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Hiroaki Miyajima - One of the best experts on this subject based on the ideXlab platform.
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Aceruloplasminemia with Abnormal Compound Heterozygous Mutations Developed Neurological Dysfunction during Phlebotomy Therapy.
Internal medicine (Tokyo Japan), 2018Co-Authors: Maki Watanabe, Ken Ohyama, Masashi Suzuki, Yasunobu Nosaki, Takashi Hara, Katsushige Iwai, Satoshi Kono, Hiroaki Miyajima, Kenji MokunoAbstract:Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with Aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in Aceruloplasminemia patients with other gene mutations.
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Investigated and available therapeutic options for treating Aceruloplasminemia
Expert Opinion on Orphan Drugs, 2015Co-Authors: Hiroaki MiyajimaAbstract:Introduction: Ceruloplasmin regulates the efficiency of iron efflux from the cells, functioning as a ferroxidase, and stabilizes the cell surface iron transporter ferroportin. Aceruloplasminemia is an autosomal recessive disorder associated with iron accumulation in the brain and viscera caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical manifestations of retinal degeneration, diabetes mellitus, iron-refractory anemia and neurologic disease correspond to the regions of iron deposition.Areas covered: Oxidative stress and increased lipid peroxidation are closely related to the increased iron levels in the brain and visceral organs. Iron-chelating agents decrease brain and liver iron stores, improve the diabetic mellitus condition and prevent the progression of neurologic symptoms in symptomatic individuals. However, there is no universally accepted regimen.Expert opinion: Zinc concentrations in these patients were decreased in the brain and visceral organs, and zinc showed op...
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chapter 45 Aceruloplasminemia
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015Co-Authors: Satoshi Kono, Hiroaki MiyajimaAbstract:Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA). This disorder is caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microscopic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements and cognitive dysfunction. The diagnosis of Aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resonance imaging (MRI). Pathological and molecular biological investigations have revealed the pathogenesis of neurodegeneration to involve iron-mediated radical cellular injury resulting from marked accumulation of iron in the affected parenchymal tissues due to an iron efflux impairment caused by the absence of ferroxidase activity of ceruloplasmin.
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Chapter 45 – Aceruloplasminemia
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 2015Co-Authors: Satoshi Kono, Hiroaki MiyajimaAbstract:Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA). This disorder is caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microscopic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements and cognitive dysfunction. The diagnosis of Aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resonance imaging (MRI). Pathological and molecular biological investigations have revealed the pathogenesis of neurodegeneration to involve iron-mediated radical cellular injury resulting from marked accumulation of iron in the affected parenchymal tissues due to an iron efflux impairment caused by the absence of ferroxidase activity of ceruloplasmin.
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Brain And Liver Iron Accumulation Demonstrated By 1.5-tesla and 3-tesla MRI in Aceruloplasminemia (P4.032)
Neurology, 2014Co-Authors: Koji Fujita, Satoshi Kono, Hiroaki Miyajima, Yusuke Osaki, Masafumi Harada, Yuishin Izumi, Ryuji KajiAbstract:OBJECTIVE: To demonstrate 3-tesla MRI findings in a patient with Aceruloplasminemia, an important differential diagnosis of neurodegeneration with brain iron accumulation (NBIA). BACKGROUND: Aceruloplasminemia is typically characterized by involuntary movements, cerebellar ataxia and dementia. However, neurological symptoms can be mild in some patients with Aceruloplasminemia. DESIGN/METHODS: A 68-year-old woman with diabetes mellitus, anemia, and retinal degeneration developed mild cognitive impairment and subtle gait ataxia. The mini-mental state examination score was 22. On laboratory examination, hemoglobin level was 10.6 g/dl, mean corpuscular volume was 81.5 fl, alkaline phosphatase level was 402 U/l, hemoglobin A1c was 8.7%, iron level was 22 μg/dl (reference range, 62-159), ferritin level was 677 ng/ml (reference range, 4-204), and copper level was 13 μg/dl (reference range, 64-142). Moreover, serum ceruloplasmin was undetectable and genetic testing revealed a homozygous mutation (p.W858X) in the ceruloplasmin gene, confirming the diagnosis of Aceruloplasminemia. Brain MRI was performed with 1.5-tesla and 3-tesla machines, and liver MRI was performed with a 1.5-tesla machine (Signa HDx; GE Healthcare, MI). RESULTS: Gradient echo-type T2*-weighted brain MRI showed symmetric hypointensity in the striatum, thalamus, red nucleus, and dentate nucleus and on the brain surface, more prominently on high-field imaging. T2-weighted and diffusion-weighted (b=800 s/mm2) MRI of the liver showed diffuse hypointensity. CONCLUSIONS: This case underlies the importance of T2*-weighted MRI in diagnosing and assessing Aceruloplasminemia even in patients with minimum neurological symptoms. 3-tesla T2*-weighted MRI is effective in demonstrating iron deposition on the brain surface in Aceruloplasminemia. Study Supported by: None. Disclosure: Dr. Fujita has nothing to disclose. Dr. Osaki has nothing to disclose. Dr. Harada has nothing to disclose. Dr. Kono has nothing to disclose. Dr. Miyajima has nothing to disclose. Dr. Izumi has nothing to disclose. Dr. Kaji has received personal compensation for activities with GlaxoSmithKline, Inc. as a consultant. Dr. Kaji has received research support from GlaxoSmithKline, Inc.
Kunihiro Yoshida - One of the best experts on this subject based on the ideXlab platform.
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Deferasirox Might Be Effective for Microcytic Anemia and Neurological Symptoms Associated with Aceruloplasminemia: A Case Report and Review of the Literature.
Internal medicine (Tokyo Japan), 2020Co-Authors: Zenshi Miyake, Kiyotaka Nakamagoe, Kunihiro Yoshida, Tadashi Kondo, Akira TamaokaAbstract:The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with Aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with Aceruloplasminemia might respond to deferasirox in less than one year.
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Superficial siderosis associated with Aceruloplasminemia. Case report.
Journal of the neurological sciences, 2014Co-Authors: Akira Matsushima, Kunihiro Yoshida, Shinji Ohara, Toshikazu Yoshida, Yasuko Toyoshima, Akiyoshi Kakita, Shu-ichi IkedaAbstract:A 63-year-old woman with a past history of right subdural hematoma (SDH) at the age of 61 years was referred to our hospital under a suspicion of Aceruloplasminemia (ACP). A neurological examination revealed very mild cognitive impairment and cerebellar ataxia. Blood chemistry data showed deficient ceruloplasmin (Cp), decreased copper, and increased ferritin. A nonsense mutation (c.2630G>A, p.Trp858Ter) was detected in the Cp gene. Brain magnetic resonance imaging (MRI) showed marked hypointensity at the surface of the cerebrum, cerebellum, and brainstem bilaterally, in addition to the bilateral basal ganglia, thalamus, and dentate nucleus, suggesting the coexistence of ACP and superficial siderosis (SS). The characteristics of SS in ACP have not been examined neuroradiologically or neuropathologically in great detail, while SDH and its curative surgery are known to cause SS. The distribution of the hypointensity areas on MRI was expanded bilaterally to the subtentorial areas of this patient, which was much more widespread than observed in typical SS after SDH. We speculate that the underlying ACP may expand the SS induced by SDH. Cp would accelerate iron export from the brain via the blood-cerebrospinal fluid (CSF) barrier, or CSF-brain barrier when excessive iron is loaded into the subarachnoid space.
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Extensive brain pathology in a patient with Aceruloplasminemia with a prolonged duration of illness.
Human pathology, 2011Co-Authors: Kazuma Kaneko, Kunihiro Yoshida, Akiyo Hineno, Shinji Ohara, Hiroshi Morita, Shu-ichi IkedaAbstract:We report the sixth autopsy case of a patient with Aceruloplasminemia. He was the younger brother of the first reported autopsy case of this disease. Among autopsy cases with Aceruloplasminemia reported to date, he had the longest duration of neurologic disorders. The neuropathologic findings showed that the basal ganglia and dentate nuclei were most severely affected. The most striking finding in the present case was that marked iron deposition was evident in the cerebral cortex. Many enlarged or deformed astrocytes and globular structures, both of which were heavily iron loaded, were found in the cerebral cortex as well as in the basal ganglia. Pyramidal neurons in his cerebral cortex were fewer in number than observed in the previous reported cases. There was a negative correlation between the number of cortical pyramidal neurons and globular structures. The present case clearly indicates that the neuropathologic process in Aceruloplasminemia extends beyond the basal ganglia to the cerebral cortex with time.
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Criteria for early identification of Aceruloplasminemia.
Internal medicine (Tokyo Japan), 2011Co-Authors: Masaro Ogimoto, Kunihiro Yoshida, Keizo Anzai, Hiromasa Takenoshita, Kazuhiko Kogawa, Yuko Akehi, Ryoko Yoshida, Makiko Nakano, Junko OnoAbstract:A 52-year-old Japanese woman being treated for type 1 diabetes showed forgetfulness and microcytic anemia with a high serum ferritin concentration. Serum and brain radiological examinations revealed Aceruloplasminemia, which was confirmed by genetic testing. Aceruloplasminemia is characterized by the triad of retinal degeneration, diabetes mellitus, and adult-onset disorder of the extrapyramidal system. Though physicians should treat such patients earlier, it is difficult to diagnose the disease before the presentation of neurological symptoms. Despite the presence of microcytic anemia, Aceruloplasminemia patients usually have a high serum ferritin concentration due to the complete absence of ceruloplasmin ferroxidase activity. Thus, physicians should consider Aceruloplasminemia when diabetic patients present with microcytic anemia and a high serum ferritin concentration.
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Increased vulnerability to rotenone-induced neurotoxicity in ceruloplasmin-deficient mice
Neuroscience letters, 2008Co-Authors: Kazuma Kaneko, Kunihiro Yoshida, Akiyo Hineno, Shu-ichi IkedaAbstract:Ceruloplasmin (Cp) is the strongest ferroxidase in human plasma. Hereditary deficiency of this protein, named Aceruloplasminemia, is an interesting model to elucidate the pathogenesis and pathophysiology of neurodegeneration induced by oxidative stress. Enhanced oxidative stress due to excessive iron accumulation is observed in the brains of Aceruloplasminemia patients. Rotenone, a selective mitochondrial complex I inhibitor, induces neurodegeneration mimicking Parkinson's disease. We investigated the influence of Cp deficiency upon neurodegeneration using rotenone-treated, Cp-deficient mouse brains. Immunohistochemical examination showed that acrolein, one of the products of lipid peroxides, and ubiquitin were more markedly immunoreacted in the brains of rotenone-treated, Cp-deficient mice than in rotenone-untreated, Cp-deficient or rotenone-treated, wild-type mice. These molecules were localized in neuronal cells. These results suggested that rotenone-induced lipid peroxidation and accumulation of ubiquitin immunoreactivity were enhanced in the absence of Cp. Therefore, Cp may protect neuronal cells from oxidative stress-induced neurodegeneration.
Jonathan D. Gitlin - One of the best experts on this subject based on the ideXlab platform.
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The copper-iron connection: Hereditary Aceruloplasminemia
Seminars in hematology, 2002Co-Authors: Thalia Nittis, Jonathan D. GitlinAbstract:Abstract Hereditary Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis due to loss-of-function mutations in the ceruloplasmin gene. Affected individuals may present in adulthood with evidence of hepatic iron overload, diabetes, peripheral retinal degeneration, dystonia, dementia, or dysarthria. Laboratory studies demonstrate microcytic anemia, elevated serum ferritin, and a complete absence of serum ceruloplasmin ferroxidase activity. Consistent with the observed neurologic findings, magnetic resonance imaging reveals iron accumulation within the basal ganglia. Histologic studies detect abundant iron in hepatocytes, reticuloendothelial cells of the liver and spleen, β cells of the pancreas, and astrocytes and neurons throughout the central nervous system. Characterization of this disorder reveals an essential role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores and provides new insights into the mechanisms of human iron metabolism. Semin Hematol 39:282-289. Copyright 2002, Elsevier Science (USA). All rights reserved.
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Biochemical analysis of a missense mutation in Aceruloplasminemia.
The Journal of biological chemistry, 2001Co-Authors: Nathan E. Hellman, Satoshi Kono, Hiroaki Miyajima, Jonathan D. GitlinAbstract:Aceruloplasminemia is an inherited neurodegenerative disease characterized by parenchymal iron accumulation secondary to loss-of-function mutations in the ceruloplasmin gene. To elucidate the molecular pathogenesis of Aceruloplasminemia, the biosynthesis of a missense mutant ceruloplasmin (P177R) occurring in an affected patient was examined. Chinese hamster ovary cells transfected with cDNAs encoding secreted and glycosylphosphatidylinositol (GPI)-linked wild-type or P177R human ceruloplasmin were examined by pulse-chase metabolic labeling. These experiments, as well as immunofluorescent analysis andN-linked glycosylation studies, indicate that both the secreted and GPI-linked forms of the P177R mutant are retained in the endoplasmic reticulum (ER). The P177R mutation resides within a novel motif, which is repeated six times in human ceruloplasmin and is conserved in the homologous proteins hephaestin and factor VIII. Analysis of additional mutations in these motifs suggests a critical role for this region in ceruloplasmin trafficking and indicates that substitution of the arginine residue is critical to the ER retention of the P177R mutant. Metabolic labeling of transfected Chinese hamster ovary cells with 64Cu indicates that the P177R mutant is retained in the ER as an apoprotein and that copper is incorporated into both secreted and GPI-linked ceruloplasmin as a late event in the secretory pathway. Taken together, these studies reveal new insights into the determinants of holoceruloplasmin biosynthesis and indicate that Aceruloplasminemia can result from retention of mutant ceruloplasmin within the early secretory pathway.
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targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Leah Z Harris, Alison P Durley, Tszkwong Man, Jonathan D. GitlinAbstract:Aceruloplasminemia is an autosomal recessive disorder of iron metabolism. Affected individuals evidence iron accumulation in tissue parenchyma in association with absent serum ceruloplasmin. Genetic studies of such patients reveal inherited mutations in the ceruloplasmin gene. To elucidate the role of ceruloplasmin in iron homeostasis, we created an animal model of Aceruloplasminemia by disrupting the murine ceruloplasmin (Cp) gene. Although normal at birth, Cp−/− mice demonstrate progressive accumulation of iron such that by one year of age all animals have a prominent elevation in serum ferritin and a 3- to 6-fold increase in the iron content of the liver and spleen. Histological analysis of affected tissues in these mice shows abundant iron stores within reticuloendothelial cells and hepatocytes. Ferrokinetic studies in Cp+/+ and Cp−/− mice reveal equivalent rates of iron absorption and plasma iron turnover, suggesting that iron accumulation results from altered compartmentalization within the iron cycle. Consistent with this concept, Cp−/− mice showed no abnormalities in cellular iron uptake but a striking impairment in the movement of iron out of reticuloendothelial cells and hepatocytes. Our findings reveal an essential physiologic role for ceruloplasmin in determining the rate of iron efflux from cells with mobilizable iron stores.
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Aceruloplasminemia
Pediatric Research, 1998Co-Authors: Jonathan D. GitlinAbstract:Aceruloplasminemia is an autosomal recessive disorder of iron metabolism characterized by diabetes, retinal degeneration, and neurologic symptoms. Affected patients evidence marked parenchymal iron accumulation in conjunction with an absence of circulating serum ceruloplasmin and molecular genetic analysis reveals inherited mutations in the ceruloplasmin gene. Taken together with earlier studies that characterized ceruloplasmin as a ferroxidase and recent work indicating an essential role for a homologous multicopper oxidase in iron metabolism in Saccharomyces cerevisiae , these findings reveal an essential role for ceruloplasmin in human iron metabolism. The presence of neurologic symptoms in patients with Aceruloplasminemia is unique among the characterized disorders of iron metabolism, and recent findings indicate that astrocyte-specific ceruloplasmin gene expression is critical for iron metabolism and neuronal survival in the retina and basal ganglia. The discovery of this disease provides new insights into the pathways of CNS iron metabolism of direct relevance to a variety of nutritional and genetic disorders of childhood.
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use of desferrioxamine in the treatment of Aceruloplasminemia
Annals of Neurology, 1997Co-Authors: Hiroaki Miyajima, Yoshitomo Takahashi, Naoki Sakai, Tadashi Kamata, Hideaki Shimizu, Jonathan D. GitlinAbstract:Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism resulting in neurodegeneration of the retina and basal ganglia. We report here on the treatment of a patient who developed progressive extrapyramidal symptoms that included blepharospasm, grimacing, and rigidity associated with increased iron deposition in the brain and visceral organs. Treatment for 10 months with the iron chelator desferrioxamine decreased brain iron stores, prevented progression of the neurological symptoms, and reduced plasma lipid peroxidation. These data suggest that early treatment with this chelator may be useful in such patients to diminish central nervous system iron accumulation and to prevent or ameliorate neurological symptoms associated with neurodegeneration.
Satoshi Kono - One of the best experts on this subject based on the ideXlab platform.
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Aceruloplasminemia with Abnormal Compound Heterozygous Mutations Developed Neurological Dysfunction during Phlebotomy Therapy.
Internal medicine (Tokyo Japan), 2018Co-Authors: Maki Watanabe, Ken Ohyama, Masashi Suzuki, Yasunobu Nosaki, Takashi Hara, Katsushige Iwai, Satoshi Kono, Hiroaki Miyajima, Kenji MokunoAbstract:Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with Aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in Aceruloplasminemia patients with other gene mutations.
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chapter 45 Aceruloplasminemia
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition), 2015Co-Authors: Satoshi Kono, Hiroaki MiyajimaAbstract:Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA). This disorder is caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microscopic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements and cognitive dysfunction. The diagnosis of Aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resonance imaging (MRI). Pathological and molecular biological investigations have revealed the pathogenesis of neurodegeneration to involve iron-mediated radical cellular injury resulting from marked accumulation of iron in the affected parenchymal tissues due to an iron efflux impairment caused by the absence of ferroxidase activity of ceruloplasmin.
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Chapter 45 – Aceruloplasminemia
Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease, 2015Co-Authors: Satoshi Kono, Hiroaki MiyajimaAbstract:Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis that is classified as an inherited neurodegenerative disorder called “neurodegeneration with brain iron accumulation” (NBIA). This disorder is caused by loss-of-function mutations encoding the ceruloplasmin gene. The clinical presentation involves hepatic iron overload, microscopic anemia, retinal degeneration, diabetes mellitus, and neurological symptoms, including cerebellar ataxia, involuntary movements and cognitive dysfunction. The diagnosis of Aceruloplasminemia is made based on the complete absence of serum ceruloplasmin, marked elevation of the ferritin concentration and abnormally low levels of intensity in the liver and brain, including the basal ganglia, thalamus, and dentate nucleus, on both T1- and T2-weighted magnetic resonance imaging (MRI). Pathological and molecular biological investigations have revealed the pathogenesis of neurodegeneration to involve iron-mediated radical cellular injury resulting from marked accumulation of iron in the affected parenchymal tissues due to an iron efflux impairment caused by the absence of ferroxidase activity of ceruloplasmin.
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Brain And Liver Iron Accumulation Demonstrated By 1.5-tesla and 3-tesla MRI in Aceruloplasminemia (P4.032)
Neurology, 2014Co-Authors: Koji Fujita, Satoshi Kono, Hiroaki Miyajima, Yusuke Osaki, Masafumi Harada, Yuishin Izumi, Ryuji KajiAbstract:OBJECTIVE: To demonstrate 3-tesla MRI findings in a patient with Aceruloplasminemia, an important differential diagnosis of neurodegeneration with brain iron accumulation (NBIA). BACKGROUND: Aceruloplasminemia is typically characterized by involuntary movements, cerebellar ataxia and dementia. However, neurological symptoms can be mild in some patients with Aceruloplasminemia. DESIGN/METHODS: A 68-year-old woman with diabetes mellitus, anemia, and retinal degeneration developed mild cognitive impairment and subtle gait ataxia. The mini-mental state examination score was 22. On laboratory examination, hemoglobin level was 10.6 g/dl, mean corpuscular volume was 81.5 fl, alkaline phosphatase level was 402 U/l, hemoglobin A1c was 8.7%, iron level was 22 μg/dl (reference range, 62-159), ferritin level was 677 ng/ml (reference range, 4-204), and copper level was 13 μg/dl (reference range, 64-142). Moreover, serum ceruloplasmin was undetectable and genetic testing revealed a homozygous mutation (p.W858X) in the ceruloplasmin gene, confirming the diagnosis of Aceruloplasminemia. Brain MRI was performed with 1.5-tesla and 3-tesla machines, and liver MRI was performed with a 1.5-tesla machine (Signa HDx; GE Healthcare, MI). RESULTS: Gradient echo-type T2*-weighted brain MRI showed symmetric hypointensity in the striatum, thalamus, red nucleus, and dentate nucleus and on the brain surface, more prominently on high-field imaging. T2-weighted and diffusion-weighted (b=800 s/mm2) MRI of the liver showed diffuse hypointensity. CONCLUSIONS: This case underlies the importance of T2*-weighted MRI in diagnosing and assessing Aceruloplasminemia even in patients with minimum neurological symptoms. 3-tesla T2*-weighted MRI is effective in demonstrating iron deposition on the brain surface in Aceruloplasminemia. Study Supported by: None. Disclosure: Dr. Fujita has nothing to disclose. Dr. Osaki has nothing to disclose. Dr. Harada has nothing to disclose. Dr. Kono has nothing to disclose. Dr. Miyajima has nothing to disclose. Dr. Izumi has nothing to disclose. Dr. Kaji has received personal compensation for activities with GlaxoSmithKline, Inc. as a consultant. Dr. Kaji has received research support from GlaxoSmithKline, Inc.
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Case of presymptomatic Aceruloplasminemia treated with deferasirox.
Hepatology research : the official journal of the Japan Society of Hepatology, 2014Co-Authors: Mayumi Tai, Satoshi Kono, Hiroaki Miyajima, Tatsuhiro Terada, Nobuo Matsuhashi, Osamu Ichii, Tomohiro Suzuki, Yutaka Ejiri, Masaru HaradaAbstract:Aceruloplasminemia is an autosomal recessive disease characterized by an abnormal iron metabolism. The absence of ferroxidase activity caused by mutation of ceruloplasmin leads to iron overload in the brain, liver and other organs. We report a 35-year-old man who was diagnosed with Aceruloplasminemia without neurological manifestation despite the accumulation of iron in the brain and liver. To prevent the development of neurodegenerative disorder related to iron toxicity, iron depletion therapy was performed. Iron chelator deferasirox was effective in reducing serum ferritin level and to prevent the progression of the disease.
Yoshitomo Takahashi - One of the best experts on this subject based on the ideXlab platform.
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treatment of symptomatic heterozygous Aceruloplasminemia with oral zinc sulphate
Brain & Development, 2007Co-Authors: Jens Kuhn, Hiroaki Miyajima, Yoshitomo Takahashi, H Bewermeyer, K F Kuhn, T U HoogenraadAbstract:Aceruloplasminemia is an autosomal recessive and phenotypically primarily neurodegenerative disease caused by a homozygous mutation of the ceruloplasmin gene. The absence of ceruloplasmin and its ferroxidase activity leads to pathological iron overload in the brain and other organs. While heterozygous carriers of ceruloplasmin gene mutations have been believed to be asymptomatic, a number of cases with neurological deficits have recently been described. To date, an effective treatment has not been established for either Aceruloplasminemia or symptomatic heterozygous Aceruloplasminemia. The present report concerns the beneficial treatment of an 18-year-old girl with extrapyramidal and cerebellar-mediated movement disorder caused by a heterozygous mutation of the ceruloplasmin gene using oral zinc sulphate.
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Cys-881 is essential for the trafficking and secretion of truncated mutant ceruloplasmin in Aceruloplasminemia.
Journal of hepatology, 2007Co-Authors: Satoshi Kono, Yoshitomo Takahashi, Hitoshi Suzuki, Kentaro Shirakawa, Toshiaki Oda, Masatoshi Kitagawa, Hiroaki MiyajimaAbstract:Background/Aims Aceruloplasminemia is an inherited iron overload disorder caused by a mutation in the ceruloplasmin gene and characterized by iron accumulation in both the liver and brain. The aim of this study was to elucidate the molecular pathogenesis of Aceruloplasminemia by a functional analysis of mutant ceruloplasmin. Methods The effects of nonsense mutations including Y694ter, W858ter and R882ter were studied by the expression in cultured cells. Results A biogenesis study demonstrated that the Y694ter and W858ter mutants showed protein synthesis identical to that of wild type protein, however, the mutants were retained in the endoplasmic reticulum (ER), while R882ter mutant was secreted out. Site-directed mutagenesis analyses suggested that Cys-881 was necessary for the secretion of the truncated ceruloplasmin. The W858ter mutant decreased viability in the transfected cells. The expression and the promoter activity of glucose-regulated protein 78 that is an ER stress sensor protein, were up-regulated in the transfected cells. Conclusions The truncated mutant containing Cys-881 was able to pass through the ER and was secreted, while the truncated mutant protein without Cys-881 appeared to accumulate in the ER thus leading to ER stress and eventually resulting in cell death.
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Identification and in silico characterization of a novel compound heterozygosity associated with hereditary Aceruloplasminemia.
Scandinavian journal of gastroenterology, 2007Co-Authors: Wolf Peter Hofmann, Hiroaki Miyajima, Yoshitomo Takahashi, Christoph Welsch, Ulrike Mihm, Christoph Krick, Stefan Zeuzem, Christoph SarrazinAbstract:Background. Hereditary Aceruloplasminemia is an adult-onset autosomal recessive disease characterized by increased iron overload in the liver, pancreas, retina, and central nervous system. So far, 45 families with cases of Aceruloplasminemia have been reported world-wide and mainly missense and nonsense mutations in the ceruloplasmin gene were detected. Material and methods. Here, we report the identification, clinical characterization, and in silico analysis of a novel compound heterozygosity in the ceruloplasmin gene of a 31-year-old man with iron overload. Results. Increased serum ferritin levels, elevated iron saturation, as well as results of iron quantification in the liver and magnetic resonance imaging-based measurement of T2 relaxation times of the substantia nigra consistently suggested iron overload. By sequencing the ceruloplasmin gene, so far unknown nucleotide replacements G229C, and C2131A were detected in exons 2 and 12, respectively. In silico analyses showed that the resulting amino acid...
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Hepatic iron overload associated with a decreased serum ceruloplasmin level in a novel clinical type of Aceruloplasminemia.
Gastroenterology, 2006Co-Authors: Satoshi Kono, Yoshitomo Takahashi, Hitoshi Suzuki, Kazuo Takahashi, Kentaro Shirakawa, Yohko Murakawa, Shuhei Yamaguchi, Hiroaki MiyajimaAbstract:Background & Aims: Aceruloplasminemia is a novel hereditary iron overload disease caused by a mutation in the ceruloplasmin gene and characterized by a complete deficiency of serum ceruloplasmin and iron accumulation in the liver and brain. Methods: We herein studied a novel clinical type of Aceruloplasminemia in which a low amount of ceruloplasmin was detected in the serum of a patient. The patient presented with an asymptomatic hepatic iron overload, retinal degeneration, and diabetes mellitus. Magnetic resonance imaging of the liver and basal ganglia showed T2-hypointensity signals associated with parenchymal iron accumulation because of an absence of the ferroxidase activity in ceruloplasmin. Results: A gene analysis showed a novel G969S mutation in the ceruloplasmin gene. A biochemical analysis of the patients' serum and a biogenesis study of G969S mutant ceruloplasmin using mammalian cell culture system resulted in the synthesis and secretion of only apoceruloplasmin without any ferroxidase activity. Conclusions: This novel clinical type of Aceruloplasminemia should therefore be considered in the differential diagnosis of unexplained hemochromatosis, which is associated with a decrease in the serum ceruloplasmin level.
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Biochemical features of ceruloplasmin gene mutations linked to Aceruloplasminemia.
Neuromolecular medicine, 2006Co-Authors: Satoshi Kono, Hiroaki Miyajima, Yoshitomo Takahashi, Hitoshi Suzuki, Kentaro Shirakawa, Toshiaki Oda, Kuniko Ishikawa, Masatoshi KitagawaAbstract: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 glycosylphosphatidy linositol (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 aggresomelike inclusions, especially in the presence of proteasome inhibitors. As expected from the properties of aggresomes, the inclusions were colocalized with γ-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. Animmunofluorescent 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 cerulop lasmin 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 inculsions, 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.
