Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders
Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders
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DOI：
10.1038/ejhg.2014.112
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发表时间：
2015-03-01
影响因子：
5.2
通讯作者：
Mendoza-Londono, Roberto
中科院分区：
文献类型：
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作者：
Al-Maawali, Almundher;Dupuis, Lucie;Mendoza-Londono, Roberto
PRPS 1编码磷酸核糖焦磷酸合成酶-1（PRS-1）。与活动减少相关的PRPS 1相关疾病包括Arts综合征、腓骨肌萎缩症-5（CMTX 5）和X连锁非综合征性感觉神经性耳聋（DFN 2）。我们描述了一种新的表型与PRS-1功能下降，在两个受影响的男性同胞。利用全外显子组和桑格测序技术，我们确定了一个新的错义突变PRPS 1。在我们的患者的临床表型的特点是高产前母体甲胎蛋白，宫内生长受限，畸形的面部特征，严重的智力残疾和痉挛性四肢轻瘫。其他表型特征包括黄斑缺损样病变伴视网膜营养不良、严重身材矮小和尿崩症。两个受影响的男性兄弟姐妹的外显子组测序确定了一个共同的推定致病突变c.586C> Tp。（Arg 196 Trp）在PRPS 1基因是母系遗传。后续检测显示，尿液样本中的次黄嘌呤水平和血清中的尿酸水平正常。两例患者红细胞PRS活性均明显降低。红细胞中的核苷酸分析显示三磷酸鸟苷和二磷酸鸟苷异常低。这种表现是迄今为止描述的最严重形式的PRPS 1缺乏综合征，并扩大了PRPS 1相关疾病的范围。
PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal alpha-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.