Vodopiutz Julia, Seidl Rainer, Prayer Daniela, Khan M Imran, Mayr Johannes A, Streubel Berthold, Steiß Jens-Oliver, Hahn Andreas, Csaicsich Dagmar, Castro Christel, Assoum Mirna, Müller Thomas, Wieczorek Dagmar, Mancini Grazia M S, Sadowski Carolin E, Lévy Nicolas, Mégarbané André, Godbole Koumudi, Schanze Denny, Hildebrandt Friedhelm, Delague Valérie, Janecke Andreas R, Zenker Martin
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria.
Division of Neuroradiology and Musculoskeletal Radiology, Medical University of Vienna, Austria.
Hum Mutat. 2015 Nov;36(11):1021-8. doi: 10.1002/humu.22828. Epub 2015 Aug 6.
Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with brain anomalies including CA in some cases, intellectual disability, and early-infantile-onset nephrotic syndrome. Very recently, WDR73 deficiency was identified as the cause of GMS in five individuals. To evaluate the role of WDR73 mutations as a cause of GMS and other forms of syndromic CA, we performed Sanger or exome sequencing in 51 unrelated patients with CA and variable brain anomalies and in 40 unrelated patients with a diagnosis of GMS. We identified 10 patients from three CA and from two GMS families with WDR73 mutations including the original family described with CA, mental retardation, optic atrophy, and skin abnormalities (CAMOS). There were five novel mutations, of which two were truncating and three were missense mutations affecting highly conserved residues. Individuals carrying homozygous WDR73 mutations mainly presented with a pattern of neurological and neuroimaging findings as well as intellectual disability, while kidney involvement was variable. We document postnatal onset of CA, a retinopathy, basal ganglia degeneration, and short stature as novel features of WDR73-related disease, and define WDR73-related disease as a new entity of infantile neurodegeneration.
婴儿期起病的小脑萎缩（CA）是一种临床和遗传异质性特征。加洛韦 - 莫瓦特综合征（GMS）是一种罕见的常染色体隐性疾病，其特征为小头畸形伴脑部异常，在某些情况下包括小脑萎缩、智力残疾和早发性婴儿肾病综合征。最近，已确定WDR73缺陷是5例患者患GMS的病因。为了评估WDR73突变作为GMS和其他形式综合征性CA病因的作用，我们对51例患有CA和各种脑部异常的无关患者以及40例诊断为GMS的无关患者进行了桑格测序或外显子组测序。我们在来自三个CA家族和两个GMS家族的10例患者中鉴定出WDR73突变，其中包括最初描述的患有CA、智力发育迟缓、视神经萎缩和皮肤异常（CAMOS）的家族。有五个新突变，其中两个是截短突变，三个是影响高度保守残基的错义突变。携带纯合WDR73突变的个体主要表现出神经学和神经影像学表现模式以及智力残疾，而肾脏受累情况各不相同。我们记录了CA的产后发病、视网膜病变、基底神经节变性和身材矮小作为WDR73相关疾病的新特征，并将WDR73相关疾病定义为婴儿期神经退行性变的一种新实体。
