Acute Hepatic Porphyrias: Review and Recent Progress.

The acute hepatic porphyrias (AHPs) are a group of four inherited diseases of heme biosynthesis that present with episodic, acute neurovisceral symptoms. The four types are 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria. Their diagnoses are often missed or delayed because the clinical symptoms mimic other more common disorders. Recent results indicate that acute intermittent porphyria, the most severe of the more common types of AHP, is more prevalent than previously thought, occurring in about 1 in 1600 Caucasians, but with low clinical penetrance (approximately 2%-3%). Here we provide an updated review of relevant literature and discuss recent and emerging advances in treatment of these disorders. Symptomatic attacks occur primarily in females between 14 and 45 years of age. AHP is diagnosed by finding significantly elevated levels of porphyrin precursors ALA and porphobilinogen in urine. Acute attacks should be treated promptly with intravenous heme therapy to avoid the development of potentially irreversible neurologic sequelae. All patients should be counseled about avoiding potential triggers for acute attacks and monitored regularly for the development of long-term complications. Their first-degree relatives should undergo targeted gene testing. Patients who suffer recurrent acute attacks can be particularly challenging to manage. Approximately 20% of patients with recurrent symptoms develop chronic and ongoing pain and other symptoms. We discuss newer treatment options in development, including small interfering RNA, to down-regulate ALA synthase-1 and/or wild-type messenger RNA of defective genes delivered selectively to hepatocytes for these patients. We expect that the newer treatments will diminish and perhaps obviate the need for liver transplantation as treatment of these inborn metabolic disorders

Études moléculaires de DMT1, un transporteur membranaire du fer

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

TRANSPORT DU FER ET ANEMIES FERRIPRIVES (EXEMPLE DE LA PROTEINE NRAMP2/DMT1 (DES BIOL. MED.))

PARIS7-Xavier Bichat (751182101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

The E148QMEFV allele is not implicated in the development of familial Mediterranean fever

International audienceFamilial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and serositis, common in populations of Armenian, Arab, Sephardic Jewish and Turkish origin. Early diagnosis is crucial to start colchicine therapy that prevents the occurrence of attacks and renal amyloidosis. In the absence of functional test for FMF, the diagnosis remains clinical and is generally confirmed by molecular analysis of the MEFV gene. More than 40 missense mutations and two in-frame deletions have been reported, most of them being located in exon 10 of the gene. The M694V (c.2080A>G) mutation, the most frequent defect, is responsible for a severe phenotype when present in the homozygous state. The E148Q (c.442G>C) sequence variant, which is situated in exon 2, is also common, but its role in FMF is controversial. In order to assess the implication of the E148Q variation in FMF, we investigated 233 patients of Sephardic Jewish origin living in France and 213 disease-free relatives of these patients. The frequency of the E148Q allele was found to be similar in the two groups (3.62% a nd 3.75%, respectively, p=0.93). Most importantly, the frequency of the M694V/E148Q compound heterozygous genotype was comparable between the patients group (3.9%) and the healthy relatives group (4.2%, p=0.85). This population-based study, therefore, strongly supports the hypothesis that E148Q is a just a benign polymorphism and not a disease-causing mutation. Considering this variant as a mutation may lead to set false positive diagnoses and to neglect the likely existence of genetic heterogeneity in FM