Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia
Compound heterozygosity of two functional null mutations in the ALPL gene associated with deleterious neurological outcome in an infant with hypophosphatasia
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DOI：
10.1016/j.bone.2013.02.017
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发表时间：
2013-07-01
期刊：
影响因子：
4.1
通讯作者：
Mentrup, B.
中科院分区：
文献类型：
--
作者：
Hofmann, C.;Liese, J.;Mentrup, B.
低磷酸酶症（HPP）是一种异质性罕见的遗传性骨和矿物质代谢疾病，由编码同工酶组织非特异性碱性磷酸酶（TNAP）的ALPL基因的不同突变引起。严重的围产期形式的预后非常差，大多数患者死于骨骼疾病的肺部并发症。然而，TNAP缺乏也可能导致神经系统症状，如新生儿癫痫发作。TNAP在人脑中的确切生物学作用仍然未知，并且由于HPP中TNAP缺乏而引起的神经症状的病理生理学也没有详细了解。在这份报告中，我们描述了一个严重的围产期HPP患者的临床特征和功能研究，表现为快速进行性脑病引起的新的复合杂合突变的ALPL基因，导致功能ALPL“敲除”，在体外证明。相反，在体外模拟的遗传状态，他目前无症状的父母都是杂合的一个突变，显示出残留的体外AP活性超过50%。有趣的是，在我们的患者中，致死性结局是由于进行性脑病，这是抗癫痫治疗（包括吡哆醇）难治性的，而不是HPP患者中常见的低矿化和呼吸功能不全。患者的头颅MRI显示皮质和外周白色物质进行性囊性退化，大脑几乎完全破坏。据我们所知，这是第一个基于MRI的报告，由于进行性脑病的婴儿窝藏一个功能性的人类ALPL“敲除”的有害的神经系统的临床结果。这种临床病程的疾病表明，TNAP参与发展，并可能是负责人类大脑的多种功能。根据我们的数据，一定量的残留TNAP活性可能是新生儿和幼儿正常CNS功能的必需品。(C)2013 Elsevier Inc. All rights reserved.
Hypophosphatasia (HPP) is a heterogeneous rare, inherited disorder of bone and mineral metabolism caused by different mutations in the ALPL gene encoding the isoenzyme, tissue-nonspecific alkaline phosphatase (TNAP). Prognosis is very poor in severe perinatal forms with most patients dying from pulmonary complications of their skeletal disease. TNAP deficiency, however, may also result in neurological symptoms such as neonatal seizures. The exact biological role of TNAP in the human brain is still not known and the pathophysiology of neurological symptoms due to TNAP deficiency in HPP is not understood in detail. In this report, we describe the clinical features and functional studies of a patient with severe perinatal HPP which presented with rapidly progressive encephalopathy caused by new compound heterozygous mutations in the ALPL gene which result in a functional ALPL "knock out", demonstrated in vitro. In contrast, an in vitro simulation of the genetic status of his currently asymptomatic parents who are both heterozygous for one mutation, showed a residual in vitro AP activity of above 50%. Interestingly, in our patient, the fatal outcome was due to progressive encephalopathy which was refractory to antiepileptic therapy including pyridoxine, rather than hypomineralization and respiratory insufficiency often seen in HPP patients. The patient's cranial MRI showed progressive cystic degradation of the cortex and peripheral white matter with nearly complete destruction of the cerebrum. To our knowledge, this is the first MRI-based report of a deleterious neurological clinical outcome due to a progressive encephalopathy in an infant harboring a functional human ALPL "knock out".This clinical course of disease suggests that TNAP is involved in development and may be responsible for multiple functions of the human brain. According to our data, a certain amount of residual TNAP activity might be mandatory for normal CNS function in newborns and early childhood. (C) 2013 Elsevier Inc. All rights reserved.