyneuropathies. Distal paresthesias may occur, but sensory findings are not prominent. The severity of the disease is dependent on the extent of axonal injury. Severe weakness may result in respiratory failure due to weakness of the intercostal muscles and diaphragm. Kuo and co-workers described a case of chronic distal porphyric neuropathy. The sural nerve biopsy showed a marked loss of myelinated and unmyelinated fibers because of repeated porphyric attacks (40).
Sudden death, presumably from cardiac arrhythmia, may also occur during an acute attack (03). Neuropathy in acute intermittent porphyria can have a small-fiber component rather than being solely a large-fiber neuropathy. In porphyric neuropathy, there may be dominant neuropathic or myalgic pain (50). The nerve biopsy in a 60-year-old male patient with acute intermittent porphyria who presented with initial abdominal pain and subsequent quadriplegia and respiratory failure demonstrated the presence of small-fiber neuropathy (31). In one observation, acute intermittent porphyria was diagnosed within 2 months of the first manifestation of neuropathy. Neuropathy predominantly involved an upper extremity and was dominantly motor and proximal. Nerve conduction studies recovery rates were slower in the lower than in the upper limbs. Two patients diagnosed more than 2 months after symptom onset had distal sensorimotor polyneuropathy (84).
In a series of 12 patients, nine patients had neurologic symptoms involving the central nervous system (consciousness disturbance, eight; convulsion/seizure, four; behavior change, one), whereas seven patients had peripheral nervous system involvement (motor paresis, seven; impairment of bulbar or respiratory function, four) (38). Between 2010 and 2012, 108 subjects with acute porphyrias (90 acute intermittent porphyria, nine hereditary coproporphyria, nine variegate porphyria) were enrolled in an observational study. Most subjects (88/108, 81%) were female. The most common symptom was abdominal pain. Appendectomies and cholecystectomies were common prior to a diagnosis of porphyria. The diagnosis was delayed by a mean of 15 years. Anxiety and depression were common, and 18% complained of chronic symptoms, especially neuropathic pains. The incidences of systemic arterial hypertension, chronic kidney disease, seizure disorders, and psychiatric conditions were markedly high in these patients (13). Kevelam and coworkers described a single family with acute intermittent porphyria with a distinct leukoencephalopathy with autosomal recessive inheritance. Whole-exome sequencing revealed compound heterozygous missense variants in the porphobilinogen deaminase gene. Clinical features were childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and optic atrophy as well as vertical gaze and convergence palsies and nystagmus. MRI showed symmetrical signal changes in the periventricular and deep white matter, thalami, and central part of the pons. Cerebellar atrophy was noted in advanced stages (37).
Recovery from an acute neurovisceral attack is usually rapid with appropriate treatment and supportive care. Mortality from the acute attacks is less than 10% (65). In some patients, persistent hypertension and chronic renal insufficiency may occur. There is increased psychiatric morbidity in patients with porphyria. The prognosis of recovery from porphyric polyneuropathy is dependent on the degree of axonal injury. In the majority of cases, a person remains asymptomatic throughout life. About 1% of acute attacks can be fatal.
The quality of life of patients with porphyria is markedly affected. There is always a risk for recurrence and patients may need intensive care as well. Patients need long-term treatment with heme arginate and continuous monitoring for iron levels and kidney functions (14).
Chronic complications of porphyria are hypertension, chronic renal failure, and liver malignancy. Regular hepatic imaging and monitoring blood pressure and renal function after the age of 50 years are highly recommended. Patients experiencing frequent porphyric episodes are likely to have many persistent symptoms, such as pain, mood and sleep disturbance, tiredness, and gastrointestinal symptoms (58).
Porphyrias are autosomal dominant disorders, in which there are mutations of genes of enzymes responsible for normal hepatic heme biosynthesis. Many environmental, nutritional, hormonal, and genetic factors contribute to the critical deficiency of heme, the end-product of the hepatic heme biosynthesis pathway within hepatocytes. Ultimately, there is marked hepatic overproduction of 5-aminolevulinic acid and porphobilinogen (12).
Each of the seven types of porphyria is caused by partial deficiency of a different enzyme in the heme biosynthesis pathway. Disease-specific mutations in the genes encoding these enzymes have been identified in all of the inherited porphyrias. Acute intermittent porphyria is an autosomal dominant condition resulting in a deficiency of porphobilinogen-deaminase, the cytosolic enzyme in the heme biosynthetic pathway that catalyzes the condensation of four molecules of porphobilinogen by a series of deaminations to form the linear tetrapyrrole, hydroxymethylbilane, which is then enzymatically cyclized to form uroporphyrinogen-3 by uroporphyrinogen-3-synthase. There is feedback inhibition of the enzyme aminolevulinic acid-synthase by the end product, heme. A variety of deletions and point mutations have been characterized in the gene sequence coding for porphobilinogen-deaminase on chromosome 11. In porphyrias, enzyme deficiency is associated with the accumulation of metabolic intermediates, presumed to be responsible for the clinical features of the condition.
Owing to a defect in one of the enzymes of the heme biosynthesis pathway, protoporphyrins or porphyrins (heme precursors) are prevented from proceeding further along the pathway. Specific symptoms depend on the point at which heme biosynthesis is blocked and precursors accumulate. Although there are eight steps in heme biosynthesis, there are only seven types of porphyrias; a defect in aminolevulinic acid synthase activity does not have a corresponding porphyria. The genetic defects in porphyria (26) result in half-normal levels of porphobilinogen-deaminase activity in most patients (66), resulting in increased levels of aminolevulinic acid (150 to 760 µmol per day) and porphobilinogen (220 to 880 µmol per day) in the plasma and urine during attacks. This is the basis for the Watson-Schwartz test (80). Fecal porphyrins in acute intermittent porphyria are usually normal.
It has been established that a single gene codes for porphyria, with two different promotor regions that result in two forms of the disease. The enzyme deficiency is detectable in erythrocytes in “classic” porphyria. In contrast, this deficiency is normal in erythrocytes but detectable in other tissues in the rare erythroid form of porphyria. The vast majority of patients are heterozygotes, but a few cases of patients who are homozygotic have been reported (11).
The pathophysiology of porphyric neuropathy is not exactly clear; axonal dysfunction is, possibly, linked to the effects of neural energy deficits acquired through haem deficiency along with the toxic effects of porphyrin precursors (44). The accumulated metabolic intermediates are directly toxic to neural and other tissues. However, interference in the oxygen-transporting (hemoglobin) and (cytochrome) energetic systems may also be important because of the high degree of dependence of neurons on oxidative energy metabolism. The underlying pathophysiology of porphyric neuropathy may be related to the direct neurotoxicity of elevated levels of delta-aminolevulinic acid (71).
It has been suggested that disturbed heme synthesis in neural tissue results in the depletion of essential cofactors and substrates. The central nervous system involvement may be due to the action of porphobilinogen as a false neurotransmitter, mimicking the action of serotonin. It has also been suggested that the neuropathic effects of delta-aminolevulinic acid are attributable to its pro-oxidant properties, which damage myelinating Schwann cells (21). Porphyrin neurotoxicity causes reduced activity of the Na(+)/K(+) pump resulting in membrane depolarization (43). The N-methyl-diethyl-aspartate (NMDA) receptor has been reported to play an important role in the pathogenesis of neurologic complications of porphyria (42).
In rare homozygous dominant-acute intermittent porphyria, patients may have a chronic, progressive, neurodegenerative disease. The neuroradiologic findings in a reported patient and his heterozygous relatives provided insight into the pathogenesis of homozygous dominant-acute intermittent porphyria and the acute neurologic attacks in heterozygous acute intermittent porphyria (64). Neuroradiologic studies in this patient 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. His brain magnetic resonance imaging studies suggested selective cerebral oligodendrocyte postnatal involvement, whereas most structures developed prenatally were intact. The selective white matter damage was associated with an arrest of myelin maturation at the 8- to 10-month milestones, and later with progressive vacuolation and cavitation in the periventricular white matter. The findings were consistent with aminolevulinic acid-mediated neurotoxicity, which manifested postnatally. These findings indicated that the neurologic manifestations result from porphyrin precursor toxicity rather than heme deficiency. The study also suggested that porphyrin precursor toxicity was primarily responsible for the acute neurologic attacks in heterozygous family members with acute intermittent porphyria and other porphyrias.
The blood-nerve barrier is an effective barrier like the blood-brain barrier and it helps in protecting peripheral nerves from various toxic agents present in the blood. Autopsy studies have demonstrated that the blood-nerve barrier is less restrictive in the nerve roots, myenteric plexus, and autonomic ganglia. This results in increased concentrations of aminolevulinic acid in these structures, resulting in recurrent abdominal pain and autonomic manifestations (36).
Porphyria is listed as a "rare disease" by the Office of Rare Diseases of the National Institutes of Health. This means that porphyria, or a subtype of porphyria, affects less than 200,000 people in the United States population. Approximately 5 to 10 per 100,000 persons in the United States carry a gene for acute intermittent porphyria, but only 10% of these people ever develop symptoms of the disease. Sweden has a particularly high incidence of porphyria (about 1 to 1000) and is where Wallenberg made his original observations of the disease (73). Its prevalence in the Argentinean population is about 1:125,000. Variegate porphyria is relatively common in Afrikaans-speaking South Africans. Among that population, the incidence is approximately 3 in 1000 persons. Females are more often acutely affected than males. The symptoms usually occur after puberty. Family members of affected individuals may have low levels of porphobilinogen deaminase. The European Porphyria Network collected information prospectively over a 3-year period about the number of newly diagnosed symptomatic patients with an inherited porphyria (335 patients from 11 countries). The incidence of symptomatic acute intermittent porphyria was similar in all countries (0.13 per million per year) except Sweden (0.51 per million per year). The incidence ratio for symptomatic acute intermittent porphyria: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of acute intermittent porphyria was 5.4 per million. The estimated percentage of patients with acute intermittent porphyria who would develop recurrent acute attacks was 3% to 5% (20).
The risk factors known to precipitate acute attacks should be avoided by patients. Most important among these are certain drugs, steroid hormones, and anesthetic agents, as well as severe fasting, stress, infections, smoking, and alcohol. Categories of drugs contraindicated in porphyria are listed in Table 1. Many of these are inducers of the hepatic cytochrome P450 enzyme system, which together with hemoglobin, is the major destination for the heme produced in the marrow and liver. Induction of this pathway results in the diversion of heme, with the consequent withdrawal of the inhibitory influence on aminolevulinic acid-synthase, and additional traffic in the heme pathway, leading to a buildup in porphyrin intermediates. Other drugs act to induce the rate-limiting enzyme aminolevulinic acid-synthase. One should avoid going without food for more than 12 hours if possible. Screening of families to identify presymptomatic carriers is crucial to decrease the risk of overt disease of acute porphyrias through counseling about avoidance of potential precipitants (54).
Drugs that may be used with care:
Levels of gonadal hormones are associated with a worsening of porphyria and provide an explanation for the rarity of the expression of the disease before puberty and its frequency in adult women in the luteal phase of the menstrual cycle. In women where such an association is recognized, attacks can be prevented with a luteinizing hormone-releasing hormone analogue (04).
Information, counseling, and education for asymptomatic and symptomatic patients are crucial; this helps in avoiding triggering factors of acute intermittent porphyria (29). Dietary precautions can help in preventing the next attack. High intake of energy, sugar, and candies and a low alcohol intake keep biochemical disease activity at a lower level (68).
A high index of suspicion is required to make the diagnosis of porphyria in an undiagnosed patient. A motor-predominant peripheral neuropathy (axonal predominant), abdominal symptoms, and neuropsychiatric manifestations should raise suspicion for porphyria. Clinical confirmation can be made through the evaluation of urine porphyrins during an exacerbation of the disease (72). A family history and recurrence of otherwise unexplained neurologic symptoms should alert the clinician to a possible diagnosis of porphyria (63).
The onset of acute abdominal symptoms frequently mimics many of the more common causes of an acute abdomen and may first be considered by the physician. The severity of the pain, the associated symptoms of paralytic ileus, and the sympathetically induced hypertension and tachycardia are all features in common. Because the pain is neuropathic, rather than inflammatory, signs of peritoneal irritation (guarding, rigidity) may be less pronounced, and high fever and a raised peripheral leukocyte count should not be present in a porphyric attack. The recent administration of medication or a history of darkly stained urine may raise suspicion.
Neuropsychiatric manifestations may range from mild restlessness to full-blown psychosis. Often in association with an abdominal crisis, these symptoms may be mistaken for an exaggerated behavioral response to abdominal pain.
Porphyric polyneuropathy must be distinguished from the other causes of acute or subacute motor neuropathy. Porphyric neuropathy is an acute to subacute, predominantly motor neuropathy with a predilection for the upper extremities. Porphyric neuropathy is an axonal type of neuropathy usually preceded by a dominant parasympathetic autonomic neuropathy. The rapid progression and preceding parasympathetic autonomic neuropathy mimic Guillain-Barré syndrome but are distinguished by the absence of cerebrospinal fluid albuminocytologic dissociation, progression beyond 4 weeks, and associated abdominal pain (24).
Generalized areflexia, in patients presenting with cortical blindness and posterior leukoencephalopathy syndrome, points towards acute intermittent porphyria. Electromyography testing and cerebrospinal fluid protein serve to distinguish one from the other. Arsenic and thallium poisoning may be associated with an acute or subacute motor polyneuropathy and, like porphyria, be associated with gastrointestinal and central nervous system changes. If strongly suspected, blood and urine assays should be performed. Other conditions that may mimic acute porphyria include lead poisoning and hereditary tyrosinemia type I.
A urine porphyrin screen should always be performed in patients with acute polyneuropathy or encephalopathy. In one study evaluating the number of patients with acute porphyria, porphyrin metabolites were measured in 108 patients with acute polyneuropathy or encephalopathy associated with pain or dysautonomia (51). Urinary porphyrins and their precursors were increased in 21% of the cases. Twelve patients had acute intermittent porphyria, and 11 had false-positive results. Secondary porphyrinuria, which was mainly transient coproporphyrinuria because of hepatopathy, was seen in 10% of the patients.
Ponciano and colleagues reported a case of acute intermittent porphyria that mimicked Guillain-Barré syndrome (53). Generally, porphyria neuropathy differs from Guillain-Barré syndrome as neuropathy associated with acute intermittent porphyria dominantly affects proximally and upper limbs. Nerve conduction study in porphyria neuropathy shows axonal changes. Guillain-Barré syndrome on the CSF examination typically shows cyto-albuminic dissociation, which is not present in porphyria neuropathy (53).
The decreased production of heme leads to increased production of precursors, porphobilinogen being one of the first substances in the porphyrin synthesis pathway. In patients with an attack of acute porphyria, porphobilinogen concentrations are at least 10 times the upper limit of normal within one week of the onset of symptoms. At these concentrations, urine samples may develop a brownish-red color on standing, especially in sunlight. The Watson-Schwartz test or the Hoesch test is used as qualitative tests of the urine to determine whether the amount of porphobilinogen is increased. In both of these tests, porphobilinogen reacts with 4-dimethylaminobenzaldehyde in acid (Ehrlich reagent) to form a red color. The result is interpreted as "positive" or "negative.” Measuring the amount of porphobilinogen in a 24-hour specimen or even a spot sample of urine is a much better test. A high urine porphobilinogen, when determined by a reliable method such as the Mauzerall-Granick method, is diagnostic for the presence of an acute porphyria. Urinary porphobilinogen is best analyzed in a fresh, random sample collected without any preservative but protected from light. For rapid detection of increased porphobilinogen levels in urine, the Trace porphobilinogen kit can be used. This commercially available kit detects porphobilinogen levels at concentrations greater than 6 mg/L and has a color chart for semi-quantitative estimation of higher levels (05; 01). Further tests are done to measure heme precursor levels in red blood cells and stool. The presence and estimated quantity of porphyrin and protoporphyrins in biological samples are easily detected using spectrofluorometric testing. Definitive diagnosis requires the demonstration of erythrocyte porphobilinogen-deaminase deficiency. This generally is not necessary in the immediate clinical setting but may be useful to screen asymptomatic family members. Once biochemical studies have determined the type of acute porphyria, DNA studies can identify the disease-causing mutation or mutations in the defective gene. This permits rapid and accurate testing of asymptomatic at-risk family members by DNA studies.
Brain MRI in patients with acute porphyria is usually normal; occasionally a few contrast-enhancing lesions may be seen (02). Infrequently, CT and MRI in patients with porphyria show posterior reversible encephalopathy syndrome. Posterior reversible encephalopathy syndrome typically manifests with symmetrically distributed areas of vasogenic edema predominantly within the territories of the posterior circulation. The abnormalities affect primarily the white matter, but the gray matter may also be involved. MRI lesions may also be extensive most frequently in frontal and subcortical regions. Simultaneous cerebral vasoconstriction can be demonstrated in approximately 42% of the patients (33).
MRI findings of acute intermittent porphyria can differ from those in other causes by virtue of intense contrast enhancement. In this particular case report, diffusion-weighted MRI was normal and MRI spectroscopy excluded acute demyelination or tissue necrosis. Because diffusion-weighted MRI imaging and spectroscopy were normal, it was suggested that the lesions were likely caused by reversible vasogenic edema and transient disruption of the blood-brain barrier (46). Diffuse cerebral vasospasm may be encountered in many patients during an exacerbation of acute porphyria (49). A case report described recurrent posterior reversible encephalopathy syndrome coinciding with each attack of acute intermittent porphyria (22).
Electrodiagnostic testing may help to confirm the diagnosis of porphyric polyneuropathy, exclude other neuropathies, and judge the severity and monitor the course of the axonopathy. The EMG findings are consistent with a motor-predominant, axonal polyneuropathy: compound motor action potential and sensory nerve action potential amplitudes are depressed or absent, with nerve conduction velocity preserved or slightly slowed as a consequence of axonal injury. Needle EMG may demonstrate reduced recruitment alone initially, followed in days by fibrillation potentials indicating acute denervation. Later, in parallel with the clinical recovery, the presence of polyphasic, long-duration motor units suggests reinnervation (03).
The key to long-term, ongoing management of porphyria is the avoidance of factors known to precipitate attacks of porphyria. Many categories of drugs are contraindicated in porphyria, and it is prudent to avoid all but essential medication in a known porphyric. Inappropriate sedation of an undiagnosed porphyric in the acute phase of a neurovisceral attack with severe pain and behavioral symptoms is frequent. Attention to nutrition and fluid balance is essential.
Analgesics should always be used with caution. In a case report, metamizole, a dipyrone compound that helps in relieving pain and spasm, produced another episode while a patient was recovering following treatment from her first episode of porphyria (61). Pain is usually severe and narcotic analgesics are the best option for relief. Phenothiazines can be used to counter nausea, vomiting, and anxiety, and chloral hydrate or diazepam is useful for sedation or to induce sleep. Treatment of seizures is particularly problematic as many of the commonly used anticonvulsants are contraindicated in porphyria. It may be possible to avoid treatment altogether, particularly in the case of an isolated seizure with the prompt management of the underlying porphyria (05). Despite the development of new antiepileptic agents, the therapy of epilepsies along with hepatic porphyrias remains difficult. Most antiepileptic drugs such as carbamazepine, phenytoin, valproate, and lamotrigine may precipitate clinically latent porphyria by inducing hepatic metabolism and increasing hepatic heme synthesis. Gabapentin, an antiepileptic drug without any hepatic metabolism, is considered a good drug for the therapy of partial seizures in patients having hepatic forms of porphyria. Other antiepileptic drugs, levetiracetam and oxcarbazepine, can successfully be given to patients with porphyria (41).
Heme is particularly effective when given early in the course of an attack and is the most effective treatment available. These heme-like substances inhibit aminolevulinic acid synthase causing less accumulation of toxic precursors. Heme may be given in the form of hematin, heme albumin, or heme arginate at a dose of 3 mg to 4 mg per day by intravenous infusion for 4 days. An open-label study further demonstrated the efficacy and safety of hemin therapy (06). Hemin was administered to 111 patients for treatment of 305 acute attacks and to 40 patients for prophylaxis. Hemin was regarded as effective for all attacks in 73% of patients. Doses for acute attacks were less than the recommended 3 to 4 mg/kg/day in 20% of patients. Among 31 patients who received hemin prophylaxis for more than 1 month, 68% did not require subsequent hemin treatment for acute attacks. Most adverse events were attributed to porphyria rather than to treatment and were more common in patients treated for acute attacks rather than prophylaxis (06). The findings of a case report suggest that early hematin treatment is associated with a steady and gradual improvement in porphyric motor neuropathy. During the 1-year follow-up period in one patient, six courses of hematin infusion, with 150 mg daily for 4 consecutive days every month, were administrated (39). Heme arginate is a more stable heme compound; it has not been approved for use in the United States. Clinical improvement is rapid, often within 1 to 2 days, when hemin therapy is started early in an attack. But when treatment is delayed, neuronal damage may be advanced and recovery may be slower. Hematin should be administered via a large vein; administration is generally safe, but it may cause thrombophlebitis. Thrombophlebitis is less likely if hematin is mixed with human albumin before administration (05). Reconstitution with albumin produces a significantly more stable preparation than reconstitution with sterile water and may lead to a more tolerable administration with less hemostatic interference (60).
Prophylactic heme therapy on a weekly basis helped two patients who had frequent attacks of acute intermittent porphyria. Frequent attacks were defined as more than three attacks in 1 year, and at least one attack requiring heme therapy. Prophylactic heme therapy led to a complete absence of acute attacks and hospital admissions in one patient and to a 75% reduction in attacks in the other (85).
Glucose is clearly less effective and is recommended only for attacks with mild pain and no paresis. Intravenous glucose alone (10%, at least 300 g daily) may resolve mild attacks (mild pain, no paresis, or hyponatremia) or can be given while awaiting delivery of hemin. In some patients with porphyria, treatment with erythropoietin reduces urinary delta-aminolevulinic acid, porphobilinogen, and porphyrin levels with an increase in well-being and a reduction in the severity of porphyria attacks (83).
A gonadotropin-releasing hormone analogue can prevent cyclical attacks of porphyria. Gonadotropin-releasing hormone analogues can prevent ovulation by reducing the secretion of the luteinizing hormone and follicle-stimulating hormone.
A trial of recombinant human porphobilinogen deaminase was conducted in healthy subjects and asymptomatic porphobilinogen deaminase-deficient subjects with high concentrations of plasma porphobilinogen. The recombinant human porphobilinogen deaminase enzyme preparation was found to be safe to administer and effective for the removal of the accumulated metabolite porphobilinogen from plasma and urine. However, the therapeutic efficacy of the enzyme recombinant human porphobilinogen deaminase during periods of overt disease has not been studied (56).
Studies have explored the use of a gene therapy vector containing combinations of liver-specific enhancers and promoters for producing maximal hepatic hydroxymethylbilane synthase enzyme expression in patients with acute intermittent porphyria (88). In a mouse model, liver-directed gene therapy provided successful long-term correction of hepatic metabolic abnormalities. Intraperitoneal administration of the adeno-associated viral vector resulted in a rapid and dose-dependent increase of hydroxymethylbilane synthase activity in the liver. Stable expression of hepatic hydroxymethylbilane synthase was achieved. When heme synthesis was periodically induced by a series of phenobarbital injections, the treated mice did not accumulate urinary delta-aminolevulinic acid or porphobilinogen, indicating that the expressed enzyme was functional in vivo and prevented the induction of the acute attack (86). In an experimental study, phenobarbital injections, in acute intermittent porphyria mice, induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve (74). Recombinant adeno-associated virus vectors expressing human porphobilinogen deaminase protein driven by a liver-specific promoter provided sustained protection against induced attacks in animal models for acute intermittent porphyria. Sustained hepatic expression of human porphobilinogen deaminase protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity. Gene therapy has promise for the future in patients with recurrent life-threatening porphyria attacks. In a phase 1 open-label, dose-escalation, multicenter clinical trial, investigators showed that the administration of porphobilinogen deaminase gene rAAV2/5-PBGD to patients with severe acute intermittent porphyria is safe, but metabolic correction was not achieved at the doses tested. In this trial, four cohorts of two patients each received a single intravenous injection of the vector ranging from 5x1011 to 1.8x1013 genome copies/kg (17).
Liver transplantation may be needed for recurrent or life-threatening acute attacks of acute intermittent porphyria or in erythropoietic protoporphyria. Liver transplantation in acute intermittent porphyria is curative. Patients with erythropoietic protoporphyria who need liver transplantation should be considered for bone marrow transplantation to achieve a cure (59; 62).
Acute intermittent porphyria is caused by the induction of delta-aminolevulinic acid synthase 1 gene expression. Accumulation of neurotoxic intermediates results in clinical manifestations of acute intermittent porphyria. Givosiran is an investigational drug as of 2022 that has shown promising results in alleviating recurrent attacks of acute intermittent porphyria. Givosiran inhibits hepatic delta-aminolevulinic acid synthase 1 synthesis, resulting in lower delta-aminolevulinic acid synthase 1mRNA levels and normal levels of the neurotoxic delta-aminolevulinic acid and porphobilinogen. In a phase 1 trial this drug was associated with mainly low-grade adverse events and a lower attack rate than that seen in controls (55; 18). In November 2019, the United States FDA approved givosiran for the treatment of acute hepatic porphyria in adults (57).
After a placebo-controlled randomized trial, Balwani and colleagues reported that the patients with acute intermittent porphyria who received givosiran had a significantly fewer number of porphyria attacks (07). In this trial, 94 patients with symptomatic porphyria were randomly assigned to receive either subcutaneous givosiran (2.5 mg/Kg) or placebo monthly for 6 months. The primary endpoint was the number of porphyria attacks within 6 months. Treatment with givosiran resulted in 74% reduction in porphyria attacks in patients with acute intermittent porphyria. Similar results were noted in patients with acute hepatic porphyria as well. The common adverse events in the givosiran group were elevated liver enzymes and alterations in renal function along with a high frequency of local injection site reactions (07). Poli and colleagues, in a retrospective review of 25 patients, noted that givosiran was most effective when administered early in the course of the disease (52).
Chaperones are small molecular weight compounds that interact with unstable and incorrectly folded proteins and help to stabilize them. They also protect them from early degradation, thus, increasing their half-life cellular activity to target unstable protein. In an experimental study, it has been demonstrated that chaperone compound can help in stabilizing the enzyme hydroxymethylbilane synthase in hydroxymethylbilane synthase-deficient mice leading to improvement of the enzymatic activity (15).
Pregnancy and its associated hormonal changes increase porphyrin metabolism and, therefore, can precipitate acute porphyria attacks, which usually present with gastrointestinal symptoms and personality changes. A case report suggests that acute hepatic porphyria in pregnancy rarely can lead to untreatable convulsions that leave no option but to terminate the pregnancy (81). Worsening symptoms during pregnancy are sometimes due to harmful drugs (for example, metoclopramide), inadequate nutrition, or both. A first attack of acute porphyria with pregnancy is rare. A significant risk to the fetus exists with an acute exacerbation of porphyria; spontaneous abortion occurs in 30%, and there is a 40% fetal loss rate. Some series have shown a 20% maternal mortality. If the pregnancy goes to term, labor and delivery are not affected. No neonatal effects are known despite the passive placental transfer of porphyrins. Hemin can be administered safely during pregnancy. Acute intermittent porphyria may manifest in patients with primary infertility undergoing ovulation induction and should be considered in these patients if they develop unexplained hyponatremia or neurovisceral symptoms (78).
Acute attacks of porphyria may be precipitated by many factors during surgery and anesthesia, including fasting, dehydration, stress, infection, and drugs (30). Many anesthetic agents are unsafe with porphyria, and it is vital to recognize the condition in patients scheduled for surgery in order to avoid inducing an acute attack. Barbiturates are contraindicated, as are many non-barbiturate sedative agents, such as lidocaine, phenytoin, and ethyl alcohol (see Table 1). Propofol appears to be a safe induction agent, although ketamine may be used if required. Most muscle relaxants appear to be reasonably safe, and all of the inhalational agents, with the possible exception of enflurane, can probably be used. Analgesia can be provided with opiates. Safe use of rocuronium and sevoflurane for long exposure in a patient affected with acute intermittent porphyria has been demonstrated (30). Regional anesthesia, with any of the currently available agents, is not contraindicated and may be of benefit where appropriate (32).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Ravindra Kumar Garg MD
Dr. Garg of King George's Medical University in Lucknow, India, has no relevant financial relationships to disclose.See Profile
Douglas J Lanska MD FAAN MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.See Profile
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