Acaeruloplasminemia

Classification according to ICD-10
E83.1	Iron metabolism disorders
ICD-10 online (WHO version 2019)

Acaeruloplasminemia , also called acoeruloplasminemia (from Latin coeuruleus = blue), is an inheritable metabolic disease with a complete lack of ferroxidase activity of ceruloplasmin , which is caused by mutations in the corresponding gene. Genetically heterozygous manifestations can also lead to symptoms, especially in the event of a failure of ferroxidase activity despite the presence of ceruloplasmin in the serum (hypocaeruloplasminemia, hypocoeruloplasminemia).

Acaeruloplasminemia was first described in 1987 by Miyajima et al. The disease is very rare and is most frequently observed in Japan with an incidence of about 1 in 2,000,000. The age range of neurological diagnosis is between 16 and 72 years, with a mean value of 51. In the course of the disease, the failure of the oxidation of Fe ²⁺ to Fe ³⁺ leads to an increased accumulation of toxic divalent iron . This leads to iron deposits in the body, especially in the brain , liver and pancreas , but also in other organs and tissues. The clinical triad of retinal degeneration (approx. 93%), diabetes mellitus (approx. 89%) and neurological symptoms (approx. 73%) such as ataxia , involuntary movements and dementia are often found . An anemia is also found frequently (about 80%). In addition, there are studies according to which, in some cases, impairment of the mitochondrial energy metabolism and lipid peroxidation through radical formation (as a result of iron accumulation) can also occur, as well as hormonal impairments of the hypothalamus and thus hypothyroidism and diabetes insipidus .

Blood tests, imaging tests and genetic tests are the main types of diagnosis. Particularly relevant for differential diagnosis are hemochromatosis (iron storage disease) and Wilson's disease , in which ceruloplasmin is also reduced, but the symptoms primarily result from copper accumulation. Imaging methods such as MRI can make metallic deposits visible in acaeruloplasminemia. The serum shows a lack of ferroxidase activity, a lack of ceruloplasmin (or low ceruloplasmin in heterozygous patients), a low copper level, as well as a low iron level and an increased level of ferritin (in heterozygous patients iron and ferritin are mostly normal ). Increased lipid peroxidation can be determined using malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) as well as prostaglandin F _2α (PGF _2α ). In contrast to Wilson's disease, the urinary copper level is not increased in acaeruloplasminemia.

If the diagnosis is confirmed, iron chelators can be used to reduce iron deposits in the body. However, there have been reports of patients who show little or no improvement with this treatment.

One study suggests that in very specific cases in heterozygous patients, "environmental conditions" can determine whether a patient develops symptoms or not; for example, cases have been reported in which a parent and a child have the same heterozygous mutation, but only the child is affected.

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1. ↑ HF Shang / Movement Disorder Society: High Brain Iron Level in Asymptomatic Carriers of Heterozygous Ceruloplasmin Gene Mutations. Vol. 23, No. 6, 2008, pp. 916-917.
2. ↑ Y. Takeuchi, M. Yoshikawa, T. Tsujino, S. Kohno, N. Tsukamoto, A. Shiroi, E. Kikuchi, H. Fukui, H. Miyajima: A case of aceruloplasminaemia: abnormal serum ceruloplasmin protein without ferroxidase activity. 2002, engl.
3. ^ Alisdair McNeill, Massimo Pandolfo, Jens Kuhn, Huifang Shang, Hiroaki Miyajima: The Neurological Presentation of Ceruloplasmin Gene Mutations. 2008, doi: 10.1159 / 000148691 , engl.
4. ↑ Hiroaki Miyajima: Genetic Disorders Affecting Proteins of Iron and Copper Metabolism: Clinical Implications. 2002.
5. ↑ Hiroaki Miyajima, Yoshitomo Takahashi, Satoshi Kono, Masahiro Sugimoto, Yoji Suzuki, Hishida, Masanobu Sakamoto, Yasuomi Ouchi: Glucose and Oxygen Hypometabolism in Aceruloplasminemia Brains. 2002.
6. ↑ Minemori Watanabe, Chikako Asai, Kota Ishikawa, Atsushi Kiyota, Tatsuhiro Terada, Satoshi Kono, Hiroaki Miyajima, Ataru Okumura: Central Diabetes Incipidus and Hypothalamic Hypothyroidism Associated with Aceruloplasminemia Case Report, 2010, engl.
7. ↑ Hiroaki Miyajima, Y. Takahashi, S. Kono: Aceruloplasminemia, an inherited disorder of iron metabolism. In: BioMetals. Volume 16, Number 1, March, 2003, pp. 205-213, doi: 10.1023 / A: 1020775101654 , engl.
8. ^ Alisdair McNeill, Massimo Pandolfo, Jens Kuhn, Huifang Shang, Hiroaki Miyajima: The Neurological Presentation of Ceruloplasmin Gene Mutations. 2008, doi: 10.1159 / 000148691 , engl.
9. ↑ Hiroaki Miyajima, Satoshi Kono, Yoshitomo Takahashi, Masahiro Sugimoto: Increased Lipid Peroxidation and Mitochondrial Dysfunction in Aceruloplasminemia Brains Sept. 2012, doi: 10.1006 / bcmd.2002.0561 , engl.
10. ↑ J.-M. Trocello, P. Chappuis, S. El Balkhi, J. Poupon, A. Leyendecker, P. Chaine, F. Woimant: Anomalies du métabolisme du cuivre chez l'adulte 2009, French.
11. ↑ Ping-Lei Pan, He-Han Tang, Qin Chen, Wei Song, Hui-Fang Shang: Desferrioxamine treatment of aceruloplasminemia: Long-term follow-up. 2011, doi: 10.1002 / mds.23797 , engl.
12. ↑ Maria Carmela Bonaccorsi di Patti, Nunziata Maio, Gianluca Rizzo, Giovanni De Francesco, Tiziana Persichini, Marco Colasanti, Fabio Polticelli, Giovanni Musci: Dominant Mutants of Ceruloplasmin Impair the Copper Loading Machinery in Aceruloplasminemia. July 2008, doi: 10.1074 / jbc.M805688200 , engl.

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