Hereditary Coproporphyria (HCP)
HCP is an inherited autosomal dominant and a rare recessive disorder form of hepatic porphyria and less common than AIP, though latent HCP and HCP-carriers are being increasingly recognized. The prevalence of HCP in Denmark is approximately 2 per million. HCP is the least prevalent of the three principal types of acute porphyria: AIP, VP, and HCP. However, symptoms in HCP may be less frequent than in AIP or VP. Environmental or physiologic factors play a role in the pathogenesis of acute attack (Badminton and Elder, 2005).
2.2.1. Clinical features of HCP
HCP is an acute hepatic porphyria with neurovisceral symptoms, usually occurring as attacks that are indistinguishable from those in AIP (Bissell et al., 2012). Attacks typically start with low-grade abdominal pain that slowly increases over a period of hours or days, often with nausea and vomiting. Sometimes pain is predominantly in the back or extremities. A motor neuropathy may develop over a period of days or weeks if not treated. The neuropathy and weakness is often first noted proximally in the arms and legs, and may then progress distally. Respiratory insufficiency may result from impaired innervation of the diaphragm and respiratory muscles. Acute attacks are often associated with use of certain medications, caloric deprivation, and luteal phase increases in progesterone. About 20% of those with an acute attack report photosensitivity although bullae and skin fragility are much less common than in VP (Anderson et al., 2005 and 2014; Anderson and Lee, 2010). Of 46 individuals tested in Germany 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).
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 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. In general, HCP is milder than AIP and is associated with fewer attacks. For example, in 32 members of an Australian family, 14 (including 10 adults) were determined to have HCP on the basis of a high fecal coproporphyrin III/I ratio and/or low lymphocyte CPOX enzyme activity, but only one had clinical symptoms of porphyria (Blake et al., 1992).
In rare homozygous cases of HCP, a CPOX mutation is inherited from each parent, with at least one of the mutant alleles expressing some enzyme activity. Characteristically, photosensitivity and chronic neurological manifestations begin in childhood, but acute attacks are seldom described (Schmitt et al., 2005).
2.2.2. Etiology and Pathogenesis of HCP
Like AIP and VP, HCP is inherited in an autosomal dominant manner with low penetrance. Heme production in most heterozygotes appears to be adequate. HCP results from coproporphyrinogen oxidase (CPOX) deficiency. At least 64 CPOX gene mutations involving all seven exons have been identified in different HCP families, including missense and nonsense mutations, large and small deletions and insertions, and splice site mutations (Rosipal et al., 1999; Schmitt et al., 2005; HGMD, 2014), as well as a few large deletions (Whatley et al., 2009; Barbaro et al., 2012). The enzyme functions as a homodimer, and some CPOX mutations may disrupt dimer formation (Lee et al., 2005). Homozygous cases of HCP have more severe CPOX deficiency, with onset of the disease in childhood.
CPOX catalyzes the 2-step decarboxylation of coproporphyrinogen III to protoporphyrinogen IX. Certain CPOX mutations release the substrate after one decarboxylation as harderoporphyrinogen, a tricarboxylate porphyrinogen that is then oxidized to the corresponding porphyrin. Homozygotes for these mutations have some distinct features, such as hemolysis early in life, whereas heterozygotes are similar to other HCP patients.
Because of reduced penetrance, many individuals with a CPOX mutation have no signs or symptoms of HCP. Given the rarity of acute attacks of HCP relative to AIP, it is suspected that only a small minority of CPOX heterozygotes express the clinical disease.