Kim Ja Hye, Lee Beom Hee, Kim Yoo-Mi, Choi Jin-Ho, Kim Gu-Hwan, Cheon Chong Kun, Yoo Han-Wook
Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, South Korea.
Metab Brain Dis. 2015 Feb;30(1):75-81. doi: 10.1007/s11011-014-9569-5. Epub 2014 Jun 13.
Menkes disease is a very rare X-linked copper metabolism disorder that results from an ATP7A gene mutation. With the advent of subcutaneous copper-histidine therapy, the early diagnosis of Menkes disease becomes of utmost importance for patients' prognosis. In the present study, the clinical characteristics of 12 Korean patients with Menkes disease (11 males and 1 female from 11 unrelated families) were described along with the mutation spectrum. Only 2 male patients were diagnosed in the neonatal period, and the other male patients were diagnosed at age 4.3 ± 1.9 months. The presenting signs included depigmented kinky hair, neurologic deficits, and hypotonia. Serum copper and ceruloplasmin levels were markedly decreased. Intracranial vessels were dilated with tortuosity and accompanied by regional cerebral infarctions, even at an early age. Of note, the female patient was diagnosed at age 18 months, during the evaluation for developmental delay, by characteristic MRA findings, biochemical profiles, and genetic evaluation. A total of 11 ATP7A mutations were identified, including five previously unreported mutations. Most mutations were truncated (except 1 missense mutation), including 3 frameshift, 2 nonsense, 3 large deletion, and 2 splice-site variants. The age at commencement of copper-histidine treatment was variable among patients age 7.3 ± 7.5 (0.5-27) months. Despite the treatment, seven patients died before age 5 years, and the remaining patients were severely retarded in neurodevelopment. The poor outcomes of our patients might be related to delayed therapy, but severe ATP7A mutations should be noted as well.
门克斯病是一种非常罕见的X连锁铜代谢紊乱疾病，由ATP7A基因突变引起。随着皮下注射组氨酸铜疗法的出现，门克斯病的早期诊断对患者的预后至关重要。在本研究中，描述了12例韩国门克斯病患者（来自11个无亲缘关系家庭的11名男性和1名女性）的临床特征以及突变谱。仅2例男性患者在新生儿期被诊断，其他男性患者在4.3±1.9个月时被诊断。出现的体征包括色素脱失的卷曲毛发、神经功能缺损和肌张力减退。血清铜和铜蓝蛋白水平明显降低。即使在早期，颅内血管也会扩张迂曲并伴有局部脑梗死。值得注意的是，该女性患者在18个月大时，在评估发育迟缓过程中，通过特征性的磁共振血管造影（MRA）结果、生化指标和基因评估被诊断。共鉴定出11种ATP7A突变，包括5种先前未报道的突变。大多数突变是截短突变（除1种错义突变外），包括3种移码突变、2种无义突变、3种大片段缺失和2种剪接位点变异。患者开始组氨酸铜治疗的年龄各不相同，平均为7.3±7.5（0.5 - 27）个月。尽管进行了治疗，7例患者在5岁前死亡，其余患者神经发育严重迟缓。我们患者的不良预后可能与治疗延迟有关，但严重的ATP7A突变也应予以关注。
