Clinicopathological study of Japanese patients with genetic iron overload syndromes

Hattori, Ai; Miyajima, Hiroaki; Tomosugi, Naohisa; Tatsumi, Yasuaki; Hayashi, Hisao; Wakusawa, Shinya

doi:10.1111/j.1440-1827.2012.02848.x

Cited by 23 publications

(49 citation statements)

References 29 publications

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“…Affected patients exhibit dystonia, chorea, diabetes mellitus, and pigmentary retinopathy. ACP pathology has been described in detail by Kaneko et al (2002, 2012), Oide, Yoshida, Kaneko, Ohta, and Arima (2006), and Hattori et al (2012).…”

Section: Aceruloplasminemia (Acp)mentioning

confidence: 99%

The Neuropathology of Neurodegeneration with Brain Iron Accumulation

Kruer

2013

International Review of Neurobiology

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Neuropathology plays a key role in characterizing the pathogenesis of neurodegenerative diseases including forms of neurodegeneration with brain iron accumulation (NBIA). Despite important differences, several genetically diverse forms of NBIA nevertheless share common features in addition to iron deposition, such as the presence of neuroaxonal spheroids. Multiple forms of NBIA also demonstrate tau or synuclein pathology, suggesting parallels with both Alzheimer and Parkinson diseases. This chapter summarizes what has been learned from the study of human patient tissues. Gross and microscopic findings are delineated, and similarities and differences between forms of NBIA are presented. Neuropathologic findings often help characterize fundamental features of disease and provide a springboard for more focused hypothesis-driven studies. Lessons learned from neuropathology thus contribute much to the characterization of the molecular mechanisms of disease.

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Section: Aceruloplasminemia (Acp)mentioning

confidence: 99%

The Neuropathology of Neurodegeneration with Brain Iron Accumulation

Kruer

2013

International Review of Neurobiology

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“…Although serum levels of a circulating hepcidin25 in Japanese patients with iron overload syndromes were measured and reported by our laboratory, there has been no report on WD patients, and so we determined their circulating hepcidin25s using the same method . Results were compared with the reported data of ACP, TFR2, and FPD (Table ).…”

Section: Iron and Copper Homeostasismentioning

confidence: 99%

“…According to the hepcidin/FP/DMT1 system, genetic iron overload syndromes can be classified into pre‐hepatic forms of iron loading anemias and ACP, hepatic forms of HFE‐, TFR2‐, HJV‐, and HAMP‐HH, and post‐hepatic FPD A and B (Table ) . Iron loading anemias include a variety of anemias associated with non‐erythropoietic hypohepcidinemia .…”

Section: Classifications Of Genetic Iron Overload Syndromes and Primamentioning

confidence: 99%

“…Iron overload of ACP is characterized by low iron saturation of the circulating transferrin. The false signal mimicking an iron deficiency may be transferred to HAMP via TFR2, resulting in the reduced synthesis and secretion of hepacidin25 into the circulation (pre‐hepatic) . In addition, considering a poor recovery from post‐phlebotomy anemia in ACP, iron, once entering hepatocytes, will not be exported into the circulation.…”

Section: Classifications Of Genetic Iron Overload Syndromes and Primamentioning

confidence: 99%

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The interactions between iron and copper in genetic iron overload syndromes and primary copper toxicoses in Japan

Tatsumi

Kato

et al. 2018

Hepatology Research

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Iron and copper are trace elements essential for health, and iron metabolism is tightly regulated by cuproproteins. Clarification of the interactions between iron and copper may provide a better understanding of the pathophysiology and treatment strategy for hemochromatosis, Wilson disease, and related disorders. The hepcidin/ferroportin system was used to classify genetic iron overload syndromes in Japan, and ceruloplasmin and ATP7B were introduced for subtyping Wilson disease into the severe hepatic and classical forms. Interactions between iron and copper were reviewed in these genetic diseases. Iron overload syndromes were classified into pre-hepatic iron loading anemia and aceruloplasminemia, hepatic hemochromatosis, and post-hepatic ferroportin disease. The ATP7B-classical form with hypoceruloplasminemia has primary hepatopathy and late extra-hepatic complications, while the severe hepatic form is free from ATP7B mutation and hypoceruloplasminemia, and silently progresses to liver failure. A large amount of iron and trace copper co-exist in hepatocellular dense bodies of all iron overload syndromes. Cuproprotein induction to stabilize excess iron should be differentiated from copper retention in Wilson disease. The classical form of Wilson disease associated with suppressed hepacidin25 secretion may be double-loaded with copper and iron, and transformed to an iron disease after long-term copper chelation. Iron disease may not be complicated with the severe hepatic form with normal ferroxidase activity. Hepatocellular dense bodies of iron overload syndromes may be loaded with a large amount of iron and trace copper, while the classical Wilson disease may be double-loaded with copper and iron.

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“…In addition, families with various types of HH were sporadically reported from Asian countries, including Japan, China, and Pakistan [67,87,[89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104]. In Japan, mutations in HFE2 (type 2A), TFR2 (type 3), and SLC40A1 (type 4) seem relatively common causes of HH [97].…”

Section: Various Types Of Hhmentioning

confidence: 99%

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

Kawabata

2017

Int J Hematol

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Hereditary hemochromatosis (HH) is a group of genetic iron overload disorders that manifest with various symptoms, including hepatic dysfunction, diabetes, and cardiomyopathy. Classic HH type 1, which is common in Caucasians, is caused by bi-allelic mutations of HFE. Severe types of HH are caused by either bi-allelic mutations of HFE2 that encodes hemojuvelin (type 2A) or HAMP that encodes hepcidin (type 2B). HH type 3, which is of intermediate severity, is caused by bi-allelic mutations of TFR2 that encodes transferrin receptor 2. Mutations of SLC40A1 that encodes ferroportin, the only cellular iron exporter, causes either HH type 4A (loss-of-function mutations) or HH type 4B (gain-of-function mutations). Studies on these gene products uncovered a part of the mechanisms of the systemic iron regulation; HFE, hemojuvelin, and TFR2 are involved in iron sensing and stimulating hepcidin expression, and hepcidin downregulates the expression of ferroportin of the target cells. Phlebotomy is the standard treatment for HH, and early initiation of the treatment is essential for preventing irreversible organ damage. However, because of the rarity and difficulty in making the genetic diagnosis, a large proportion of patients with non-HFE HH might have been undiagnosed; therefore, awareness of this disorder is important.

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Clinicopathological study of Japanese patients with genetic iron overload syndromes

Cited by 23 publications

References 29 publications

The Neuropathology of Neurodegeneration with Brain Iron Accumulation

The Neuropathology of Neurodegeneration with Brain Iron Accumulation

The interactions between iron and copper in genetic iron overload syndromes and primary copper toxicoses in Japan

The mechanisms of systemic iron homeostasis and etiology, diagnosis, and treatment of hereditary hemochromatosis

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