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Mutations in the NKX2.1 gene, which is essential for the development, differentiation and organization of the basal ganglia, cause benign hereditary chorea (BHC) characterized by childhood-onset non-progressive chorea. We herein report the clinical features of six patients from a single family with a novel intronic mutation and present the dopaminergic neuronal imaging by using positron emission tomography (PET) imaging to assess the integrity of the striatal dopaminergic system using [(11)C]-CFT for the presynaptic dopamine transporter function and [(11)C]-raclopride for the postsynaptic D2 receptor function. The patients showed mild generalized chorea without either congenital hypothyroidism or a history of pulmonary infection and some of the patients had goiter. Genetic analyses of NKX2.1 gene showed a novel heterozygous c.464-9C>A mutation that created a new acceptor splice site resulting in the production of an aberrant transcript with a 7-bp insertion identical to a intronic sequence of genomic DNA. Oral levodopa failed to improve the involuntary movement, while haloperidol, a dopamine D2 receptor blocking agent, exacerbated the choric movement in a single patient. The dopaminergic PET studies in the two patients revealed decreased raclopride binding in the striatum, while the CFT binding was not altered. The impairment of D2 receptor function in the basal ganglia may result in exacerbation of the chorea induced by haloperidol. The molecular brain imaging and therapeutic response may help elucidate the pathophysiological mechanism of the motor control in the BHC-associated NKX2.1 mutation.

A 59-year-old man presented with refractory anemia, choreoathetosis in the left upper extremity, an unsteady gait and cognitive dysfunction. The laboratory findings showed a marked decrease in ceruloplasmin. Magnetic resonance images revealed iron deposition in the brain and visceral organs. Iron accumulation was also observed in hepatocytes. Genetic analyses of the ceruloplasmin gene revealed a novel homozygous mutation of c.2185 delC in exon 12. The oral chelator deferasirox was effective in treating the left-side choreoathetosis and unsteady gait. Providing early treatment using deferasirox may be useful for preventing the progression of symptomatic neurological dysfunction.

Ceruloplasmin plays an essential role in cellular iron efflux by oxidizing ferrous iron exported from ferroportin. Ferroportin is posttranslationally regulated through internalization triggered by hepcidin binding. Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis resulting from mutations in the ceruloplasmin gene. The present study investigated the biological effects of glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on the hepcidin-mediated internalization of ferroportin. The prevention of hepcidin-mediated ferroportin internalization was observed in the glioma cells lines expressing endogenous ceruloplasmin as well as in the cells transfected with GPI-linked ceruloplasmin under low levels of hepcidin. A decrease in the extracellular ferrous iron by an iron chelator and incubation with purified ceruloplasmin in the culture medium prevented hepcidin-mediated ferroportin internalization, while the reconstitution of apo-ceruloplasmin was not able to prevent ferroportin internalization. The effect of ceruloplasmin on the ferroportin stability was impaired due to three distinct properties of the mutant ceruloplasmin: namely, a decreased ferroxidase activity, the mislocalization in the endoplasmic reticulum, and the failure of copper incorporation into apo-ceruloplasmin. Patients with aceruloplasminemia exhibited low serum hepcidin levels and a decreased ferroportin protein expression in the liver. The in vivo findings supported the notion that under low levels of hepcidin, mutant ceruloplasmin cannot stabilize ferroportin because of a loss-of-function in the ferroxidase activity, which has been reported to play an important role in the stability of ferroportin. The properties of mutant ceruloplasmin regarding the regulation of ferroportin may therefore provide a therapeutic strategy for aceruloplasminemia patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Aceruloplasminemia is a neurodegenerative disease characterized by parenchymal iron accumulation owing to mutations in the ceruloplasmin gene. Ceruloplasmin is expressed in the central nervous system in which most of the ceruloplasmin is located on the surface of astrocytes in a glycosylphosphatidylinositol (GPI)-anchored form. We herein describe the biochemical features of wild-type and mutant GPI-anchored ceruloplasmin. An overexpression of wild-type GPI-anchored ceruloplasmin in Chinese hamster ovary cells led to the formation of aggresome-like inclusions, especially in the presence of proteasome inhibitors. As expected from the properties of aggresomes, the inclusions were colocalized with gamma-tubulin and a disruption of microtubules using nocodazole blocked the formation of such inclusions. Aceruloplasminemia-linked mutant proteins failed to form such inclusions even after treatment with proteasomal inhibitors. An immunofluorescent analysis indicated that the mutant proteins were thus retained in the endoplasmic reticulum (ER), whereas the transfected cells showed a decreased viability. The expression of glucose-regulated protein 78 that is one of the ER stress sensor proteins, and the activity of glucose-regulated protein 78 promoter was upregulated in the cells transfected with the mutants. These findings indicated that when the overexpressed cytoplasmic wild-type ceruloplasmin was not subjected to degradation by the proteasome-ubiquitin system, then the wild-type protein was transported along the microtubules, thus forming inclusions at the microtubule organizing center, whereas the mutant ceruloplasmin failed to form any such inclusions, because the mutant protein might not have been translocated across the ER into the cytoplasm. Therefore, the mutant protein was considered to have accumulated in the ER thus leading to the ER stress, which resulted in cell death.