GENE ANALYSIS AND LIPID PEROXIDATION ASSOCIATED WITH INCREASED IRON IN PATIENTS WITH ACERULOPLASMINEMIA

血浆无铜蓝蛋白血症是一种新发现的常染色体隐性遗传性铁代谢疾病，可导致视网膜和基底节神经退行性变以及糖尿病。临床上它被认为是糖尿病、视网膜变性和神经系统疾病的三联征。这种疾病的特征是血浆铜蓝蛋白基因突变，血清铜蓝蛋白缺乏，血清铁浓度低，以及脑，肝和其他组织中的铁积累。1）铁是氧自由基介导的细胞和组织损伤的重要催化剂。从受影响的患者脑脊液中发现铁浓度增加了三倍，这与超氧化物歧化酶活性和脂质过氧化产物增加。这些发现支持了铁介导的脂质过氧化作用导致血浆凝固蛋白血症患者神经退行性变的假设。这种测量可能在评估疾病进展以及铁螯合和其他治疗干预的结果方面具有价值。2）我们筛选了4，990名健康成年人的血清铜蓝蛋白浓度。随后的突变等位基因的序列测定显示三个突变（一个纯合子和五个杂合子）。基因频率为70 x/100，000。在日本，非近亲婚姻中血浆铜蓝蛋白血症的发病率估计约为2，000，000分之一。3）我们报告了一名70岁的帕金森综合征和迟发性糖尿病妇女，她的血浆铜蓝蛋白基因发生了新的突变。铜蓝蛋白基因的核苷酸序列分析显示，在外显子11的单碱基缺失（G：nt 2068）。该突变产生了移码，导致在aa 690处的提前终止。

Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism resulting in neurodegeneration of the retina and basal ganglia as well as diabetes mellitus. Clinically it is recognized as a triad of diabetes, retinal degeneration and neurologic disease. This disease is characterized by mutations in the ceruloplasmin gene, the absence of serum ceruloplasmin, low serum iron concentration, and iron accumulation in the brain, liver, and other tissues.1) Iron in an important catalyst of oxyradical-mediated cellular and tissue injury. CSF from affected patients revealed a three-fold increased iron concentration which was associated with increased superoxide dismutase activity and lipid peroxidation products. These findings support the hypothesis that iron-mediated lipid peroxidation contributes to neurodegeneration in patients with aceruloplasminemia. Such measurements may have value in assessing disease progression as well as the results of iron chelation and other therapeutic interventions.2) We screened the serum ceruloplasmin concentrations of 4,990 healthy adult individuals. Subsequent sequence determination of the mutant alleles showed three mutations (one homozygote and five heterozygotes). The gene frequency was 70x/100,000. In Japan, the incidence of aceruloplasminemia was estimated to be approximately one per 2,000,000 in the case of non consanguineous marriages.3) We report a 70-year-old woman with parkinsonism and late onset diabetes mellitus who had a novel mutation in the ceruloplasmin gene. Nucleotide sequence analysis of the ceruloplasmin gene showed a single bp deletion (G : nt 2068) in exon 11. This mutation produced a frame shift, resulting in the premature termination at aa 690.