PhD defence L.H.P. (Lena) Vroegindeweij

Summary:

The clinical phenotype of aceruloplasminemia was extensively studied in (local) Caucasian patients and the literature. It could be characterized by a triad of antibody-negative, insulin-dependent diabetes, microcytic or normocytic anemia, and a broad spectrum of neurological manifestations. Neurological manifestations are a late clinical characteristic of the disease and vary with ataxia, hyperkinetic movement disorders, parkinsonism, cognitive decline, and psychiatric changes. Antibody-negative, insulin-dependent diabetes manifesting in non-obese adults > 30 years of age or unexplained microcytic or normocytic anemia should prompt the early consideration of aceruloplasminemia. Combined measurement of ferritin and transferrin saturation can easily support or rule out the diagnosis. In aceruloplasminemia patients with normal hemoglobin levels or mild asymptomatic anemia, iron chelation therapy with deferiprone and phlebotomy is recommended. The combination of deferiprone and deferoxamine might be a reasonable alternative approach for patients with symptomatic anemia. Initiation of iron chelation therapy before the onset of neurological manifestations has the potential to delay its onset by ten years, while iron chelation seems unable to rescue further neurological deterioration at the neurologically symptomatic stage of the disease. Although iron has been considered the major determinant of neurodegeneration in aceruloplasminemia, the relationship between clinical manifestations of the disease and the (regional) amount of iron has not been clarified. The iron-sensitive MRI metric R2* that has now been validated as a non-invasive quantitative measure of brain iron content in aceruloplasminemia, reflecting total iron content rather than changes in its oxidation state, might help to address this in future studies.