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Background: Recent descriptions of the clinical and laboratory features of subjects with acute porphyrias in the US are lacking. Our aim was to describe clinical, biochemical, and genetic features of 108 subjects., Methods: Between September 2010 and December 2012, 108 subjects with acute porphyrias (90 acute intermittent porphyrias, 9 hereditary coproporphyrias, 9 variegate porphyrias) were enrolled into an observational study. Genetic testing was performed at a central genetic testing laboratory and clinical information entered into a central database. Selected features were compared with data for adults in the US., Results: Most subjects (88/108, 81%) were female, with self-reported onset of symptoms in the second through fourth decades of life. The most common symptom was abdominal pain. Appendectomies and cholecystectomies were common before 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 and other pains. The incidences of systemic arterial hypertension, chronic kidney disease, seizure disorders, and psychiatric conditions were markedly increased. Mutations of the known causative genes were found in 102/105 of those tested, with novel mutations being found in 37, including in 7/8 subjects with hereditary coproporphyria. Therapy with intravenous hematin was the most effective therapy both for treatment of acute attacks and for prevention of recurrent attacks., Conclusions: Acute porphyrias often remain undiagnosed for more than a decade after first symptoms develop. Intravenous hematin is the treatment of choice, both for treatment of acute attacks and for prevention of recurrent attacks., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The porphyrias are a group of disorders characterized by defects in the heme biosynthesis pathway. Many present with skin findings including photosensitivity, bullae, hypertrichosis, and scarring. Systemic symptoms may include abdominal pain, neuropsychiatric changes, anemia, and liver disease. With advances in DNA analysis, researchers are discovering the underlying genetic causes of the porphyrias, enabling family members to be tested for genetic mutations. Here we present a comprehensive review of porphyria focusing on those with cutaneous manifestations. In Part I, we have included the epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Treatment and management options will be discussed in Part II., (© 2013 The International Society of Dermatology.)

Retrospective estimates of the prevalence of porphyrias have been reported but there has been no large scale prospective study of their incidence. 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). Prevalence was calculated from the incidence and mean disease duration. The incidence of hepato-cellular carcinoma (HCC) in acute hepatic porphyria and the prevalence of patients with recurrent acute attacks of porphyria were also investigated. The incidence of symptomatic acute intermittent porphyria (AIP) was similar in all countries (0.13 per million per year; 95 % CI: 0.10 - 0.14) except Sweden (0.51; 95 % CI: 0.28-0.86). The incidence ratio for symptomatic AIP: variegate porphyria: hereditary coproporphyria was 1.00:0.62: 0.15. The prevalence of AIP (5.4 per million; 95 % CI: 4.5-6.3) was about half that previously reported. The prevalence of erythropoietic protoporphyria (EPP) was less uniform between countries and, in some countries, exceeded previous estimates. Fourteen new cases of HCC (11 from Sweden) were reported in patients with acute porphyria. Sixty seven patients (3 VP; 64 AIP: 53 females, 11 males) with recurrent attacks of acute porphyria were identified. The estimated percentage of patients with AIP that will develop recurrent acute attacks was 3-5 %. In conclusion, the prevalence of symptomatic acute porphyria may be decreasing, possibly due to improved management, whereas the prevalence of EPP may be increasing due to improved diagnosis and its greater recognition as a cause of photosensitivity.

It has been suggested that King George III of Great Britain suffered from the haem biosynthetic disorder, variegate porphyria. This diagnosis is pervasive throughout the scientific and popular literature, and is often referred to as the 'Royal Malady.' The authors believe it inappropriate to view the case for porphyria purely in terms of symptoms, as has generally been the case in his presumptive acute porphyria diagnosis. Accordingly, this review provides a current description of the natural history and clinical presentation of the porphyrias, against which we measure the case for porphyria in George III and his relatives. The authors have critically assessed the prevalence of porphyria in a population, the expected patterns and frequency of inheritance, its penetrance and its expected natural history in affected individuals, and conclude that neither George nor his relatives had porphyria, based on four principal reasons. First, the rarity of the disease mandates a very low prior probability, and therefore implies a vanishingly low positive predictive value for any diagnostic indicator of low specificity, such as a historical reading of the symptoms. Second, penetrance of this autosomal dominant disorder is approximately 40%, and one may expect to have identified characteristic clinical features of porphyria in a large number of descendants without difficulty. Third, the symptoms of both George III and his relatives are highly atypical for porphyria and are more appropriately explained by other much commoner conditions. Finally, the natural history of the illnesses reported in this family is as atypical for variegate porphyria as are their symptoms.

Variegate porphyria (VP), one of the acute hepatic porphyrias, results from an autosomal dominantly inherited deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in heme biosynthesis. Affected individuals can develop both cutaneous symptoms and potentially life-threatening neurovisceral attacks. Thirty unrelated VP index patients and families are currently known in the Swiss Porphyrin Reference Laboratory in Zürich. In 16 of a total of 24 genetically tested families, we detected a recurrent mutation in the PPOX gene, designated 1082-1083insC, reflecting a prevalence of 67%. Haplotype analysis revealed that 1082-1083insC arose on a common genetic background and, thus, represents a novel founder mutation in the Swiss population. Knowledge on the carrier status within a family does not only allow for adequate genetic counseling but also for prevention of the potentially life-threatening acute porphyric attacks. Hence, future molecular screening in Swiss VP patients might be facilitated by first seeking for mutation 1082-1083insC.

Background: Variegate porphyria (VP), also known as South African porphyria, is a low-penetrance, autosomal dominant disorder as the result of a partial deficiency of protoporphyrinogen oxidase (PPOX). Clinically, VP is characterised by photosensitivity and neurovisceral attacks whereby the two symptoms can appear separately or together in patients. VP is little known in Switzerland. In this study, we report a clinical, biochemical and mutational study of eight Swiss VP patients and their families., Results: Six of the eight index patients presented with only skin symptoms, and one with only neurological symptoms. Another patient had both skin and neurological symptoms. Faecal porphyrin excretion was elevated in all patients thus enabling diagnosis. Four different mutations including three novel mutations (G11D, 1041-1042 ins T and 1262-1263 ins 22bp) were identified in this cohort. Mutation 1082-1083 ins C, which had been reported in the French VP population, was shared by five apparently unrelated patients of this study., Conclusion: The novel PPOX gene mutations are apparently unique to the Swiss population. Both clinical and biochemical presentations varied considerably even among those patients who carried an identical mutation, which does not favour the existence of a genotype-phenotype correlation in VP.

A 7-year-old Chilean boy presented with severe photosensitivity, blistering, erosions and scarring on sun-exposed areas of the body since the age of 6 months. Additionally, he showed a short stature and shortening of the fingers. Laboratory examination revealed greatly elevated protoporphyrin levels in the blood. Such biochemical findings can be observed in homozygous variants of usually autosomal dominantly inherited acute porphyrias such as variegate porphyria (VP) and hereditary coproporphyria, which usually do not become manifest before the second or third decade of life in heterozygotes. Using polymerase chain reaction-based techniques we identified a missense mutation in exon 7 on the paternal allele and a frameshift mutation in exon 13 on the maternal allele of the protoporphyrinogen oxidase gene that harbours the mutations underlying VP. This is the first homozygous case of VP in South America. As VP represents the most frequent type of acute porphyria not only in Chile but also in South Africa, more such cases could be expected in the future, particularly because a founder mutation for this disease has already been described in the Chilean and South African population.