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The American Journal of Medicine Dec 2014Recent 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... (Observational Study)
Observational Study
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.
Topics: Adult; Anxiety; Coproporphyria, Hereditary; Delayed Diagnosis; Depression; Epilepsy; Female; Humans; Hypertension; Incidence; Male; Middle Aged; Neuralgia; Porphyria, Acute Intermittent; Porphyria, Variegate; Renal Insufficiency, Chronic; Sex Distribution; United States; Young Adult
PubMed: 25016127
DOI: 10.1016/j.amjmed.2014.06.036 -
Swiss Medical Weekly Apr 2009The porphyrias, a group of seven metabolic disorders in the haem biosynthesis, can be classified into acute and non-acute porphyrias. A common symptom of acute...
BACKGROUND
The porphyrias, a group of seven metabolic disorders in the haem biosynthesis, can be classified into acute and non-acute porphyrias. A common symptom of acute porphyrias is severe acute abdominal pain, whereas cutaneous photosensitivity can occur in both acute and non-acute porphyrias. All porphyrias, except for sporadic porphyria cutanea tarda (sPCT), are hereditary disorders caused by mutations in the respective genes. We present porphyria cases documented in our porphyria centre during the past 15 years.
METHODS
Diagnosis was based on clinical symptoms and biochemical analyses. Mutation analysis was performed in patients/families with a confirmed hereditary porphyria.
RESULTS AND CONCLUSIONS
As the porphyria specialist centre of Switzerland, we perform the specialized analyses required for the diagnosis of all types of porphyrias, and give advice to patients, physicians and other laboratories. We therefore estimated that our data cover 80-90% of all diagnosed Swiss cases. A total of 217 patients from 170 families were diagnosed including, 111 acute intermittent porphyria, 45 erythropoietic protoporphyria, 30 variegate porphyria, 21 sPCT, five congenital erythropoietic porphyria, four hereditary coproporphyria and one hepatoerythropoietic porphyria patient. Systematic monitoring of the patients would allow early detection of the potential life-threatening complications such as hepatocellular carcinoma and renal insufficiency in acute porphyrias, and liver failure in EPP. Seventy-five percent of all families underwent genetic testing. Identification of pre-symptomatic mutation carriers so that these individuals and their physicians can be consulted with safety on drug use and other preventive measures, is important in managing acute porphyrias. The unique phenomenon of founder mutations in the Swiss population is also discussed.
Topics: Carcinoma, Hepatocellular; Female; Ferrochelatase; Flavoproteins; Founder Effect; Heterozygote; Humans; Hydroxymethylbilane Synthase; Male; Mitochondrial Proteins; Porphyria, Erythropoietic; Prevalence; Protoporphyrinogen Oxidase; Switzerland; Uroporphyrinogen III Synthetase
PubMed: 19350426
DOI: 10.4414/smw.2009.12496 -
American Journal of Human Genetics May 2001Hereditary coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from mutations in the CPO gene that encodes the...
Characterization of mutations in the CPO gene in British patients demonstrates absence of genotype-phenotype correlation and identifies relationship between hereditary coproporphyria and harderoporphyria.
Hereditary coproporphyria (HCP) is the least common of the autosomal dominant acute hepatic porphyrias. It results from mutations in the CPO gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. A few patients have also been reported who are homoallellic or heteroallelic for CPO mutations and are clinically distinct from those with HCP. In such patients the presence of a specific mutation (K404E) on one or both alleles produces a neonatal hemolytic anemia that is known as "harderoporphyria"; mutations on both alleles elsewhere in the gene give rise to the "homozygous" variant of HCP. The molecular relationship between these disorders and HCP has not been defined. We describe the molecular investigation and clinical features of 17 unrelated British patients with HCP. Ten novel and four previously reported CPO mutations, together with three previously unrecognized single-nucleotide polymorphisms, were identified in 15 of the 17 patients. HCP is more heterogeneous than other acute porphyrias, with all but one mutation being restricted to a single family, with a predominance of missense mutations (10 missense, 2 nonsense, 1 frameshift, and 1 splice site). Of the four known mutations, one (R331W) has previously been reported to cause disease only in homozygotes. Heterologous expression of another mutation (R401W) demonstrated functional properties similar to those of the K404E harderoporphyria mutation. In all patients, clinical presentation was uniform, in spite of the wide range (1%-64%) of residual coproporphyrinogen oxidase activity, as determined by heterologous expression. Our findings add substantially to knowledge of the molecular epidemiology of HCP, show that single copies of CPO mutations that are known or predicted to cause "homozygous" HCP or harderoporphyria can produce typical HCP in adults, and demonstrate that the severity of the phenotype does not correlate with the degree of inactivation by mutation of coproporphyrinogen oxidase.
Topics: Amino Acid Sequence; Amino Acid Substitution; Coproporphyrinogen Oxidase; Coproporphyrins; DNA Mutational Analysis; Escherichia coli; Exons; Feces; Female; Gene Frequency; Genotype; Humans; Male; Molecular Sequence Data; Mutation; Pedigree; Phenotype; Phylogeny; Polymorphism, Single Nucleotide; Porphyrias, Hepatic; Porphyrins; Promoter Regions, Genetic; RNA Splice Sites; Sequence Alignment; United Kingdom
PubMed: 11309681
DOI: 10.1086/320118 -
Journal of Internal Medicine Sep 2017Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published.
OBJECTIVES
Our aim was to investigate the risk of PLC and other cancers in persons with AHP using a nationwide cohort design. Given that greater numbers of women than men tend to have manifest and more severe AHP, a further aim was to investigate sex differences in this risk.
METHODS
The study sample consisted of all Norwegian residents aged 18 years or older during the period 2000-2011. Persons with AHP (n = 251) were identified through the Norwegian Porphyria Centre, and patients with a cancer diagnosis were identified by linkage to the Cancer Registry of Norway.
RESULTS
For persons with AHP, the annual incidence rate of PLC was 0.35%. PLC risk was substantially higher for individuals with an AHP diagnosis compared to the reference population [adjusted hazard ratio (aHR) 108, 95% confidence interval (CI) 56-207]. In a meta-analysis of published studies on PLC and AHP, including ours, women had a higher risk than men. In addition, our results suggested that persons with AHP may have increased risks of kidney (aHR 7.4, 95% CI 2.4-23.1) and endometrial cancers (aHR 6.2, 95% CI 2.0-19.3).
CONCLUSIONS
Our findings confirmed a substantially higher risk of PLC associated with AHP compared to the general population. In a meta-analysis, the risk was shown to be greater for women than men. The novel findings of a moderate to substantial association between AHP and kidney and endometrial cancers should be investigated further.
Topics: Adult; Aged; Aged, 80 and over; Cohort Studies; Comorbidity; Endometrial Neoplasms; Female; Humans; Incidence; Kidney Neoplasms; Liver Neoplasms; Male; Middle Aged; Norway; Porphobilinogen Synthase; Porphyrias, Hepatic; Risk Factors; Sex Distribution; Sex Factors; Young Adult
PubMed: 28730628
DOI: 10.1111/joim.12646 -
Molecular Genetics and Metabolism... Mar 2022Acute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include...
BACKGROUND
Acute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include acute attacks, occurring mainly among female patients. This study describes the diversity of acute symptoms, changes in triggering factors and life expectancy among female patients during the past five decades.
METHODS
107 Finnish female patients were enrolled into a retrospective, longitudinal study during 2015. Clinical, biochemical and genetic data was obtained from the medical reports, registry data and a questionnaire designed for the study. Causes of death were studied in additional 32 female patients.
RESULTS
Of the 43 patients with hospitalization, 33% had non-complicated, 35% prolonged and 28% severe attacks with no correlation with the disease-causing mutation. Of the deceased patients, 31% died of an acute attack during 1957-1979. Thereafter the incidence and severity of acute attacks have decreased substantially. 55% of the subjects reported acute symptoms (dysautonomia and mental symptoms) without hospitalization, 29% had porphyria symptoms >10 times, and 23% within the last year. Despite 22% of the female patients had died of primary liver cancer, the life expectancy increased more than 10 years during the follow-up, and did not differ from the normal population at present.
CONCLUSIONS
The incidence of acute attacks requiring hospitalization has decreased, but more than half of the female patients reported acute symptoms affecting their well-being. Symptoms are currently triggered by hormonal changes and weight loss emphasizing the importance of early recognition and active management to avoid disease exacerbation. Death due to primary liver cancer is common and should be screened regularly.
PubMed: 35242573
DOI: 10.1016/j.ymgmr.2022.100842 -
Acta Dermato-venereologica Nov 2016Porphyrias are rare diseases caused by altered haem synthesis leading to the accumulation of different haem intermediates. Neurovisceral attacks may occur in acute...
Porphyrias are rare diseases caused by altered haem synthesis leading to the accumulation of different haem intermediates. Neurovisceral attacks may occur in acute porphyrias, while photosensitivity is the presenting symptom in cutaneous porphyrias. We present here an overview of symptoms and a flowchart for the diagnosis of cutaneous porphyrias, with recommendations for monitoring and an update of treatment options. From the Danish Porphyria Register, we present the incidences and approximate prevalences of cutaneous porphyrias within the last 25 years. A total of 650 patients with porphyria cutanea tarda were identified, 73 with erythropoietic protoporphyria, 9 with variegate porphyria, 4 with hereditary coproporphyria and one with congenital erythropoietic porphyria. The total incidence of all porphyrias was ~0.52/100,000 per year.
Topics: Denmark; Diagnosis, Differential; Female; Humans; Incidence; Male; Porphyrias; Prevalence; Risk Factors; Skin Diseases
PubMed: 27139922
DOI: 10.2340/00015555-2444 -
Pakistan Journal of Medical Sciences Apr 2013Acute porphyrias are rare diseases with varying incidences worldwide. These diseases are disorders of heme biosynthesis characterized by acute attacks of neurological...
Acute porphyrias are rare diseases with varying incidences worldwide. These diseases are disorders of heme biosynthesis characterized by acute attacks of neurological symptoms. Acute porphyria should be considered in patients with unexplained abdominal pain or neurological damage. Clinical manifestations of acute porphyria are nonspecific and are associated with multiple organ systems. This report examines a rare case of an uncommon type of acute porphyria in a patient with an initial presentation of abdominal pain and progressive polyneuropathy.
PubMed: 24353603
DOI: 10.12669/pjms.292.3202 -
Orphanet Journal of Rare Diseases Dec 2023Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and...
Clinical features of acute attacks, chronic symptoms, and long-term complications among patients with acute hepatic porphyria in Japan: a real-world claims database study.
BACKGROUND
Acute hepatic porphyria (AHP) is a family of rare genetic diseases, including acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and delta-aminolevulinic acid dehydratase-deficient porphyria. The objective of this retrospective cohort study was to provide information on the clinical features of AHP in Japan-including acute attacks, chronic symptoms, and long-term complications.
METHODS
Patients with AHP between April 2008 and June 2020 were selected from Japan's Medical Data Vision claims database. Patients with AHP were matched 1:10, by sex and age, to patients without AHP. The outcomes were evaluated overall, for patients age ≥ 55 years, and for the matched population.
RESULTS
A total of 391 patients with AHP were included from the Japanese Medical Data Vision database. During the observation period (April 2008-June 2020), 18.2% (71/391) of patients experienced 1 acute attack and 10.5% (41/391) experienced ≥ 2 attacks. Chronic symptoms with rates ~ 10% or higher in the AHP population compared with the matched population included neurotic, stress-related, and somatoform disorders (21.7% vs. 6.7% [15.0% difference]); sleep disorders (23.0% vs. 9.9% [13.1% difference]); other and unspecified abdominal pain (13.6% vs. 3.7% [9.9% difference]); and nausea and vomiting, excluding chemotherapy-induced emesis (17.9% vs. 8.1% [9.8% difference]). Long-term complications with higher incidence rates in the AHP population compared with the matched population included fibrosis and cirrhosis of liver (15.9% vs. 3.0% [12.9% difference]), polyneuropathies and other disorders of the peripheral nervous system (20.5% vs. 7.9% [12.6% difference]), liver cancer (16.9% vs. 4.7% [12.2% difference]), renal failure (16.4% vs. 4.3% [12.1% difference]), and hypertension (26.1% vs. 18.8% [7.3% difference]). Among AHP patients age ≥ 55 years, the most common long-term complications were hypertension, kidney failure, and liver cancer.
CONCLUSIONS
In Japan, patients with AHP experience a high clinical burden in terms of acute attacks, chronic symptoms, and long-term complications. The clinical burden related to chronic symptoms and long-term complications was substantially higher in Japanese patients with AHP compared with a matched population without AHP. Recognizing these signs and symptoms of AHP may aid physicians in making an earlier diagnosis, which may help patients avoid attack triggers, implement disease management, and reduce lifetime disease burden.
Topics: Humans; Middle Aged; Porphobilinogen Synthase; Japan; Retrospective Studies; Porphyrias, Hepatic; Porphyria, Acute Intermittent; Hypertension; Liver Neoplasms
PubMed: 38066651
DOI: 10.1186/s13023-023-02913-0 -
Tremor and Other Hyperkinetic Movements... 2013Hereditary coproporphyria (HCPO) is a low-penetrance, autosomal dominant, acute hepatic porphyria characterized by the overproduction and excretion of coproporphyrin....
BACKGROUND
Hereditary coproporphyria (HCPO) is a low-penetrance, autosomal dominant, acute hepatic porphyria characterized by the overproduction and excretion of coproporphyrin. The most common neurological manifestations of this entity include peripheral, predominantly motor dysfunction, and central nervous system dysfunction. Ataxia associated with HCPO has not been reported previously. The aim of this article is to report a patient with HCPO presenting with acute ataxia.
CASE REPORT
We describe a 44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCPO; mutations were analyzed in the coproporphyrin-oxidase III (CPOX) gene in the patient and in six asymptomatic first-degree relatives.
DISCUSSION
The patient was heterozygous for a mutation causing the amino acid exchange Q306X in the CPOX gene. No relatives carried the same or another mutation in the CPOX gene. HCPO should be considered in the differential diagnosis for patients presenting with ataxia.
PubMed: 24156084
DOI: 10.7916/D8DF6PXW -
Turkish Archives of Pediatrics Jan 2023Porphyrias are inborn errors of heme biosynthesis pathway that result in neurovisceral and/ or cutaneous manifestations which occur with episodic attacks, usually...
Porphyrias are inborn errors of heme biosynthesis pathway that result in neurovisceral and/ or cutaneous manifestations which occur with episodic attacks, usually accompanied by a multisystemic involvement. Acute hepatic porphyrias include acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and aminolevulinic acid dehydratase deficiency porphyria. Acute hepatic porphyrias may present with symptoms of an affected central, peripheral, and autonomic nervous system and are generally diagnosed in time of an acute neurovisceral attack. In children, clinical picture is more complicated and presents with neurological findings predominantly. First-line investigation should be the urinary porphobilinogen and aminolevulinic acid performance when acute hepatic porphyria is clinically suspected. Comprehensive testing including urine porphyrin separation, fluorescence scanning of diluted plasma at neutral pH, evaluation of fecal porphyrins, and measurement of erythrocyte porphobilinogen deaminase activity is indicated for confirmation or exclusion of the porphyria and define the type of acute hepatic porphyrias. The main aim of the treatment is to decrease aminolevulinic acid, porphobilinogen, and porphyrins by reducing hepatic ALAS1 activity. The first measure should always be the avoidance of any porphyrinogenic drugs. Hemin therapy should not be delayed in the treatment of a severe acute attack. Gonadotropin-releasing hormone analogs and prophylactic hemin protocols can be used for selected cases with more than 4 attacks per year. Givosiran is a promising treatment option for severe cases.
PubMed: 36598205
DOI: 10.5152/TurkArchPediatr.2022.22301