Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.
Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss.
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DOI：
10.1212/nxg.0000000000000014
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发表时间：
2015-08
期刊：
影响因子：
--
通讯作者：
Lockhart PJ
中科院分区：
文献类型：
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作者：
Marsh AP;Lukic V;Pope K;Bromhead C;Tankard R;Ryan MM;Yiu EM;Sim JC;Delatycki MB;Amor DJ;McGillivray G;Sherr EH;Bahlo M;Leventer RJ;Lockhart PJ
确定一个具有胼胝体（ACC）完全发育不全、桥小脑发育不全（PCH）和周围轴索神经病的大型近亲家族中严重神经系统疾病的分子基础。评估包括临床评价、神经影像学和神经传导研究（NCS）。连锁分析使用了来自7个家庭成员的基因型，并对3个患病同胞的外显子组进行了测序。分子分析使用桑格测序进行分离研究和群组分析以及患者来源的细胞的蛋白质印迹。受影响的家庭成员出现出生后小头畸形和严重的发育迟缓，3例早期死亡。神经影像学，包括30周时的胎儿MRI，显示完全ACC和PCH。临床评价显示无反射，NCS显示2例可用于电生理研究的患者存在严重轴突神经病变。在1号染色体上的连锁区域内鉴定了腺苷酸脱氨酶2（AMPD 2）的一种新的纯合停止增益突变。分子分析证实，突变与疾病分离，导致AMPD2的丢失。随后对42名具有相关成像表型的不相关个体的队列进行筛查，未发现额外的AMPD 2突变。我们描述了一个AMPD 2突变的家族。我们扩展了最近描述为PCH 9型的表型，包括进行性出生后小头畸形，完全ACC和周围轴索神经病变。对其他具有相关成像表型的个体进行筛查未能识别AMPD 2突变，这表明AMPD 2突变不是胼胝体和桥小脑联合缺陷的常见原因。
To determine the molecular basis of a severe neurologic disorder in a large consanguineous family with complete agenesis of the corpus callosum (ACC), pontocerebellar hypoplasia (PCH), and peripheral axonal neuropathy. Assessment included clinical evaluation, neuroimaging, and nerve conduction studies (NCSs). Linkage analysis used genotypes from 7 family members, and the exome of 3 affected siblings was sequenced. Molecular analyses used Sanger sequencing to perform segregation studies and cohort analysis and Western blot of patient-derived cells. Affected family members presented with postnatal microcephaly and profound developmental delay, with early death in 3. Neuroimaging, including a fetal MRI at 30 weeks, showed complete ACC and PCH. Clinical evaluation showed areflexia, and NCSs revealed a severe axonal neuropathy in the 2 individuals available for electrophysiologic study. A novel homozygous stopgain mutation in adenosine monophosphate deaminase 2 (AMPD2) was identified within the linkage region on chromosome 1. Molecular analyses confirmed that the mutation segregated with disease and resulted in the loss of AMPD2. Subsequent screening of a cohort of 42 unrelated individuals with related imaging phenotypes did not reveal additional AMPD2 mutations. We describe a family with a novel stopgain mutation in AMPD2. We expand the phenotype recently described as PCH type 9 to include progressive postnatal microcephaly, complete ACC, and peripheral axonal neuropathy. Screening of additional individuals with related imaging phenotypes failed to identify mutations in AMPD2, suggesting that AMPD2 mutations are not a common cause of combined callosal and pontocerebellar defects.