The two critical HLA regions for susceptibility to AIP are limited to the HLA-DRB1*0405-DQB1*0401 in the class II and the ABCF1 proximal to C3-2-11, telomeric of HLA-E, in the class I regions.
These results provide evidence for a structural mutation of the gene specifying the enzyme PBG-S connected with a homozygous state of this new enzymatic type of hereditary acute porphyria.
Induction of delta aminolevulinic acid synthase 1 ( ALAS1) gene expression and accumulation of neurotoxic intermediates result in neurovisceral attacks and disease manifestations in patients with acute intermittent porphyria, a rare inherited disease of heme biosynthesis.
To introduce next generation sequencing (NGS) to the porphyria diagnosis, we designed a panel that contained four genes, <i>ALAS1, HMBS</i>, <i>CPOX</i> and <i>PPOX</i> for mutational analysis of acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP).
Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS1, ALAS2 and PBGD were increased only at 11 p.m. in subjects with active AIP.
The clinical performance of givosiran revealed that suppression of ALAS1 by GalNac-decorated siRNAs represents an additional approach for the treatment of patients with AIP that manifests recurrent acute neurovisceral attacks.
Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti-inflammatory therapies should be considered in patients with recurrent AIP.
Many interactions and cross-talk take place within the tangle of genomic circuits that control ALAS1-transcription, which may explain the extreme inter- and intra-individual variability in morbidity in acute porphyria.
Negative feedback regulation of ALAS-1 by the end product heme is well documented and provides the foundation for heme treatment of acute porphyrias, a group of diseases caused by genetic defects in the heme biosynthesis pathway and exacerbated by controlled up-regulation of ALAS-1.
Levels of clock-controlled gene mRNAs showed significant increases over baseline in all subjects at 5 a.m. and 11 p.m., whereas mRNA levels of ALAS1, ALAS2 and PBGD were increased only at 11 p.m. in subjects with active AIP.
Seven out of 10 clones were amylase alpha-2A, the autoantibody to which was specifically detected in sera from patients with AIP and fulminant type 1 diabetes (FT1DM) [T. Endo, S. Takizawa, S. Tanaka, M. Takahashi, H. Fujii, T. Kamisawa, T. Kobayashi, Amylase alpha-2A autoantibodies: novel marker of autoimmune pancreatitis and fulminant type 1 diabetes mellitus, Diabetes 58 (2009) 732-737].
These results suggest that an autoantibody against amylase alpha-2A is a novel diagnostic marker for both AIP and fulminant type 1 diabetes and that, clinically and immunologically, AIP and fulminant type 1 diabetes are closely related.
This specific distribution of serum apoA2 isoforms might provide important information about the disease states of AIP patients and aid the differential diagnosis of AIP versus pancreatic cancer.
Additionally, comparison analyses (visual SPA assessment and % minimal lumen diameter [MLD] stenosis) among normal pancreas, PAC, and AIP groups were performed using early arterial phase (EAP) reconstructed images.
A polymorphism in the ATP synthase 8 (ATP8) gene of the murine mitochondrial genome, G-to-T transversion at position 7778, has been suggested to increase susceptibility to multiple autoimmune diseases, including autoimmune pancreatitis (AIP).
Patients who had AIP with IgG4-RKD were more likely to have extrapancreatic lesions other than those in the kidney, and their serum creatinine and urinary β2-microglobulin concentrations were significantly higher than in those without IgG4-RKD.