Preventing hyperhomocysteinemia using vitamin B6 supplementation in Givosiran-treated acute intermittent porphyria: Highlights from a case report and brief literature review.

Acute hepatic porphyrias are inherited metabolic disorders of heme biosynthesis characterized by the accumulation of toxic intermediate metabolites responsible for disabling acute neurovisceral attacks. Givosiran is a newly approved siRNA-based treatment of acute hepatic porphyria targeting the first and rate-limiting δ-aminolevulinic acid synthase 1 (ALAS1) enzyme of heme biosynthetic pathway. We described a 72-year old patient who presented with severe inaugural neurological form of acute intermittent porphyria evolving for several years which made her eligible for givosiran administration. On initiation of treatment, the patient developed a major hyperhomocysteinemia (>400 µmol/L) which necessitated to discontinue the siRNA-based therapy. A thorough metabolic analysis in the patient suggests that hyperhomocysteinemia could be attributed to a functional deficiency of cystathionine ß-synthase (CBS) enzyme induced by givosiran. Long-term treatment with vitamin B6, a cofactor of CBS, allowed to normalize homocysteinemia while givosiran treatment was maintained. We review the recently published cases of hyperhomocysteinemia in acute hepatic porphyria and its exacerbation under givosiran therapy. We also discuss the benefits of vitamin B6 supplementation in the light of hypothetic pathophysiological mechanisms responsible for hyperhomocysteinemia in these patients. Our results confirmed the importance of monitoring homocysteine metabolism and vitamin status in patients with acute intermittent porphyria in order to improve management by appropriate vitamin supplementation during givosiran treatment.

Late diagnosis of primary hyperoxaluria type III.

We report the case of a 78-year-old patient with late diagnosis of hyperoxaluria type III (PH3). He developed renal failure after nephrectomy for clear cell papillary renal carcinoma and complained of recurrent urolithiasis for some 30 years, whose aetiology was never identified. Biochemical laboratory investigations of urine and urolithiasis composition revealed marked hyperoxaluria but normal concentrations of urinary glyceric and glycolic acid as well as stones of idiopathic calcium-oxalate appearance. Furthermore, the dietary survey showed excessive consumption of food supplements containing massive amounts of oxalate precursors. However, the persistence of excessive hyperoxaluria after his eating habits was changed leading us to perform molecular genetic testing. We found heterozygous mutations of the recently PH3-associated HOGA1 gene when sequencing PH genes. This is the first description of late diagnosis primary PH3 in a patient with several additional pro-lithogenic factors. This case illustrates the importance of undertaking a complete biological work-up to determine the aetiology of hyperoxaluria. This may reveal underdiagnosed primary hyperoxaluria, even in older patients.

Down-regulation of the phosphoenolpyruvate carboxykinase gene in human colon tumors and induction by omega-3 fatty acids.

The polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduces proliferation of several cell types, including colon tumor cells, and regulates gene expression in a cell- and gene-selective manner. In hepatocytes, the fatty acid synthase (FAS) gene is down-regulated by DHA whereas the carnitine palmitoyltransferase-1 (CPT-1) gene is up-regulated. In adipocytes but not in hepatocytes, the expression of the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) gene is stimulated by unsaturated FA, including DHA. We monitored the expression of the FAS, CPT-1 and PEPCK-C genes in rat and human colon and in colonic tumors from humans. The ratio of PEPCK-C to FAS transcripts was in favor of PEPCK-C in human and rat colon, whereas the opposite occurred in Caco2 tumoral cells. FAS gene expression declined from proliferative to differentiated Caco2 cells, while in contrast the expression of PEPCK-C and CPT-1 genes increased. DHA strongly induced expression of the PEPCK-C and CPT-1 genes, in correlation with decreased cell growth, while, as expected, it reduced FAS mRNA. We assessed the relative expression of PEPCK-C, CPT-1 and FAS genes in fragments of colonic tumors and adjacent non-tumoral tissue from a series of 10 patients. PEPCK-C and CPT-1 mRNAs are more abundant in non-tumoral tissues than in the tumoral counterpart, whereas the opposite occurred for the FAS gene. Therefore, the PEPCK-C gene can be defined as a new negative marker for colonic tumors and a target for the anti-tumorigenic action of omega-3 PUFAs.