<i>EPG5</i>-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Byrne, Susan; Jansen, Lara; U-King-Im, Jean Marie; Siddiqui, Ata; Lidov, Hart G.W.; Bódi, István; Smith, Luke; Mein, R.; Cullup, Thomas; Dionisi‐Vici, Carlo; Al‐Gazali, Lihadh; Al‐Owain, Mohammed; Bruwer, Zandrè; Thihli, Khalid Al; 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 J.; Harris, Michael A.; Hamosh, Ada; Kölker, Stefan; Ebrahimi‐Fakhari, Darius; Hoffmann, Georg F.; Manchester, David K.; Boyer, Philip J.; Manzur, Adnan; Lourenço, Charles Marques; Pilz, Daniela T.; Kamath, Arveen; Prabhakar, P; Rao, Vamshi K.; Rogers, R. Curtis; Ryan, Monique M.; Brown, Natasha J; McLean, Catriona; Said, Edith; Schara, Ulrike; Stein, Anja; Sewry, Caroline A.; Travan, Laura; Wijburg, Frits A.; Zenker, Martin; Mohammed, Shehla; Fanto, Manolis; Gautel, Mathias; Jungbluth, Heinz

doi:10.1093/brain/awv393

Cited by 115 publications

(180 citation statements)

References 53 publications

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“…Vici syndrome is a severe, multisystem disorder resulting from an autosomal recessive mutation in P‐granules autophagy protein 5 ( EPG5 , *615068), resulting in corpus callosum agenesis, cardiomyopathy, cataracts, oculocutaneous albinism, and combined immunodeficiency. The presence of the additional three features of microcephaly, developmental delay, and failure to thrive increases the likelihood of an EPG5 mutation to 89% . The median survival for the disorder is 24 months, with recurrent sepsis and cardiorespiratory failure being the most common causes of premature mortality .…”

Section: Vici Syndromementioning

confidence: 99%

“…The presence of the additional three features of microcephaly, developmental delay, and failure to thrive increases the likelihood of an EPG5 mutation to 89% . The median survival for the disorder is 24 months, with recurrent sepsis and cardiorespiratory failure being the most common causes of premature mortality . EPG5 encodes ectopic P‐granules autophagy protein 5, a RAS‐associated protein (Rab7, *602298) effector, which is important for autophagosome–lysosome fusion.…”

Section: Vici Syndromementioning

confidence: 99%

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Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

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Autophagy is a tightly modulated lysosomal degradation pathway. Genetic disorders of autophagy during nervous system development may lead to developmental delay, neurodegeneration, and other neurological signs in children. Here we aimed to summarize single gene disorders that perturb various steps of autophagy pathway and their roles in the causation of childhood neurological diseases. Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. These can manifest with a range of features including ataxia, spastic paraplegia, and intellectual disability. Defective proteins causing such diseases can interfere with autophagy flux at different stages of the itinerary. Defective autophagy may be an important contributor to the pathological features of various childhood neurodegenerative diseases and lead to the accumulation of aberrant protein and dysfunctional organelles. Insights into the relevant cell biological processes may help understand pathophysiological mechanisms and inspire autophagy‐restoring therapeutic approaches. What this paper adds Numerous childhood‐onset disorders are caused by mutations that impact the autophagy pathway. Defective autophagy is a feature of some mutations that cause ataxia, spastic paraplegia, and intellectual disability.

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Section: Vici Syndromementioning

confidence: 99%

Section: Vici Syndromementioning

confidence: 99%

Autophagy in childhood neurological disorders

Zhu¹,

Runwal²,

Obrocki³

et al. 2018

Develop Med Child Neuro

View full text Add to dashboard Cite

show abstract

“…Very few missense mutations have been identified 18 , and of these, some may induce aberrant splicing. Furthermore, Epg5 KO mice are viable and show an overlapping phenotype with VICIS patients, although with some distinct features 24 .…”

Section: Discussionmentioning

confidence: 99%

Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement

Hori

Otomo

Nakashima

et al. 2017

Sci Rep

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Vici syndrome (VICIS) is a rare, autosomal recessive neurodevelopmental disorder with multisystem involvement characterized by agenesis of the corpus callosum, cataracts, cardiomyopathy, combined immunodeficiency, developmental delay, and hypopigmentation. Mutations in EPG5, a gene that encodes a key autophagy regulator, have been shown to cause VICIS, however, the precise pathomechanism underlying VICIS is yet to be clarified. Here, we describe detailed clinical (including brain MRI and muscle biopsy) and genetic features of nine Japanese patients with VICIS. Genetic dissection of these nine patients from seven families identified 14 causative mutations in EPG5. These included five nonsense, two frameshift, three splicing, one missense, and one multi-exon deletion mutations, and two initiation codon variants. Furthermore, cultured skin fibroblasts (SFs) from two affected patients demonstrated partial autophagic dysfunction. To investigate the function of EPG5, siRNA based EPG5 knock-down, and CRISPR/Cas9 mediated EPG5 knock-out HeLa cells were generated. EPG5-depleted cells exhibited a complete block of autophagic flux caused by defective autophagosome-lysosome fusion. Unexpectedly, endocytic degradation was normal in both VICIS SFs and EPG5 depleted cells, suggesting that EPG5 function is limited to the regulation of autophagosome-lysosome fusion.

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“…Additionally, patients with Angelman syndrome also exhibit jerkiness, ataxia, tremor, mouthing of objects, stereotypies, 110 and, towards adolescence or adulthood, non-epileptic myoclonus. 116 More recently, mutations in another autophagy gene, SNX14, have been found to cause delayed development, hypotonia, absent speech, progressive cerebellar atrophy, ataxia, and seizures. 112,113 HACE1 not only functions as an E3 ubiquitin ligase but also represses the transcriptional activity of retinoic acid receptors and, hence, downstream pathways that are involved in a range of cellular processes including neuronal differentiation/regeneration and stimulation of neurite outgrowth.…”

Section: Genes Encoding Transportersmentioning

confidence: 99%

The expanding spectrum of movement disorders in genetic epilepsies

Papandreou

Danti

Spaull

et al. 2019

Develop Med Child Neuro

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An ever‐increasing number of neurogenetic conditions presenting with both epilepsy and atypical movements are now recognized. These disorders within the ‘genetic epilepsy‐dyskinesia’ spectrum are clinically and genetically heterogeneous. Increased clinical awareness is therefore necessary for a rational diagnostic approach. Furthermore, careful interpretation of genetic results is key to establishing the correct diagnosis and initiating disease‐specific management strategies in a timely fashion. In this review we describe the spectrum of movement disorders associated with genetically determined epilepsies. We also propose diagnostic strategies and putative pathogenic mechanisms causing these complex syndromes associated with both seizures and atypical motor control. What this paper adds Implicated genes encode proteins with very diverse functions. Pathophysiological mechanisms by which epilepsy and movement disorder phenotypes manifest are often not clear. Early diagnosis of treatable disorders is essential and next generation sequencing may be required.

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EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Cited by 115 publications

References 53 publications

Autophagy in childhood neurological disorders

Autophagy in childhood neurological disorders

Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement

The expanding spectrum of movement disorders in genetic epilepsies

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