Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports

Vroegindeweij, Lena H.P.; Wilson, J. H. P.; Langendonk, Janneke G.

doi:10.1186/s13023-020-01385-w

Cited by 21 publications

(25 citation statements)

References 52 publications

(53 reference statements)

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“…The maintenance of ferritin as the major iron storing protein in extremely iron-loaded brain tissue, as observed in our study, has major implications for the concept of iron chelation as the main treatment for aceruloplasminemia and other NBIA disorders. In particular, deferiprone is currently being exploited to treat several NBIA diseases (22, 49). Deferiprone is the only iron chelator known to date that is capable of transporting iron across cell membranes and across the blood brain barrier.…”

Section: Discussionmentioning

confidence: 99%

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Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

Vroegindeweij

Bossoni

Wilson

et al. 2020

Preprint

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Aceruloplasminemia is an ultra-rare neurodegenerative disorder associated with massive brain iron accumulation. It is unknown which molecular forms of iron accumulate in the brain of patients with aceruloplasminemia. As the disease is associated with at least a fivefold increase in brain iron concentration compared to the healthy brain, it offers a unique model to study the role of iron in neurodegeneration and the molecular basis of iron-sensitive MRI contrast. The iron-sensitive MRI metrics inhomogeneous transverse relaxation rate (R2*) and magnetic susceptibility obtained at 7T were combined with Electron Paramagnetic Resonance (EPR) and Superconducting Quantum Interference Device (SQUID) magnetometry to specify and quantify the different iron forms per gram wet weight in a post-mortem aceruloplasminemia brain, focused on the basal ganglia, thalamus, red nucleus, dentate nucleus, superior- and middle temporal gyrus and white matter. MRI, EPR and SQUID results that had been previously obtained from the temporal cortex of healthy controls were included for comparison. The brain iron pool in aceruloplasminemia consisted of EPR-detectable Fe3+ ions, magnetic Fe3+ embedded in the core of ferritin and hemosiderin (ferrihydrite-iron), and magnetic Fe3+ embedded in oxidized magnetite/maghemite minerals (maghemite-iron). Of all the studied iron pools, above 90% was made of ferrihydrite-iron, of which concentrations up to 1065 μg/g were detected in the red nucleus. Although deep gray matter structures in the aceruloplasminemia brain were three times richer in ferrihydrite-iron than the temporal cortex, ferrihydrite-iron was already six times more abundant in the temporal cortex of the patient with aceruloplasminemia compared to the healthy situation (162 μg/g vs. 27 μg/g). The concentration of Fe3+ ions and maghemite-iron was 1.7 times higher in the temporal cortex in aceruloplasminemia than in the control subjects. Of the two quantitative MRI metrics, R2* was the most illustrative of the pattern of iron accumulation and returned relaxation rates up to 0.49 ms-1, which were primarily driven by the abundance of ferrihydrite-iron. Maghemite-iron did not follow the spatial distribution of ferrihydrite-iron and did not significantly contribute to MRI contrast in most of the studied regions. Even in extremely iron-loaded cases, iron-related neurodegeneration remains primarily associated with an increase in ferrihydrite-iron, with ferrihydrite-iron being the major determinant of iron-sensitive MRI contrast.

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Section: Discussionmentioning

confidence: 99%

“…Formalin-fixed brain slices of one end-stage aceruloplasminemia patient (male, age range: 50-55) (19-22) were obtained from the Department of Pathology, Erasmus MC, University Medical Center Rotterdam, The Netherlands. This study has received IRB approval by the Erasmus MC Medical Ethical Committee (MEC-2011-525).…”

Section: Methodsmentioning

confidence: 99%

Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

Vroegindeweij

Bossoni

Wilson

et al. 2020

Preprint

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“…Although iron chelation appears effective in reducing systemic iron overload 8,9 there is less evidence of a beneficial effect in reversing or preventing the neurological manifestations which occur in ACP 10,11 . However, a recent analysis of aggregated case reports did conclude that neurological progression was slowed when iron chelation therapy was commenced early in the disease 12 …”

Section: Discussionmentioning

confidence: 99%

Three‐year follow up of using combination therapy with fresh‐frozen plasma and iron chelation in a patient with acaeruloplasminemia

et al. 2020

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Acaeruloplasminemia is a rare autosomal recessive condition caused by inactivating mutations of the CP gene encoding caeruloplasmin (ferroxidase). Caeruloplasmin is a copper‐containing plasma ferroxidase enzyme with a key role in facilitating cellular iron efflux. We describe a case of a patient with acaeruloplasminemia, confirmed by genetic analysis, treated with combination therapy of monthly fresh‐frozen plasma (FFP) or Octaplas and iron chelation over a 3‐year period. This 19‐year‐old male was diagnosed at the age of 14 after developing issues with social interaction at school prompting investigation. Prior to this, he had been well with a normal childhood. He was found to have an iron deficient picture with a paradoxically high ferritin, with low serum copper and undetectable caeruloplasmin. Genetic testing identified a homozygous splicing mutation, c.(1713 + delG);(c.1713 + delG), in intron 9 of the caeruloplasmin gene. Ferriscan showed a high liver iron concentration of 5.3 mg/g dry tissue (0.17‐1.8). Brain and cardiac T2‐weighted magnetic resonance (MR) imaging did not detect iron deposition of the brain or heart respectively. Treatment with monthly Octaplas infusion was commenced alongside deferasirox (540 mg o.d.) in an attempt to increase caeruloplasmin levels and reduce iron overload, respectively. After 3 years of treatment, there was biochemical improvement with a reduction in ferritin from 1084 (12‐250) to 457 μg/L, ALT from 87 (<50) to 34 U/L together with improvement in his microcytic anaemia. No significant adverse events occurred. This case report adds further evidence of treatment efficacy and safety of combined FFP and iron chelation therapy in acaeruloplasminemia.

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“…Most importantly, neurological symptoms are not reduced by iron chelation treatment. 406,427 Some mitigation of neurological symptoms has been described when iron-chelation with deferiprone is used in combination with phlebotomy. 427 Intravenous administration of fresh-frozen plasma (FFP) partially and temporarily restores circulating ceruloplasmin, reduces brain iron deposition and reduces neurological symptoms, although exactly how the ceruloplasmin crosses the BBB is not clear.…”

Section: Deregulated Iron Homeostasis and Neurodegenerative Disordersmentioning

confidence: 99%

“…406,427 Some mitigation of neurological symptoms has been described when iron-chelation with deferiprone is used in combination with phlebotomy. 427 Intravenous administration of fresh-frozen plasma (FFP) partially and temporarily restores circulating ceruloplasmin, reduces brain iron deposition and reduces neurological symptoms, although exactly how the ceruloplasmin crosses the BBB is not clear. 428 Given the heavy iron overload in the epithelial cells of the choroid plexus, one possibility is that ceruloplasmin enters the brain through a damaged choroid plexus lining or of the BBB.…”

Section: Deregulated Iron Homeostasis and Neurodegenerative Disordersmentioning

confidence: 99%

Overdosing on iron: Elevated iron and degenerative brain disorders

D’Mello¹,

Kindy

2020

Exp Biol Med (Maywood)

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All cells in organisms ranging from yeast to humans utilize iron as a cofactor or structural element of proteins that function in diverse and critical cellular functions. However, deregulation of the homeostatic mechanisms regulating iron metabolism resulting in a reduction or excess of iron within the cell or outside of it can have serious effects to the health of cells and the organism. This review provides a brief overview of the molecular and cellular mechanisms regulating iron physiology, including the molecules and processes regulating iron uptake, its storage and utilization, its recycling, and its release from the cell, such that the cellular iron levels are sufficient to meet metabolic demand but below those that cause permanent damage. The major focus of review is on the pathological consequences of dysregulation of these homeostatic mechanisms, focusing on the brain. Current advances on the role of iron accumulation to the pathogenesis of rare neurological disorders caused by genetic mutations as well as to the more prevalent and age-associated neurodegenerative diseases are described. Impact statement Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer’s disease and Parkinson’s disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.

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Effects of iron chelation therapy on the clinical course of aceruloplasminemia: an analysis of aggregated case reports

Cited by 21 publications

References 52 publications

Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

Quantification of different iron forms in the aceruloplasminemia brain to explore iron-related neurodegeneration

Three‐year follow up of using combination therapy with fresh‐frozen plasma and iron chelation in a patient with acaeruloplasminemia

Overdosing on iron: Elevated iron and degenerative brain disorders

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