Balasubramaniam Shanti, Riley Lisa G, Vasudevan Anand, Cowley Mark J, Gayevskiy Velimir, Sue Carolyn M, Edwards Caitlin, Edkins Edward, Junckerstorff Reimar, Kiraly-Borri C, Rowe P, Christodoulou J
Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA, Australia.
Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
JIMD Rep. 2018;42:19-29. doi: 10.1007/8904_2017_71. Epub 2017 Nov 21.
Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described.Autosomal recessive mutations in EPG5 encoding ectopic P-granules autophagy protein 5 (EPG5), a key autophagy regulator implicated in the formation of autolysosomes, were identified as the genetic cause of Vici syndrome. The eight key features outlined above are highly predictive of EPG5 involvement, with pathogenic EPG5 mutations identified in >90% of cases where six or more of these features are present. The manifestation of all eight features has a specificity of 97% and sensitivity of 89% for EPG5-related Vici syndrome. Nevertheless, substantial clinical overlap exists with other multisystem disorders, in particular congenital disorders of glycosylation and mitochondrial disorders. Clinical and pathological findings suggest Vici syndrome as a paradigm of congenital disorders of autophagy, a novel group of inherited neurometabolic conditions linking neurodevelopment and neurodegeneration due to primary autophagy defects.Here we describe the diagnostic odyssey in a 4-year-old boy whose clinical presentation with multisystem manifestations including skeletal myopathy mimicked a mitochondrial disorder. A genetic diagnosis of Vici syndrome was made through whole genome sequencing which identified compound heterozygous variants in EPG5. We also review the myopathic presentation and morphological characterisation of previously reported cases.
维西综合征是一种罕见的、未被充分认识的、持续进展的先天性多系统疾病，其主要特征包括胼胝体发育不全、白内障、心肌病、联合免疫缺陷和眼皮肤色素减退。此外，另外三个一致的特征（严重发育迟缓、进行性生长发育不良和后天性小头畸形）对诊断有高度支持作用。自1988年被确认为一种独特的疾病以来，已经描述了一种扩展表型，包括感音神经性听力损失、骨骼肌病以及几乎任何器官系统（包括肺、甲状腺、肝脏和肾脏）的可变受累情况。编码异位P颗粒自噬蛋白5（EPG5）的EPG5基因发生常染色体隐性突变，EPG5是一种参与自噬体形成的关键自噬调节因子，被确定为维西综合征的遗传病因。上述八个关键特征对EPG5受累具有高度预测性，在出现六个或更多这些特征的病例中，超过90%发现了致病性EPG5突变。所有八个特征的表现对于EPG5相关的维西综合征具有97%的特异性和89%的敏感性。然而，与其他多系统疾病，特别是先天性糖基化障碍和线粒体疾病存在大量临床重叠。临床和病理结果表明，维西综合征是先天性自噬障碍的一个范例，这是一组由于原发性自噬缺陷而将神经发育和神经退行性变联系起来的新型遗传性神经代谢疾病。在此，我们描述了一名4岁男孩的诊断历程，其临床表现为包括骨骼肌病在内的多系统表现，类似于线粒体疾病。通过全基因组测序对维西综合征进行了基因诊断，该测序在EPG5中鉴定出复合杂合变异。我们还回顾了先前报道病例的肌病表现和形态学特征。
