Study to Identify a Genetic Defect in Subjects With Hyperferritinemia.

Ferritin is a ubiquitous protein capable of storing iron in the cell cytosol. Cytosolic ferritin consists of two subunits, the light chain (L-ferritin) and the heavy chain (H-ferritin) that assemble in different proportions to form apo-ferritin shells. Ferritin nanoshells consist of 24 subunits of the L- and H-chains that create a cavity in which intracellular iron is collected. The stored iron is released and made available for cellular needs by the degradation of ferritin. Ferritin can bind, oxidize, and store up to 4500 Fe(II) atoms, preventing iron-mediated oxidative stress. This is achieved by regulating ferritin synthesis according to cellular iron content and oxidative stress at both the post-transcriptional (via the Iron Responsive Element (IRE)-regulatory protein (IRP) system) and transcriptional levels. Small amounts of ferritin are present in the blood and consist of ferritin L, a glycosylated form of L called ferritin G, and traces of ferritin H. It is secreted primarily by macrophages, hepatocytes, and lymphoid cells, but most aspects of its secretion remain unknown. Serum ferritin has broad clinical utility primarily as an indicator of intracellular iron stores.

The causes of increased serum ferritin are numerous, including primary and secondary iron overload disorders, but also conditions in which serum ferritin is increased disproportionately to the body's iron stores such as chronic liver disease, inflammatory and metabolic disorders that are frequently observed in the clinical setting. Therefore, the diagnosis of hyperferritinemia requires a systematic strategy including personal and family history, biochemical and instrumental tests. In addition, alterations in the regulation of ferritin synthesis due to mutations in the iron-sensitive element L-ferritin (IRE) cause hereditary hyperferritinemia cataract syndrome (HHCS), an inherited disease characterized by elevated serum ferritin without iron overload and early onset of bilateral cataracts. Recently, a second dominant form of genetic hyperferritinemia without iron overload or cataract has been reported. Amino acid substitutions at positions 26, 27, and 30 in the heterozygous state in the L-ferritin A helix have been found in these patients. The resulting ferritin appears unusually susceptible to glycosylation, leading to serum glycosylated ferritin values consistently >90%. The reason for the development of hyperferritinemia and hyperglycosylation associated with these mutant forms of ferritin has not been established. It is probably related to increased secretion, but may also contribute to delayed clearance. Some cases of hyperferritinemia still remain unexplained, and the currently unknown candidate gene that we think we have identified among candidate genes needs to be validated in a larger population of subjects with the listed characteristics.

The primary objective of the study is to sequence the candidate gene that emerged from previous studies as mutated in patients with the same clinical features.

The secondary objective is to include the candidate gene in the routine genetic diagnosis of subjects with hyperferritinemia without tissue iron overload.

The study will last about 12 months the time needed for the recovery of patients with a genetic diagnosis not yet defined, analysis of medical records and research of the DNA sample stored at the Laboratory of Cytogenetics and Medical Genetics of San Gerardo Hospital and genetic analysis by Next Generation Sequencing. The study, although simple in its idea, requires a very careful organization of access and monitoring of selected patients that require the presence of a study manager dedicated to the project.