Laboratory of Iron Metabolism, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
Centre for Disorders of Iron Metabolism, ASST-Monza, Ospedale San Gerardo, Monza, Italy.
Parkinsonism Relat Disord. 2018 Jun;51:36-42. doi: 10.1016/j.parkreldis.2018.02.036. Epub 2018 Feb 24.
Aceruloplasminemia is an ultra-rare hereditary disorder characterized by iron-restricted microcytic anemia and tissue iron overload associated with diabetes, retinal and progressive neurological degeneration. We describe genotypes and phenotypes at diagnosis, and disease evolution of seven Italian patients.
Anagraphical, biochemical, genetic, clinical and instrumental data were collected at diagnosis and during a long-term follow-up. Mutations, ferroxidase activity and Western Blot analysis of ceruloplasmin were performed according to standard protocols.
Three mutations were already described (p.Phe217Ser, deletions of exon 11 and 12), p.Ile991Thr is a very rare variant, p.Cys338Ser and IVS6+1G > A were novel mutations. In silico analyses suggested they were highly likely or likely to be damaging. At diagnosis, 100% had microcytosis, 86% had mild-moderate anemia, low serum iron and high serum ferritin. Four (57%) had type 1 diabetes or glucose intolerance, 3/7 had neurological manifestations, and only one had early diabetic retinopathy. All but one underwent iron chelation therapy requiring temporary discontinuation because of anemia worsening. At the end of follow-up, three patients aggravated and 2 developed neurological symptoms; only two patients were free of neurological manifestations and showed mild or absent brain iron.
Aceruloplasminemia phenotypes ranged from classical characterized by progressive neurologic derangement to milder in which signs of systemic iron overload prevailed over brain iron accumulation. Within this large heterogeneity, microcytosis with or without anemia, low serum iron and high serum ferritin were the early hallmarks of the disease. Therapeutic approaches other than iron chelation should be explored to reduce morbidity and improve life expectancy.
亚铁氧化酶缺乏症是一种极罕见的遗传性疾病，其特征为铁限制所致的小细胞性贫血和与糖尿病、视网膜病变和进行性神经退行性变相关的组织铁过载。我们描述了 7 名意大利患者的诊断时基因型和表型以及疾病演变。
在诊断时和长期随访期间收集了个人史、生化、遗传、临床和仪器数据。根据标准方案进行突变、亚铁氧化酶活性和铜蓝蛋白的 Western Blot 分析。
已发现 3 种突变（p.Phe217Ser、外显子 11 和 12 的缺失），p.Ile991Thr 是一种非常罕见的变体，p.Cys338Ser 和 IVS6+1G ＞A 是新的突变。计算机分析表明，它们很可能或可能具有破坏性。在诊断时，100%的患者有小细胞性贫血，86%的患者有轻度至中度贫血、低血清铁和高血清铁蛋白。4 例（57%）患有 1 型糖尿病或葡萄糖耐量异常，3/7 例有神经表现，仅有 1 例有早期糖尿病性视网膜病变。除 1 例外，所有患者均接受了铁螯合治疗，由于贫血恶化，需要暂时停止治疗。在随访结束时，3 名患者病情加重，2 名患者出现神经症状；仅有 2 名患者无神经表现且大脑铁含量轻微或无。
亚铁氧化酶缺乏症的表型范围从以进行性神经功能障碍为特征的经典表型到以全身性铁过载表现为主、大脑铁积累较轻的表型。在这种大的异质性中，伴有或不伴有贫血的小细胞性贫血、低血清铁和高血清铁蛋白是疾病的早期特征。除铁螯合治疗外，还应探索其他治疗方法，以降低发病率并提高预期寿命。
