Hereditary coproporphyria, an autosomal dominant acute hepatic porphyria, is characterized by acute attacks of neurologic dysfunction often provoked by drugs, fasting, menstrual cycle, or infectious diseases. Skin photosensitivity may also be present. Excretion of large amounts of coproporphyrin ... Hereditary coproporphyria, an autosomal dominant acute hepatic porphyria, is characterized by acute attacks of neurologic dysfunction often provoked by drugs, fasting, menstrual cycle, or infectious diseases. Skin photosensitivity may also be present. Excretion of large amounts of coproporphyrin III, mostly in feces and urine, is observed. Harderoporphyria is a rare homozygous erythropoietic variant form of HCP, characterized by neonatal hemolytic anemia, sometimes accompanied by skin lesions, and massive excretion of harderoporphyrin in feces. During childhood and adulthood, a mild residual anemia is chronically observed (review by Schmitt et al., 2005).
In a study of a large family with genetically confirmed HCP, Allen et al. (2005) found that measurement of fecal coproporphyrin III:I ratio is a highly sensitive test for the detection of asymptomatic HCP. The proband was a ... In a study of a large family with genetically confirmed HCP, Allen et al. (2005) found that measurement of fecal coproporphyrin III:I ratio is a highly sensitive test for the detection of asymptomatic HCP. The proband was a 35-year-old man who presented with unexplained severe abdominal pain and was found to have an increased fecal coproporphyrin III:I ratio of 12.7. Total urine porphyrins were also elevated. There were 13 asymptomatic mutation carriers; all had an increased fecal coproporphyrin III:I ratio (mean 14.0, normal less than 1.0), and 11 (85%) had increased fecal total porphyrin. Eight (62%) of the 13 asymptomatic carriers had increased urinary total porphyrin (up to 3-fold) due to excess coproporphyrin III. All individuals studied were older than 10 years of age; the sensitivity of the test for those under 10 years of age was uncertain. Plasma fluorescence emission scanning for porphyrin was not a useful indicator.
The first case of coproporphyria, reported by Berger and Goldberg (1955), was the offspring of first-cousin parents, both of whom showed excessive excretion of coproporphyrin III. The authors suggested that the disorder is autosomal dominant and that their ... The first case of coproporphyria, reported by Berger and Goldberg (1955), was the offspring of first-cousin parents, both of whom showed excessive excretion of coproporphyrin III. The authors suggested that the disorder is autosomal dominant and that their proband was homozygous. Barnes and Whittaker (1965) described 4 of 5 sibs who were affected. The parents were not tested. Marked elevation of coproporphyria in the feces differentiated the condition from acute intermittent porphyria (AIP; 176000) in which stool porphyrins are usually normal and from variegate porphyria (VP; 176200) in which both coproporphyrin and protoporphyrin fractions are increased in the stool. The proband experienced typical acute porphyria. Constipation and abdominal colic were striking features in these patients. Goldberg et al. (1967) added 20 new cases. A massive excretion of coproporphyrin III in the urine and predominantly in the feces was demonstrated. Attacks resembling those of AIP were precipitated by drugs, and during attacks porphobilinogen and delta-aminolevulinic acid were excreted in the urine in excess. Photosensitivity is occasionally present and the only manifestations may be psychiatric. About half of cases are asymptomatic. This is an hepatic form of porphyria. In the family of Haeger-Aronsen et al. (1968), 13 persons in 5 sibships of 2 generations showed latent coproporphyria, in addition to the symptomatic proband. Cripps and Peters (1970) found that tranquilizers, including meprobamate and chlorpromazine, precipitated attacks. McIntyre et al. (1971) noted that increased hepatic delta-aminolevulinic acid synthetase has been demonstrated in 3 forms of hereditary porphyria: AIP, VP, and coproporphyria. In cultured skin fibroblasts, Elder et al. (1976) found that the activity of coproporphyrinogen oxidase was about half normal. Similar findings were reported for leukocytes (Brodie et al., 1977). In the homozygous patient reported by Grandchamp et al. (1977), activity of coproporphyrinogen oxidase was only 2% of control values. Andrews et al. (1984) found 27 cases of coproporphyria in a kindred in which 135 members were screened for fecal porphyrins. Of the 135, 6 females and 1 male had probably suffered clinical attacks; the M:F ratio of cases revealed by screening was 13:14. The proband had her first attack at age 84 years; diazepam and nitrazepam were incriminated in her attack, and other drugs in the other patients. The late manifestation is indicated by the fact that this report was from a department of geriatric medicine. The earliest attack in an affected person was at age 14 years. Barohn et al. (1994) described acute peripheral neuropathy with hereditary coproporphyria. This is a common feature of AIP but is rare with this form of porphyria. Gross et al. (2002) reported the molecular, enzymatic, and clinical study of a family with hereditary coproporphyria in which the proband was a 30-year-old woman suffering from acute crises with abdominal, neurologic, and psychiatric complaints. The proband's father, 1 brother, and a sister were found to be new carriers. The patient was treated with intravenous interval therapy with haem arginate for 10 months, with good clinical and metabolic response. - Harderoporphyria In 3 sibs (2 boys, 1 girl) with intense jaundice and hemolytic anemia at birth, Nordmann et al. (1983) found a high level of coproporphyrin in the urine and feces. The pattern of fetal porphyrin excretion was atypical because the major porphyrin was harderoporphyrin (more than 60%; normal, less than 20%). Homozygosity was suggested by the fact that the level of lymphocyte coproporphyrinogen III oxidase was 10% of controls in the sibs and 50% of normal in both parents (who showed only mild abnormalities of porphyrin excretion). The mutant enzyme showed abnormal kinetics. Doss et al. (1984) likewise reported a case of the harderoporphyria variant. The parents were related, and the enzyme level was 7% in the patient and 53% in the mother; thus, homozygosity was suggested. The proband had severe jaundice, hemolytic anemia, and hepatosplenomegaly at birth. At age 10 slight photosensitivity and mild, compensated hemolytic anemia prompted diagnostic search for porphyria. Schmitt et al. (2005) reported a fifth patient with harderoporphyria. They demonstrated that harderoporphyric patients exhibit iron overload secondary to dyserythropoiesis.
Schmitt et al. (2005) noted that all 5 reported patients (from 3 families) with harderoporphyria had a K404E mutation (612732.0003) in the CPOX gene in homozygosity or compound heterozygosity with a null mutation. Biochemical and expression studies revealed ... Schmitt et al. (2005) noted that all 5 reported patients (from 3 families) with harderoporphyria had a K404E mutation (612732.0003) in the CPOX gene in homozygosity or compound heterozygosity with a null mutation. Biochemical and expression studies revealed that only a few missense mutations, restricted to 5 amino acids encoded by exon 6 (D400-K404), may accumulate significant amounts of harderoporphyrin. All types of mutations occurring elsewhere throughout the CPOX gene resulted in coproporphyrin accumulation and subsequently typical HCP. They stated that this was the first metabolic disorder in which clinical expression of overt disease depended on the location and type of mutation, resulting either in acute hepatic or in erythropoietic porphyria.
In the homozygous patient with coproporphyria reported by Grandchamp et al. (1977), Martasek et al. (1994) demonstrated an arg231-to-trp mutation in the CPO gene (612732.0001).
In the 3 sibs with the harderoporphyria variant reported by Nordmann ... In the homozygous patient with coproporphyria reported by Grandchamp et al. (1977), Martasek et al. (1994) demonstrated an arg231-to-trp mutation in the CPO gene (612732.0001). In the 3 sibs with the harderoporphyria variant reported by Nordmann et al. (1983), Lamoril et al. (1995) demonstrated a K404E missense mutation in exon 6 of the CPO gene (see 612732.0003). Lamoril et al. (2001) studied 17 unrelated British patients with HCP. They identified 10 novel and 4 previously reported CPO mutations in 15 of the 17 patients. All but 1 mutation were restricted to a single family, with a predominance of missense mutations. Both patients in whom mutations were not identified had an unequivocal diagnosis of HCP. Complete deletions of the CPO gene were excluded by showing that both patients were heterozygous for at least 1 intragenic SNP. It is probable that the causative mutations either lie outside the regions that were sequenced or were partial deletions or insertions not detected by the PCR-based methods. The findings of this study demonstrated that single copies of CPO mutations that are known or predicted to cause 'homozygous' HCP or harderoporphyria can produce typical HCP in adults and demonstrated that the severity of the phenotype does not correlate with the degree of inactivation by mutation of the coproporphyrinogen oxidase enzyme. In 5 of 9 Swedish families with HCP, Wiman et al. (2002) identified mutations in the CPO gene. In each of 2 of the families, a novel mutation was identified: ser208 to phe (S208F; 612732.0010) and arg328 to cys (R328C; 612732.0011). In the affected members of the other 3 families, 2 previously reported mutations, R331W (612732.0001) and R447C (612732.0009), were shown to coexist on 1 allele. This was the first report of patients carrying 2 HCP-related mutations on the same allele.
Hereditary coproporphyria (HCP) is classified as both an acute (hepatic) porphyria (with neurologic manifestations that occur as discrete, severe episodes) and a chronic (cutaneous) porphyria with longstanding photosensitivity....
DiagnosisHereditary coproporphyria (HCP) is classified as both an acute (hepatic) porphyria (with neurologic manifestations that occur as discrete, severe episodes) and a chronic (cutaneous) porphyria with longstanding photosensitivity.Acute hepatic porphyria. HCP is suspected in individuals with the following symptoms or findings:Nausea for at least 48 hoursAbdominal, back, or extremity pain for at least 48 hoursNew-onset seizures Hyponatremia Note: Although disease-causing CPOX mutations occur equally in males and females, acute attacks are much more frequent in women, mainly between ages 16 and 45 years (the years of active ovulation). Chronic cutaneous porphyria. HCP is suspected in individuals with bullae and fragility of light-exposed skin which result in depigmented scars; however, the cutaneous signs occur in only a minority of heterozygotes, even during an acute attack. TestingThe most sensitive and specific biochemical diagnostic tests for HCP are detailed in Table 1. Active HCP is suggested by a quantitative urinary PBG that is at least threefold the upper limit of normal.The characteristic finding in stool is COPRO >> PROTO, quantified as units/g dry weight of feces. Note: Some laboratories report units/24 hours, which is inherently inaccurate. US laboratories that do the more precise analysis include ARUP (Salt Lake City, UT) and the Porphyria Laboratory, University of Texas Medical Branch, K Anderson, MD, Director (Galveston, TX). The diagnosis is further substantiated by analysis of the COPRO-III/COPRO-I fecal porphyrin ratio, showing that 60%-95% of the total COPRO is isomer-III. In a normal (or ‘negative’) test, the predominant fecal porphyrin is PROTO, and the COPRO isomer III/I ratio in many cases is <0.5 [Kühnel et al 2000]. Identification of a heterozygous mutation in CPOX, encoding the enzyme coproporphyringen-III oxidase, confirms the diagnosis (Table 2).Table 1. Biochemical Characteristics of Hereditary Coproporphyria (HCP)View in own windowDeficient EnzymeUrineStoolActiveAsxActiveAsxCoproporphyringen-III oxidase 1, 2↑PBG 3, 4, 5↑COPRO 6Normal PBG COPRO 7COPRO >> PROTO 8See footnote 9Active = symptomatic CPOX heterozygotesAsx = asymptomatic CPOX heterozygotesPBG = porphobilinogenNormaI PBG = <2 mg (0.85 μmol) per g urine creatinine COPRO = coproporphyrinPROTO = protoporphyrin1. Also known as coproporphyrinogen oxidase and coproporphyrinogen decarboxylase 2. The enzyme assay is not widely available and is not used for diagnostic purposes 3. Results of the rapid qualitative test for PBG (Thermo Scientific) agree well with standard quantitative measurements [Vogeser & Stauch, 2011].4. Active HCP is suggested by a quantitative PBG that is at least 3-fold the upper limit of normal 5. Commercial laboratories offer quantitative delta aminolevulinic acid (ALA), PBG, and fractionated urine porphyrins. Values normalized to urine creatinine are satisfactory for clinical use, making a 24-hour collection unnecessary. 6. See Differential Diagnosis for discussion of nonspecific elevation of COPRO in the urine.7. Fractionated urine porphyrins may reveal a minor rise in COPRO (<3-fold the upper limit of normal); however, this is nonspecific and insufficient for diagnosis (see Differential Diagnosis).8. 60%-95% of the total COPRO is isomer-III.9. Fecal porphyrin analysis is the best test for distinguishing HCP from nonspecific coproporphyrinuria: heterozygotes show a predominance of fecal COPRO and an elevated COPRO III/I ratio (see Testing).Molecular Genetic TestingGene. CPOX is the only gene in which mutations are known to cause hereditary coproporphyria (HCP). Table 2. Summary of Molecular Genetic Testing Used in Hereditary Coproporphyria View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCPOXSequence analysisSequence variants 229/31 3ClinicalDeletion / duplication analysis 4 Exonic or whole-gene deletionsSee footnote 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. Sequence analysis found a mutation in 29 of 31 (94%) individuals with the clinical and biochemical diagnosis of HCP [Whatley et al 2009].4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. To date, a 13-kb deletion extending from exon 4 to the 3’UTR [Whatley et al 2009] and a 1.3-kb deletion spanning exon 5 (found in four Swedish families) [Barbaro et al 2012] have been reported.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandFor an individual with pain and neurologic signs, the initial goal is to determine if the symptoms can be attributed to an attack related to any one of the acute porphyrias (i.e., ALA dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, or variegate porphyria) (see Differential Diagnosis), which can be determined by a rapid test for urinary porphobilinogen (PBG) (Table 1). Acute attacks are associated invariably with a striking increase in urinary PBG. Note: Since initial management is the same for all four types of acute porphyria, it is not necessary to determine at the outset of treatment which one of the four types of acute porphyria is present. Once the diagnosis of an acute porphyria is established, quantitative analysis of porphyrins in both urine and feces may help define the specific type (Figure 1). The specific type of porphyria is confirmed by molecular genetic testing for mutation of the relevant gene. FigureFigure 1. Excretion profile of the hepatic porphyrias Profile of heme precursor excretion for the types of hepatic porphyria. The pathway of heme synthesis (arrows) is served by a series of enzymes (boxes). Mutations that decrease the (more...)Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Note: Although some CPOX heterozygotes have a diagnostic biochemical profile of heme precursors in urine and feces (see ‘Active’ columns in Table 1), many have normal biochemical test results (see ‘Asymptomatic’ columns in Table 1) and can be diagnosed only by molecular genetic testing. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Note: Because of reduced penetrance, many individuals heterozygous for a CPOX mutation do not manifest signs and symptoms of HCP. Genetically Related (Allelic) Disorders Biallelic mutations of CPOX. Certain CPOX mutations (notably D400-K404 in exon 6) in the homozygous state result in a disorder called harderoporphyria [Hasanoglu et al 2011]. Some mutations may affect the active site of the enzyme, possibly causing premature separation of CPOX from its substrate. The result is incomplete decarboxylation of COPROgen yielding the tricarboxylic intermediate harderoporphyrinogen instead of dicarboxylic PROTOgen (Figure 1). Heterozygotes for a CPOX mutation that is associated with harderoporphyria have no symptoms; those with biallelic mutations have large amounts of harderoporphyrin in the stool and neonatal onset of hemolytic anemia and jaundice, which can resemble the findings of congenital erythropoietic porphyria, an autosomal recessive condition with hemolysis and severe photosensitivity in infancy. They can also have acute porphyric attacks with high levels of urinary ALA and PBG. One infant died at age five months, apparently from complications of an acute attack [Hasanoglu et al 2011]. Some develop normally while others exhibit short stature.
Hereditary coproporphyria (HCP) is classified as both an acute and chronic porphyria. Porphyrias with neurologic manifestations are considered acute, because the symptoms occur as discrete, severe episodes. Porphyrias with cutaneous manifestations are considered chronic, because photosensitivity is longstanding (see Table 3)....
Natural History Hereditary coproporphyria (HCP) is classified as both an acute and chronic porphyria. Porphyrias with neurologic manifestations are considered acute, because the symptoms occur as discrete, severe episodes. Porphyrias with cutaneous manifestations are considered chronic, because photosensitivity is longstanding (see Table 3).In a German study of 46 individuals with acute HCP, 90% had abdominal pain; only 13% had cutaneous findings despite substantial overproduction of coproporphyrin [Kühnel et al 2000]. An earlier British study of 111 individuals with HCP reported similar findings [Brodie et al 1977]. Fertility and longevity do not appear to be reduced in CPOX heterozygotes. Acute AttacksThe initial symptoms of an acute attack are nonspecific, consisting of low-grade abdominal pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting of all oral intake. Typically the pain is not well-localized but in some instances does mimic acute inflammation of the gallbladder, appendix, or other intra-abdominal organ. In most instances the abdominal examination is unremarkable except for diminished bowel sounds consistent with ileus, which is common and can be seen on abdominal radiography. Typically fever is absent. In a young woman of reproductive age, the symptoms may raise the question of early pregnancy. Prior to the widespread use of abdominal imaging in the emergency room setting, some individuals with abdominal pain and undiagnosed acute porphyria underwent urgent exploratory surgery. Thus, a history of abdominal surgery with negative findings was considered characteristic of acute porphyria. A minority of affected individuals has predominantly back or extremity pain, which is usually deep and aching, not localized to joints or muscle groups. Neurologic manifestations. Seizures may occur early in an attack and be the problem that brings the patient to medical attention. In a young woman with abdominal pain and new-onset seizures, it is critical to consider acute porphyria because of the implications for seizure management (see Management). When an attack is unrecognized as such or treated with inappropriate medications, it may progress to a motor neuropathy, which typically occurs many days to a few weeks after the onset of symptoms. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Neurosensory function remains largely intact. In some individuals the motor neuropathy eventually involves nerves serving the diaphragm and muscles of respiration. Ventilator support may be needed. Tachycardia and bowel dysmotility (manifest as constipation) are common in acute attacks and believed to represent involvement of the autonomic nervous system. Of note, when the acute attack is recognized early and treated appropriately (see Management), the outlook for survival and eventual complete recovery is good. Psychosis. The mental status of people presenting with an acute attack of porphyria varies widely and can include psychosis. Commonly, however, the predominant feature is distress (including pain) that may seem hysterical or feigned, given a negative examination, absence of fever, and abdominal imaging showing some ileus only. Incessant demands for relief may be interpreted as drug-seeking behavior. Because people with an acute porphyria attack may display an altered affect, it has been speculated that mental illness is a long-term consequence of acute porphyria and that mental institutions may house a disproportionately large numbers of individuals with undiagnosed acute porphyria. Screening of residents in mental health facilities by urinary PBG and/or PBG deaminase activity in blood (which diagnoses acute intermittent porphyria) has been done, with mixed results [Jara-Prado et al 2000]. The experience of those who have monitored patients over many years suggests that heterozygotes who are at risk for one of the acute porphyrias are no more prone to chronic mental illness than the general population; however, a prospective study is needed. Circumstances commonly associated with acute attacks are caloric deprivation, changes in female reproductive hormones, and use of porphyria-inducing medications or drugs: Caloric deprivation. Fasting appears to sensitize the heme-synthetic pathway to an inducer, which could be external (i.e., a medication) or internal (progesterone and related hormones). The sensitizing effect of caloric deprivation was demonstrated in the 1960s in experimental animals and has been confirmed by clinical observation. People who fail to eat because of intercurrent illness or who undertake drastic weight loss are predisposed to an acute attack. First attacks have been reported after reduction gastroplasty for obesity [Bonkovsky et al 2008]. CPOX heterozygotes undergoing surgery are at risk because of the routine preoperative fast. This and other anecdotal experience have led to consensus that the first line of treatment for an acute attack is intravenous glucose, which occasionally is helpful. Changes in female reproductive hormones. A role for female reproductive hormones can be inferred from the fact that acute attacks are infrequent prior to menarche and after menopause. Some women have monthly attacks that appear a few days before the onset of menstruation (when progestins peak). Attacks have been linked to use of oral contraceptives; the risk may be associated more with the progesterone component than the estrogen component. Use of porphyria-inducing medications or drugs. See Agents/Circumstances to Avoid.Chronic (cutaneous) manifestations. Photocutaneous damage is present in only a small minority of those with acute attacks. Bullae and fragility of light-exposed skin, in particular the backs of the hands, result in depigmented scars. Facial skin damage also occurs, with excess hair growth on the temples, ears, and cheeks; this is more noticeable in women than in men. The cutaneous findings in HCP resemble those in porphyria cutanea tarda (PCT) and in variegate porphyria (VP). Threshold for a pathogenic effect of porphyrins and their precursors. Clinically active acute porphyria is associated with substantial elevation of the precursors ALA and PBG in the blood and urine; the cutaneous porphyrias are associated with increased porphyrins in blood, urine, and feces. In the acute porphyrias and cutaneous porphyrias, a threshold for symptoms appears to exist. Acute (hepatic) porphyrias. A threshold for acute attacks is suggested by the fact that in virtually all symptomatic individuals, urinary PBG excretion exceeds 25 mg/g creatinine, or more than tenfold the upper limit of normal. Urinary ALA excretion increases roughly in parallel. In contrast, in asymptomatic individuals the baseline urinary PBG excretion varies widely, usually low or normal but occasionally exceeding 25 mg/g creatinine. For this reason, it is advisable to establish the baseline urinary PBG excretion for CPOX heterozygotes (see Evaluations Following Initial Diagnosis).Chronic (cutaneous) porphyrias. A threshold has been well defined for porphyria cutanea tarda (PCT), in which photosensitivity occurs at values of urine uroporphyrin (the predominant pathway intermediate) that are more than 20-fold the upper limit of normal. However, the same is not apparent with regard to urine coproporphyrin: only a minority of CPOX heterozygotes exhibit any photosensitivity. Of note, in individuals with HCP and chronic liver disease the cutaneous component may be more prominent than expected for the observed urine or plasma PBG concentration. Coproporphyrin leaves the plasma largely via the liver going into bile. In chronic liver disease, bile transport processes or bile formation may be impaired, leading to accumulation of coproporphyrin in plasma, which then results in photosensitivity.
HCP. HCP-causing mutations in CPOX are not clustered around the enzymatic site. Furthermore, no correlation exists between the clinical phenotype and the residual enzymatic activity measured in vitro for a given mutation [Lamoril et al 2001]. ...
Genotype-Phenotype Correlations HCP. HCP-causing mutations in CPOX are not clustered around the enzymatic site. Furthermore, no correlation exists between the clinical phenotype and the residual enzymatic activity measured in vitro for a given mutation [Lamoril et al 2001]. Homozygotes for CPOX mutations that cause minimal or no symptoms in heterozygotes have been reported to have very low coproporphyringen-III oxidase activity and a severe phenotype [Schmitt et al 2005, Hasanoglu et al 2011]. (See Genetically Related Disorders.)Double heterozygosity for mutations in genes causing two different types of acute (hepatic) porphyria. Double heterozygotes for a mutation in CPOX and either a mutation in PPOX (variegate porphyria [VP]) [van Tuyll van Serooskerken et al 2011] or ALAD (ALA dehydratase deficiency porphyria [ADP]) [Akagi et al 2006] have been described. The phenotypes of such double heterozygotes vary but are not necessarily more severe than those associated with heterozygosity for either mutation alone, suggesting that double heterozygotes for two different types of acute porphyria may not be as rare as has been assumed.
The genetic porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in accumulation of a specific substrate (Figure 1). ...
Differential DiagnosisThe genetic porphyrias comprise a group of distinct diseases, each resulting from alteration of a specific step in the heme synthesis pathway that results in accumulation of a specific substrate (Figure 1). In Table 3 the porphyrias are grouped by their principal clinical manifestations (neurolovisceral or cutaneous) and the tissue origin of the excess production of pathway intermediates (liver [i.e., hepatic] or bone marrow [i.e., erythropoietic]). Porphyrias with neurovisceral manifestations are considered acute because the symptoms occur as discrete, severe episodes, which may be spontaneous but frequently are induced by external factors. The four acute porphyrias are: ALA dehydratase deficiency porphyria (ADP), acute intermittent porphyria (AIP), HCP, and variegate porphyria (VP). Only a few cases of ADP have been reported in the world literature.Porphyrias with cutaneous manifestations include either chronic blistering skin lesions (i.e., VP as well as PCT, HCP, CEP, and HEP) or acute non-blistering photosensitivity (i.e., EPP and XLP). Table 3. Classification of the Hereditary PorphyriasView in own windowType of PorphyriaFindingsMode of InheritanceNeurovisceral 1 Photocutaneous HepaticADP+0ARAIP+0ADHCP++ADPCT type II0+ADVP++ADErythropoieticCEP0+AREPP, AR0+ 2ARXLP0+ 2XLADP = ALA dehydratase deficiency porphyriaAIP = acute intermittent porphyriaHCP = hereditary coproporphyriaPCT = porphyria cutanea tardaVP = variegate porphyriaCEP = congenital erythropoietic porphyriaEPP = erythropoietic protoporphyriaXLP= X-Linked protoporphyria0 = no symptoms+ = mild to severe symptomsAR=autosomal recessiveAD=autosomal dominantXL=X-linked 1. Porphyrias with neurovisceral manifestations have been considered ‘acute’ in part because the most common of these disorders, named “acute intermittent porphyria,” is the prototype for the neurovisceral porphyrias in which symptoms can occur acutely as discrete, severe episodes; however, affected individuals develop chronic manifestations and remain susceptible to exacerbating factors throughout their lives. 2. Photocutaneous manifestations of EPP are acute and non-blistering, in contrast to the chronic blistering in the other cutaneous porphyrias (including VP). While these clinical distinctions are important for the differential diagnosis, biochemical analysis is always necessary; however, biochemical testing may fail to distinguish HCP from VP, in which case molecular genetic testing of CPOX (HCP) and PPOX (VP) may be the only definitive diagnostic test. In individuals with progressive weakness due to the motor neuropathy caused by one of the acute porphyrias (AIP, VP, HCP, and ADP), the entity most likely to be considered is acute ascending polyneuropathy, the Guillain-Barré syndrome. However, abdominal pain, constipation, and tachycardia precede the acute neurologic illness in the acute porphyrias but not in Guillain-Barré syndrome. CSF protein is normal in the acute porphyrias, but elevated in Guillain-Barré syndrome. Urinary PBG is markedly elevated in the acute porphyrias when symptoms are present, but normal in Guillain-Barré syndrome. CoproporphyrinuriaLead intoxication. The predominant elevation of coproporphyrin that is characteristic of HCP can also be seen in lead intoxication, in which the symptoms resemble those of an acute porphyria. The additional diagnostic finding in heavy metal poisoning is elevation of ALA unaccompanied by any increase in PBG. Rotor syndrome, inherited in an autosomal recessive manner and caused by simultaneous deficiencies of the organic anion transporting polypeptides OATP1B1 and OATP1B3, is also associated with coproporphyrinuria [van de Steeg et al 2012].Nonspecific coproporphyrinuria. The most important differential diagnosis in an individual with elevated urine coproporphyrin is HCP vs. nonspecific coproporphyrinuria. Of all the people referred to a porphyria center, the largest subgroup has nonspecific coproporphyrinuria. Elevation of urine coproporphyrin is associated with a wide range of clinical conditions. It is particularly frequent in acquired liver disease (e.g., chronic viral hepatitis), but can be seen also in neurologic or hematologic diseases. Rarely, it is caused by an inherited hepatic transporter defect. Two tests helpful for the differential diagnosis of coproporphyrinuria are: Urine PBG, which is more than tenfold elevated in the inherited acute porphyrias with active symptoms ANDThe ratio of copro-III to copro-I in feces as measured by high-performance liquid chromatography (used for fecal porphyrin fractionation in most commercial labs). In nonspecific coproporphyrinuria the ratio is usually similar to that in normal controls [Gibson et al 2000]. For a case example of misdiagnosis of nonspecific coproporphyrinuria, click here. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the following evaluations are recommended in an individual with acute abdominal symptoms: ...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with hereditary coproporphyria (HCP), the following evaluations are recommended in an individual with acute abdominal symptoms: Review of medications for those that are thought to induce attacks (See Agents/Circumstances to Avoid.)Detailed neurologic examination for signs of motor neuropathy (which indicates a more advanced attack and, therefore, the need for early treatment with hematin). Inquiry into possibility of seizuresMeasurement of serum sodium concentration; hyponatremia is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis. Quantitation of urinary excretion of PBG on several occasions over a few months to establish a baseline for future use in determining if a new symptom or drug reaction is due to an acute attack (In an acute attack urinary excretion of PBG is substantially elevated over the baseline.) Medical genetics consultationTreatment of ManifestationsAcute AttacksFurther details on the treatment of acute porphyria are available in a published review [Anderson et al 2005]. In an individual presenting with acute abdominal symptoms:Identify and discontinue any medications that are thought to induce attacks (see Agents/Circumstances to Avoid). Discontinue all non-essential medications. Evaluate those with nausea and vomiting for dehydration and hyponatremia, which is characteristic and may be profound (serum sodium concentration <110 mEq/L), requiring urgent correction with due regard for the risk of central pontine myelinolysis. Provide glucose-containing IV solution to reverse the fasting state. Note: Caution is indicated in patients with hyponatremia as aggressive administration of dextrose in water may cause the serum sodium concentration to drop to a critically low level. Treat seizures with a short-acting benzodiazepine (e.g., midazolam) or with magnesium, which has been used for eclamptic seizures [Sadeh et al 1991]. Note: A number of the commonly used anti-seizure medications, including phenytoin and sodium valproate, are contraindicated because of the risk of further exacerbating an attack (see Agents/Circumstances to Avoid). Intravenous hematin is considered the treatment of choice in moderate to severe acute attacks. Order hematin at the time that an acute attack requires hospitalization. Although hematin is not stocked by most hospital pharmacies, it can be obtained by overnight express from the manufacturer (Panhematin®, Lundbeck, 1-800-455-1141). An alternative in Europe and elsewhere is heme arginate (Normosang®; not yet approved in the US).Some individuals recover with a glucose infusion only; those who do not respond in 24 to 48 hours should receive intravenous hematin. When signs of a motor neuropathy are present, hematin is given as soon as possible. Hematin given at the initial signs of motor neuropathy may halt its progression; however, it has no effect on established motor deficits, which are the result of axonal degeneration.Hematin is reconstituted at the bedside as described in the package insert. Human albumin may be used in place of water (132 mL of a 25% albumin solution) to reduce the risk of a chemical phlebitis, which is the main side effect of hematin administration [Anderson et al 2006]. The infusion is started without delay, as hematin in solution decays rapidly [Goetsch & Bissell 1986]. The preparation is given into a large peripheral vein or via central line over 10-15 minutes so as to minimize the risk of phlebitis. The dose is weight based at 3-4 mg/kg; 200 mg once daily is appropriate for most individuals. The following responses to hematin infusion can be expected:Decrease in the urine concentration of PBG, the first sign, occurs after two doses.Clinical improvement is seen after a total of three or four doses, and typically is dramatic, with no further need of narcotic analgesia [Bissell 1988]. The motor neuropathy of acute attacks, when it occurs, does not respond to hematin administration. Return of function requires axonal regeneration and takes many months. Although it can be complete, some individuals have residual wrist drop or foot drop. Liver transplantation. The experience with liver transplantation in acute porphyria is growing, with accumulating evidence that transplantation is curative in selected severe cases. The status of the disease in candidates for liver transplantation must be well-documented biochemically: they must not have responded to multiple courses of hematin and must be demonstrating neurologic complications. Chronic (Cutaneous) ManifestationsFor low-grade chronic or seasonal cutaneous symptoms, the only effective current treatment is avoidance of sun/light, whether direct or through window glass. Damage is caused by long-wave ultraviolet light, which passes through window glass:Sun protection using protective clothing such as long sleeves, gloves, and wide brimmed hatsProtective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke colored filters provide only partial protection.Note: Topical sunscreens are not helpful because they block UV light, not the blue light that causes porphyrin-related skin injury. The association of cutaneous manifestations with severe attacks (in which porphyrins as well as ALA and PBG are markedly increased) suggests that the cutaneous, as well as the neurovisceral, symptoms could respond to hematin administration. Indeed, this is the finding of a recent case report of an individual with severe HCP who was given ‘maintenance’ hematin [Ma et al 2011]. Other. For more prolonged control of seizures, the combination of gabapentin and propofol is effective and safe.Prevention of Primary ManifestationsPrevention of acute attacks involves the following: Molecular genetic testing of at-risk relatives to identify those heterozygous for the CPOX mutation identified in the proband Education of CPOX heterozygotes regarding circumstances that may trigger an acute attack (see Clinical Description). Selection of appropriate contraception for females. Oral contraceptives (birth control pills) are risky and not recommended. The recommended method of birth control for HCP heterozygotes is an IUD plus a barrier (diaphragm and/or condom). A copper-eluting IUD is theoretically the safest in porphyria. The hormone-eluting variety also may be safe because the systemic increase in hormone is quite small; however, little information exists.Suppression of menses using a GnRH agonist. Leuprolide, nafarelin, and other GnRH agonists may help CPOX heterozygotes who experience monthly exacerbations.Prevention of acute attacks does not involve the following: Use of glucose. Because glucose is used to treat acute attacks, its use in preventing attacks has been suggested, and is in fact touted in lay discussions of porphyria; however, there is no evidence that heterozygotes can protect themselves by overeating or adopting a high-carbohydrate diet; furthermore, such a diet increases the risk for obesity. Heterozygotes should adhere to a healthful diet with the usual balance of protein, fat, and carbohydrate. Weight loss is possible but only by incremental restriction of calories combined with exercise. Extreme diets (e.g., all bacon, all brown rice, starvation) are risky and should be avoided. Liver transplantation. Because the vast majority of attacks respond to hematin and other supportive measures, liver transplantation has no role in prevention of acute attacks in a CPOX heterozygote. Prevention of Secondary ComplicationsCPOX heterozygotes undergoing surgery are at increased risk for an acute attack because of the routine preoperative fast and the (former) use of barbiturate (thiopental) induction of anesthesia. Adherence to the following recommendations greatly reduces the risk of an acute attack:Minimizing the preoperative fast as much as possible and providing intravenous glucose (10% dextrose in half-normal saline) in the perioperative period.Anesthesia induction using non-barbiturate agents that have little or no P450-inducing activity (e.g., propofol, ketamine, short-acting benzodiazepines). Inhalation agents (isoflurane) and muscle relaxants also appear to be low-risk for triggering an attack. Agents/Circumstances to AvoidAvoid the following:Caloric deprivation, i.e., fasting Female reproductive hormones. Birth-control pills are risky and not recommended. For recommendations regarding contraception, see Prevention of Primary Manifestations, Selection of appropriate contraception for females. Medications. Some drugs are clearly unsafe for CPOX heterozygotes. It is important to note, however, that many drugs are safe, lest providers regard people with acute porphyria as “untreatable.” Compilations of safe and unsafe drugs are available online and are updated as new information becomes available. (www.porphyriafoundation.com; www.porphyria-europe.com). In theory, the most dangerous medications are inducers of CYPs, such as barbiturates and the related compound, phenytoin. Evaluation of Relatives at RiskTesting of at-risk relatives for the family-specific CPOX mutation allows early education of CPOX heterozygotes regarding how to avoid risk factors known to be associated with acute attacks.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management The effect of pregnancy on inducing acute attacks is unpredictable. In general, serious problems during pregnancy are unusual. In fact, some women with recurrent symptoms associated with the menstrual cycle report improvement during pregnancy. Attacks, if they occur, are usually in the first trimester. The women most at risk are those with hyperemesis gravidarum and inadequate caloric intake [Aggarwal et al 2002]. Among anti-emetics, ondansetron is not expected to precipitate or exacerbate acute attacks or to increase the risk for congenital anomalies in the fetus; however, metoclopramide (a porphyrinogenic agent) should be avoided, as it may precipitate acute attacks [Shenhav et al 1997].The experience with administration of hematin (or heme arginate, which is not available in the US) during pregnancy is limited. Badminton & Deybach [2006] published an anecdotal report of successful heme arginate treatment (without adverse fetal effect) in several women experiencing attacks of variegate porphyria or other acute porphyrias during pregnancy. Based on the absence of reported adverse effects, use of hematin to control exacerbations of acute intermittent porphyria during pregnancy has been recommended [Isenschmid et al 1992, Farfaras et al 2010]. Therapies Under InvestigationDue to the rarity of symptomatic acute porphyria, the efficacy of intravenous hematin has never been documented in a controlled trial. Efforts to accomplish this are under way. Planned studies focus onindividuals who have spontaneous acute attacks in the absence of any known external trigger in order to identify genetic co-factors that may be involved in such attacks and, thus, are potentially targets for new therapies. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hereditary Coproporphyria: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCPOX3q11.2-q12.1Coproporphyrinogen-III oxidase, mitochondrialCPOX homepage - Mendelian genesCPOXData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hereditary Coproporphyria (View All in OMIM) View in own window 121300COPROPORPHYRIA, HEREDITARY; HCP 612732COPROPORPHYRINOGEN OXIDASE; CPOXNormal allelic variants. CPOX comprises seven exons; the reference sequence of the transcript is NM_000097.5.Pathologic allelic variants. To date, at least 64 mutations involving all seven exons have been identified in persons with HCP (Human Gene Mutation Database, updated from Rosipal et al [1999]). They include missense and nonsense mutations, large deletions, small deletions and insertions, indels, and splice mutations.Normal gene product. Coproporphyringen-III oxidase (synonyms: coproporphyrinogen oxidase and coproporphyrinogen decarboxylase), the product of CPOX, performs an oxidative decarboxylation without a metal, reducing agents, or obligatory cofactors. The details of this unusual reaction remain to be elucidated. The crystal structure of human coproporphyringen-III oxidase points to a dimer as the catalytically active unit. Abnormal gene product. Some CPOX mutations that give rise to HCP likely alter enzyme activity by disrupting dimer formation [Lee et al 2005]. The 110-residue N-terminal segment is responsible for targeting the enzyme to mitochondria and is the site of its action on the substrate, coproporphyrinogen. Mutations in this region may affect translocation of the protein and, thus, reduce enzymatic function in tissues without changing activity in cell extracts.