Study to Identify a Genetic Defect in Subjects With Hyperferritinemia.

HyFerr

Ferritin is a ubiquitous protein capable of storing iron in the cell cytosol. Stored iron is released and made available for cellular needs by the degradation of ferritin itself. Small amounts of ferritin are present in the blood and consist of ferritin L, a glycosylated form of L called ferritin G, and trace amounts of ferritin H. It is secreted mainly by macrophages, hepatocytes, and lymphoid cells, but most aspects of its secretion remain not fully elucidated. Serum ferritin has broad clinical utility primarily as an indicator of iron stores, so low values of serum ferritin are indicative of a deficient state and high values of iron overload. However, the causes of increased serum ferritin are numerous, in many cases serum ferritin is increased disproportionately to iron stores such as in acute and chronic liver disease, infectious and inflammatory states, metabolic disorders, and high alcohol intake that are frequently observed in the clinical setting. Therefore, the diagnosis of hyperferritinemia requires a careful strategy including personal and family history, biochemical, instrumental, and targeted genetic testing. In fact, there are rare forms of genetically determined hyperferritinemia not associated with iron overload, such as hereditary cataract hyperferritinemia syndrome (HHCS) due to mutations in the Iron responsive Element (IRE) located in the 5' untranslated region of the FTL gene. More recently, a second dominant form of genetic hyperferritinemia without iron overload or cataract (benign hyperferritinemia) has been identified. Preliminary results obtained so far have made it possible, through WES analysis, to identify the involvement of the STAB1 gene, which was found to be mutated in the studied subjects in whom reduced serum ferritin glycosylation and reduced plasma concentration of the protein itself were observed. It is therefore deemed necessary to proceed with the assay of glycosylated ferritin and the protein encoded by the gene to assess its sensitivity and specificity as a predictive test before performing the genetic analysis of STAB1. To achieve this goal, patients with undefined hyperferritinemia afferent to the SSD Rare Diseases of the IRCCS San Gerardo Foundation in whom to perform glycosylated ferritin and STAB1 protein assay in parallel with STAB1 sequencing will be evaluated. Similar investigations will be performed in a control group consisting of cases of hyperferritinemia due to genetically determined iron overload.

2022-06-06

2024-01-03

2024-09-30

Recruiting

100

Inclusion Criteria: Among patients referred to the Center for Rare Diseases of Monza will be enrolled only subjects with: * ferritin \> 1000 g / L in men and \> 500 g / L, * transferrin saturation \<45% * absence of hepatic iron overload, evaluated by liver biopsy or MRI, as indicated in the attached flow chart. Exclusion Criteria: Patients with hyperferritinemia attributable to: * genetically determined causes \[mutations in the HFE gene (homozygosity or heterozygosity for p.Cys282Tyr, homozygosity for p.His63Asp or compound heterozygosity for variants of p.Cys282Tyr and p. His63Asp), ferroportin and L-Ferritin gene mutations\]; * presence of more than one component of metabolic syndrome (according to NCEP-ATPIII criteria: triglycerides \>150 mg/dL, blood glucose \>100 mg/dL, HDL \<40 mg/dL in men and \<50 mg/dL in women, waist circumference \>102 cm in men and \>88 cm in women; blood pressure ≥130/≥85 mm/Hg); * alcohol intake \>5 g/day chronic hepatitis, * history of blood transfusion or parenteral iron treatment, * late skin porphyria, * hyperthyroidism, * presence of cataracts or family history of early-onset cataracts * acute or chronic inflammatory disorders.

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2024-01-05