Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.
Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.
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DOI：
10.1212/wnl.0000000000005566
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发表时间：
2018-05-22
期刊：
影响因子：
9.9
通讯作者：
Horvath R
中科院分区：
文献类型：
--
作者：
Bansagi B;Phan V;Baker MR;O'Sullivan J;Jennings MJ;Whittaker RG;Müller JS;Duff J;Griffin H;Miller JAL;Gorman GS;Lochmüller H;Chinnery PF;Roos A;Swan LE;Horvath R
描述一名患有多灶性脱髓鞘运动神经病的患者，其发病于儿童期，存在磷酸酶和张力蛋白同源物（PTEN）突变，PTEN是一种与遗传性肿瘤易感性疾病、巨头畸形、自闭症、共济失调、震颤和癫痫相关的肿瘤抑制基因。该蛋白在帕金森病和阿尔茨海默病中的功能影响已被研究。
我们对患者的基因组DNA进行了全外显子组测序，并通过桑格测序进行了验证。在患者的成纤维细胞中进行了免疫印迹、体外酶活性测定和无标记鸟枪法蛋白质组学分析。
患者的主要临床表现为儿童期发病的不对称进行性多灶性运动神经病。此外，他还表现出巨头畸形、自闭症谱系障碍和皮肤错构瘤，这些被视为PTEN相关错构瘤肿瘤综合征的临床标准。广泛的肿瘤筛查未发现任何恶性肿瘤。我们检测到一种新的从头杂合c.269T>C，p.(Phe90Ser) PTEN变异，其在父母双方中均不存在。几种与肿瘤发生相关的PTEN相关蛋白表达改变支持了该变异的致病性。此外，成纤维细胞显示PTEN对第二底物磷脂酰肌醇 - 3,4 - 三磷酸的催化活性存在缺陷。支持我们研究结果的是，在PTEN缺陷小鼠中已报道有导致周围神经病的局灶性髓鞘过度形成。
我们描述了一种新的表型，即伴有皮肤错构瘤综合征的PTEN相关多灶性脱髓鞘运动神经病。类似的机制可能潜在地是涉及磷脂酰肌醇途径的其他形式的夏科 - 马里 - 图思病的基础。
To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.