Abstract
BackgroundAceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. The effects of iron chelation on neurological outcomes have only been described in case studies, and are inconsistent. Aggregated case reports were analyzed to help delineate the disease-modifying potential of treatment.MethodsData on clinical manifestations, treatment and neurological outcomes of treatment were collected from three neurologically symptomatic Dutch patients, who received deferiprone with phlebotomy as a new therapeutic approach, and combined with other published cases. Neurological outcomes of treatment were compared between patients starting treatment when neurologically symptomatic and patients without neurological manifestations.ResultsTherapeutic approaches for aceruloplasminemia have been described in 48 patients worldwide, including our three patients. Initiation of treatment in a presymptomatic stage of the disease delayed the estimated onset of neurological manifestations by 10 years (median age 61 years, SE 5.0 vs. median age 51 years, SE 0.6, p = 0.001). Although in 11/20 neurologically symptomatic patients neurological manifestations remained stable or improved during treatment, these patients were treated significantly shorter than patients who deteriorated neurologically (median 6 months vs. median 43 months, p = 0.016). Combined iron chelation therapy with deferiprone and phlebotomy for up to 34 months could be safely performed in our patients without symptomatic anemia (2/3), but did not prevent further neurological deterioration.ConclusionsEarly initiation of iron chelation therapy seems to postpone the onset of neurological manifestations in aceruloplasminemia. Publication bias and significant differences in duration of treatment should be considered when interpreting reported treatment outcomes in neurologically symptomatic patients. Based on theoretical grounds and the observed long-term safety and tolerability in our study, we recommend iron chelation therapy with deferiprone in combination with phlebotomy for aceruloplasminemia patients without symptomatic anemia.
Highlights
Aceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations
Results of up to 3 years of combined iron chelation therapy with deferiprone and phlebotomy showed that the combination can be safely performed in aceruloplasminemia patients when treatment is subject to strict monitoring of hemoglobin and granulocyte count
Neither deferiprone with phlebotomy nor deferiprone with deferoxamine could prevent further neurological deterioration, this report yields detailed information on clinical manifestations, adverse events associated with treatment and disease progression in various stages of the disease, which might be valuable for individual patient management
Summary
Aceruloplasminemia is a rare genetic iron overload disorder, characterized by progressive neurological manifestations. Aceruloplasminemia (OMIM #604290) is a rare form of neurodegeneration with brain iron accumulation (NBIA), characterized by progressive neurological deterioration and iron accumulation in visceral organs [1]. Iron chelation therapy has been shown by biochemical markers and quantitative visceral MRI to reduce body iron stores, but the reported effects on neurological outcomes are inconsistent [2, 3]. Deferiprone monotherapy is not highly effective in reducing body iron stores in aceruloplasminemia [7, 8], and needs to be combined with another chelator to achieve satisfactory rates of iron removal [8,9,10]. Deferiprone with phlebotomy has the potential to reduce both cerebral and systemic iron stores more rapidly than previously achieved, and possibly to slow disease progression
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