Byrne Susan, Jansen Lara, U-King-Im Jean-Marie, Siddiqui Ata, Lidov Hart G W, Bodi Istvan, Smith Luke, Mein Rachael, Cullup Thomas, Dionisi-Vici Carlo, Al-Gazali Lihadh, Al-Owain Mohammed, Bruwer Zandre, Al Thihli Khalid, El-Garhy Rana, Flanigan Kevin M, Manickam Kandamurugu, Zmuda Erik, Banks Wesley, Gershoni-Baruch Ruth, Mandel Hanna, Dagan Efrat, Raas-Rothschild Annick, Barash Hila, Filloux Francis, Creel Donnell, Harris Michael, Hamosh Ada, Kölker Stefan, Ebrahimi-Fakhari Darius, Hoffmann Georg F, Manchester David, Boyer Philip J, Manzur Adnan Y, Lourenco Charles Marques, Pilz Daniela T, Kamath Arveen, Prabhakar Prab, Rao Vamshi K, Rogers R Curtis, Ryan Monique M, Brown Natasha J, McLean Catriona A, Said Edith, Schara Ulrike, Stein Anja, Sewry Caroline, Travan Laura, Wijburg Frits A, Zenker Martin, Mohammed Shehla, Fanto Manolis, Gautel Mathias, Jungbluth Heinz
1 Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.
2 Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK.
Brain. 2016 Mar;139(Pt 3):765-81. doi: 10.1093/brain/awv393.
Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs5, p.Arg417, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.
维西综合征是一种进行性神经发育多系统疾病，由关键自噬基因EPG5的隐性突变引起。我们报告了来自30个家庭的50名儿童的遗传、临床、神经放射学和神经病理学特征，以及果蝇中EPG5基因敲低后的神经元表型。我们鉴定出39种不同的EPG5突变，其中大多数为截短突变，预计会导致EPG5蛋白减少。大多数突变是散发性的，但有三种复发性突变（p.Met2242Cysfs5、p.Arg417和p.Gln336Arg）表明可能存在奠基者效应。发病主要在新生儿期，伴有明显的肌张力低下和喂养困难。除了五个主要特征（胼胝体发育不全、白内障、色素减退、心肌病和免疫功能障碍）外，我们还确定了三个同样一致的特征（严重发育迟缓、进行性小头畸形和生长发育不良）。这八个特征的表现对于EPG5突变的存在具有97%的特异性和89%的敏感性，将有助于就基因检测做出明智的决定。临床进展无情，许多儿童在婴儿期死亡。生存分析显示中位生存时间为24个月（95%置信区间0 - 49个月），只有十分之一的患者存活至5岁。复合杂合突变患者（P = 0.046）以及具有复发性p.Gln336Arg突变的患者的生存结局明显更好。长期存活者出现的后天性小头畸形和技能退化表明，在主要的神经发育缺陷之上叠加了神经退行性成分。三分之二的患者患有严重癫痫障碍，这使EPG5成为与早发性癫痫性脑病相关的快速扩展基因群体中的一员。一致的神经放射学特征包括结构异常，特别是胼胝体发育不全和脑桥发育不全、髓鞘形成延迟，以及较少见的随时间演变的丘脑信号强度变化。典型的肌肉活检特征包括纤维大小变异、中央/内部核、异常糖原储存、自噬泡的存在以及继发性线粒体异常。对一例患者进行的神经活检显示有髓轴突基本缺失。对三名患者进行的尸检证实了神经发育和神经退行性特征以及多系统受累。最后，果蝇中epg5（CG14299）的下调导致自噬异常和进行性神经退行性变。我们得出结论，EPG5相关的维西综合征定义了一组新的神经发育障碍，对于具有提示性特征且已排除线粒体、糖原或溶酶体贮积症的患者应予以考虑。随着时间的推移神经功能的进展表明神经发育与神经退行性变之间存在有趣的联系，果蝇中epg5缺陷的神经退行性特征以及其他自噬调节因子最近在迟发性神经退行性疾病中的作用也支持了这一点。
