Further Characterization of the Neuroendocrine Phenotype Associated With the PPOX-Related Variegate Porphyria.

BACKGROUND: Variegate porphyria is caused by mutations in the PPOX gene; it usually presents in adolescents and adults as an autosomal dominant condition, with cutaneous features or acute peripheral and/or central nervous system crises. A rarer variant, homozygous variegate porphyria, presents in childhood with cutaneous manifestations as well as neurophenotypes. This study sought to further characterize the homozygous PPOX-related neuroendocrine phenotype. METHODS: This study is a retrospective review of the patients' charts, including their clinical evaluation and molecular genetics, neurodiagnostic, and neuroradiological investigations. RESULTS: We describe here three children from a consanguineous family who presented with nystagmus, developmental delay and ataxia, photosensitive skin manifestations, and adrenal insufficiency. Analysis of porphyrins in plasma, urine, and stool together with a genetic study of the PPOX gene confirmed the diagnosis. Interestingly, brain MRI showed severe hypomyelination, a finding rarely reported in variegate porphyria, together with adrenal insufficiency. CONCLUSION: We recommend analysis of porphyrins in unexplained hypomyelination disorders. Patients with variegate porphyria should be tested for adrenal insufficiency.

An Unusual Cause of Headache and Fatigue in a Division 1 Collegiate Athlete.

Variegate porphyria (VP) is an autosomal dominant disorder of porphyrin metabolism. We report a case of a 21-year-old male collegiate athlete who complained of recurrent headache and fatigue. Extensive testing after initial presentation failed to identify a cause. Months later, his grandmother was diagnosed with VP after being hospitalized; hence, he was tested. He was positive for a heterozygous missense mutation, R168H, in one protoporphyrinogen oxidase allele. This case highlights a rare disorder of heme synthesis that should be considered in the differential diagnosis of exertional fatigue and headaches in athletes. When other more common causes of fatigue and/or headache are unable to be identified, a more focused history and examination may lead to a more unusual but crucial diagnosis. To our knowledge, there are no reported cases of this condition in Division I collegiate athletes.

Elective cholecystectomy performed on patient with variegate porphyria-Propofol-based total intravenous anesthesia with target-controlled infusion.

Porphyria is caused by disorders of enzymes that synthetize porphyrins. Both elective and emergency surgical procedures on patient suffering from porphyria may provoke acute symptoms. These patients require special anesthetic management since some of commonly used anesthetic agents may also induce acute manifestation of porphyria. We present the case of 53-year-old woman previously diagnosed with porphyria who underwent elective laparoscopic cholecystectomy. Propofol-based total intravenous anesthesia with target-controlled infusion was used. Such conduct proved to be safe regarding clinical symptoms, although biochemical markers were slightly elevated after procedure. Propofol seems to be the safest hypnotic drug to use in porphyria; however, special care should be taken is such cases.

Transient Worsening of Photosensitivity due to Cholelithiasis in a Variegate Porphyria Patient.

Variegate porphyria (VP) is an autosomal dominant disease caused by mutations of the protoporphyrinogen oxidase (PPOX) gene. This porphyria has unique characteristics which can induce acute neurovisceral attacks and cutaneous lesions that may occur separately or together. We herin report a 58-years-old VP patient complicated with cholelithiasis. A sequencing analysis indicated a novel c.40G>C mutation (p.G14R) in the PPOX gene. His cutaneous photosensitivity had been worsening for 3 years before the emergence of cholecystitis and it then gradually improved after cholecystectomy and ursodeoxycholic acid treatment with a slight decline in the porphyrin levels in his blood, urine and stool. In VP patients, a worsening of photosensitivity can thus be induced due to complications associated with some other disease, thereby affecting their porphyrin-heme biosynthesis.

Acute Porphyria Presenting as Major Trauma: Case Report and Literature Review.

BACKGROUND: Acute porphyria is historically known as "the little imitator" in reference to its reputation as a notoriously difficult diagnosis. Variegate porphyria is one of the four acute porphyrias, and can present with both blistering cutaneous lesions and acute neurovisceral attacks involving abdominal pain, neuropsychiatric features, neuropathy, hyponatremia, and a vast array of other nonspecific clinical features. CASE REPORT: A 40-year-old man presented to the Emergency Department (ED) as a major trauma call, having been found in an "acutely confused state" surrounded by broken glass. Primary survey revealed: hypertension, tachycardia, abdominal pain, severe agitation, and confusion with an encephalopathy consistent with acute delirium, a Glasgow Coma Scale score of 13, and head-to-toe "burn-like" abrasions. Computed tomography was unremarkable, and blood tests demonstrated hyponatremia, acute kidney injury, and a neutrophilic leukocytosis. The next of kin eventually revealed a past medical history of variegate porphyria. The patient was experiencing an acute attack and received supportive management prior to transfer to intensive care, subsequently making a full recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case highlights the importance of recognizing acute medical conditions in patients thought to be suffering from major trauma. Acute porphyria should be considered in any patient with abdominal pain in combination with neuropsychiatric features, motor neuropathy, or hyponatremia. Patients often present to the ED without any medical history, and accurate diagnosis can be essential in the acute setting to minimize morbidity and mortality. The label of the major trauma call must be taken with great caution, and a broad differential diagnosis must be maintained throughout a diligent and thorough primary survey.

Biallelic inactivation of protoporphyrinogen oxidase and hydroxymethylbilane synthase is associated with liver cancer in acute porphyrias.

Variegate porphyria (VP) and acute intermittent porphyria (AIP), the two most common types of acute porphyrias (AHPs), result from a partial deficiency of protoporphyrinogen oxidase (PPOX) and hydroxymethylbilane synthase (HMBS), respectively. A rare but serious complication in the AHPs is hepatocellular carcinoma (HCC). However, the underlying pathomechanisms are yet unknown. We performed DNA sequence analysis in cancerous and non-cancerous liver tissue of a VP and an AIP patient, both with HCC. In samples of both cancerous and non-cancerous liver tissues from the patients, we identified the underlying PPOX and HMBS germline mutations, c.1082dupC and p.G111R, respectively. Additionally, we detected a second somatic mutation, only in the cancer tissue i.e., p.L416X in the PPOX gene of the VP patient and p.L220X in the HMBS gene of the AIP patient, both located in trans to the respective germline mutations. Both somatic mutations were not detected in 10 non-porphyria-associated HCCs. Our data demonstrate that in the hepatic cancer tissue of AHP patients, somatic second-hit mutations result in nearly complete inactivation of the enzymes catalyzing major steps in the heme biosynthetic pathway. Both PPOX and HMBS, which might act as tumor suppressors, play a crucial role in the development of HCC in these individuals.

Hepatocellular carcinoma in variegate porphyria: a case report and literature review.

Variegate porphyria is an autosomal dominant acute hepatic porphyria characterized by photosensitivity and acute neurovisceral attacks. Hepatocellular carcinoma has been described as a potential complication of variegate porphyria in case reports. We report a case of a 48-year-old woman who was diagnosed with hepatocellular carcinoma following a brief history of right upper quadrant pain which was preceded by a few months of blistering lesions in sun-exposed areas. She was biochemically diagnosed with variegate porphyria, and mutational analysis confirmed the presence of a heterozygous mutation in the protoporphyrinogen oxidase gene. Despite two hepatic resections, she developed pulmonary metastases. She responded remarkably well to Sorafenib and remains in remission 16 months after treatment. A review of the literature revealed that hepatocellular carcinoma in variegate porphyria has been described in at least eight cases. Retrospective and prospective cohort studies have suggested a plausible association between hepatocellular carcinoma and acute hepatic porphyrias. Hepatic porphyrias should be considered in the differential diagnoses of hepatocellular carcinoma of uncertain aetiology. Patients with known hepatic porphyrias may benefit from periodic monitoring for this complication.

Severe porphyric neuropathy--importance of screening for porphyria in Guillain-Barré syndrome.

The hepatic porphyrias are a group of rare metabolic disorders, each of which is associated with a specific enzymatic alteration in the haem biosynthesis pathway. In South Africa (SA), a high incidence of variegate porphyria (VP) is seen as a result of a founder effect, but acute intermittent porphyria (AIP) is also encountered. The development of acute neurovisceral attacks is related to environmental factors, including medications, hormones and diet. A possible manifestation of a severe attack is rapidly progressing quadriparesis, which may mimic Guillain-Barré syndrome. We present four such cases, highlighting that acute porphyria should be considered in the differential diagnosis of Guillain-Barré syndrome. Three patients presented to Steve Biko Academic Hospital, Pretoria, SA, with progressive quadriparesis, and one to a private hospital with acute abdominal pain followed by rapidly progressive quadriparesis. Two patients had started antiretroviral therapy before the development of symptoms, and one had started antituberculosis therapy. All patients had marked weakness with depressed reflexes, and showed varying degrees of confusion. An initial diagnosis of Guillain-Barré syndrome led to administration of intravenous immunoglobulins in two patients. On testing for porphyria, it was found that two patients had AIP and two VP. Electrophysiological investigations revealed severe mainly motor axonal neuropathy in all. Two patients deteriorated to the point of requiring mechanical ventilation, and one of them died due to complications of critical illness. Haemin was administered to three patients, but the process of obtaining this medication was slow, which delayed the recommended early administration. The surviving patients showed minimal recovery and remained severely disabled. Porphyric neuropathy should always be considered as a differential diagnosis in a patient with an acute neuropathy, especially in SA. Absence of abdominal pain does not exclude the possibility of porphyria, and attacks may be precipitated by antiretroviral and antituberculosis medication. The outcome of our patients was not favourable; specifically, obtaining haemin was a challenge in the state hospital setting.

A challenging diagnosis for potential fatal diseases: recommendations for diagnosing acute porphyrias.

Acute porphyrias are a heterogeneous group of metabolic disorders resulting from a variable catalytic defect of four enzymes out of the eight involved in the haem biosynthesis pathway; they are rare and mostly inherited diseases, but in some circumstances, the metabolic disturbance may be acquired. Many different environmental factors or pathological conditions (such as drugs, calorie restriction, hormones, infections, or alcohol abuse) often play a key role in triggering the clinical exacerbation (acute porphyric attack) of these diseases that may often mimic many other more common acute medical and neuropsychiatric conditions and whose delayed diagnosis and treatment may be fatal. In order to obtain an accurate diagnosis of acute porphyria, the knowledge and the use of appropriate diagnostic tools are mandatory, even in order to provide as soon as possible the more effective treatment and to prevent the use of potentially unsafe drugs, which can severely precipitate these diseases, especially in the presence of life-threatening symptoms. In this paper, we provide some recommendations for the diagnostic steps of acute porphyrias by reviewing literature and referring to clinical experience of the board members of the Gruppo Italiano Porfiria (GrIP).

Anaesthetic management of an obstetric patient with variegate porphyria.

Porphyria is an uncommon disease that can produce life-threatening attacks with a mortality rate of up to 10%, specifically as the result of administration of porphyrinogenic medications. In obstetric anaesthesia there are many situations where drugs are given in an emergency and it is therefore important to be prepared for complications to avoid inadvertently inducing an iatrogenic porphyric crisis. We discuss the case of a 20-year-old nulliparous woman with variegate porphyria who required an emergency caesarean section in labour, and the drugs that are commonly used in obstetric practice.

Porfiria variegata y fibrilación auricular: ataque agudo inducido por propafenona / Variegate porphyria and atrial fibrillation: acute attack induced by propafenone

No disponible

A case report of porphyria variegata management in the emergency department.

BACKGROUND: Porphyria variegata (VP) is one of the hepatic porphyrias that results from the deficiency of protoporphyrinogen oxidase, an enzyme in the heme synthesis pathway. The name porphyria variegata refers to its many presentations, which include various neuropsychiatric and cutaneous manifestations. Emergency department (ED) presentations due to VP are most commonly neuropathic abdominal pain. CASE REPORT: We present the case of a 57-year-old woman presenting to an ED with abdominal pain consistent with prior VP attacks. In addition to analgesics and supportive care, infusion of intravenous dextrose resulted in improvement in her symptoms. CONCLUSION: Intravenous dextrose and heme administration remain the first-line treatment for abdominal pain attributable to known acute hepatic porphyria attacks. Recently, the mechanism of action of carbohydrates in treating porphyria has been elucidated. Current information on this illness and ED management are discussed.

A review of the clinical presentation, natural history and inheritance of variegate porphyria: its implausibility as the source of the 'Royal Malady'.

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.

Hepatocellular carcinoma in variegate porphyria: a serious complication.

Variegate porphyria is an acute hepatic porphyria resulting from a partial deficiency of protoporphyrinogen oxidase, the penultimate enzyme in haem biosynthesis. Cutaneous symptoms and acute neurovisceral attacks are well-known clinical characteristics of the disease. Less studied, however, is the risk of developing hepatocellular carcinoma, an aggressive type of liver cancer. We describe here two Swiss patients with variegate porphyria and this serious complication. Common risk factors, including alcohol over-consumption or chronic hepatitis, were absent in both patients. Interestingly, one patient carried mutation 1082-1083insC in the PPOX gene, a prevalent sequence deviation in the Swiss variegate porphyria population, which was also found in a French patient with variegate porphyria and hepatocellular carcinoma. Recent studies indicate that individuals with acute hepatic porphyria have a 36- to 61-fold increased risk of manifesting hepatocellular carcinoma. The incidence rate ratio in the Swiss population was estimated to be 34, comparable with those found in the French and Finnish populations. Because this tumour is associated with a rising mortality, we suggest regular screening for hepatocellular carcinoma in all patients with variegate porphyria.

Anticancer therapy in patients with porphyrias: evidence today.

BACKGROUND: Porphyrias are rare diseases, and for these patients every administration of drugs may induce an acute attack of porphyria. The list of safe compounds allowed in these patients is available for clinicians from specific websites cited in the text. OBJECTIVES: However, data concerning anticancer therapy in patients with such diseases remain poor. Therefore any publications can help clinicians to deal with this very specific group of patients. METHODS: In our institution, three patients received docetaxel and hematologic growth factors (erythropoietin and GCSF) without unexpected toxicities. Aromatase inhibitors (anstrozole and letrozole) were also given in one patient without any related problem. CONCLUSION: The present observation adds some useful data for the possible treatment of cancer in patients with porphyria.