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

Susan Byrne; Lara Jansen; Jean Marie U-King-im; Ata Siddiqui; Hart G W Lidov; Istvan Bodi; Luke Smith; Rachael Mein; Thomas Cullup; Carlo Dionisi-Vici; Lihadh Al-Gazali; Mohammed Al-Owain; Zandre Bruwer; Khalid Al Thihli; Rana El-Garhy; Kevin M. Flanigan; Kandamurugu Manickam; Erik Zmuda; Wesley Banks; Ruth Gershoni-Baruch; Hanna Mandel; Efrat Dagan; Annick Raas-Rothschild; Hila Barash; Francis Filloux; Donnell Creel; Michael Harris; Ada Hamosh; Stefan Kölker; Darius Ebrahimi-Fakhari; Georg F. Hoffmann; David Manchester; Philip J. Boyer; Adnan Y. Manzur; Charles Marques Lourenco; Daniela T. Pilz; Arveen Kamath; Prab Prabhakar; Vamshi K. Rao; R. Curtis Rogers; Monique M. Ryan; Natasha J. Brown; Catriona A. McLean; Edith Said; Ulrike Schara; Anja Stein; Caroline Sewry; Laura Travan; Frits A. Wijburg; Martin Zenker; Shehla Mohammed; Manolis Fanto; Mathias Gautel; Heinz Jungbluth

doi:10.1093/brain/awv393

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

Susan Byrne, Lara Jansen, Jean Marie U-King-im, Ata Siddiqui, Hart G W Lidov, Istvan Bodi, Luke Smith, Rachael Mein, Thomas Cullup, Carlo Dionisi-Vici, Lihadh Al-Gazali, Mohammed Al-Owain, Zandre Bruwer, Khalid Al Thihli, Rana El-Garhy, Kevin M. Flanigan, Kandamurugu Manickam, Erik Zmuda, Wesley Banks, Ruth Gershoni-BaruchHanna Mandel, Efrat Dagan, Annick Raas-Rothschild, Hila Barash, Francis Filloux, Donnell Creel, Michael Harris, Ada Hamosh, Stefan Kölker, Darius Ebrahimi-Fakhari, Georg F. Hoffmann, David Manchester, Philip J. Boyer, Adnan Y. Manzur, Charles Marques Lourenco, Daniela T. Pilz, Arveen Kamath, Prab Prabhakar, Vamshi K. Rao, R. Curtis Rogers, Monique M. Ryan, Natasha J. Brown, Catriona A. McLean, Edith Said, Ulrike Schara, Anja Stein, Caroline Sewry, Laura Travan, Frits A. Wijburg, Martin Zenker, Shehla Mohammed, Manolis Fanto, Mathias Gautel, Heinz Jungbluth^*

^*Corresponding author for this work

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Abstract

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.Met2242Cysfs^∗5, 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.

Original language	English
Pages (from-to)	765-781
Number of pages	17
Journal	Brain
Volume	139
Issue number	3
Early online date	17 Feb 2016
DOIs	https://doi.org/10.1093/brain/awv393
Publication status	Published - 1 Mar 2016

Keywords

Callosal agenesis
Ectopic P granules autophagy protein 5
EPG5
Neurodegeneration
Neurodevelopment
Vici syndrome

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Byrne, S., Jansen, L., U-King-im, J. M., Siddiqui, A., Lidov, H. G. W., Bodi, I., Smith, L., Mein, R., Cullup, T., Dionisi-Vici, C., Al-Gazali, L., Al-Owain, M., Bruwer, Z., Al Thihli, K., El-Garhy, R., Flanigan, K. M., Manickam, K., Zmuda, E., Banks, W., ... Jungbluth, H. (2016). EPG5-related Vici syndrome: A paradigm of neurodevelopmental disorders with defective autophagy. Brain, 139(3), 765-781. https://doi.org/10.1093/brain/awv393

@article{86964d2d5ace4ba68539ba7fae115aaf,

title = "EPG5-related Vici syndrome: A paradigm of neurodevelopmental disorders with defective autophagy",

abstract = "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.Met2242Cysfs∗5, 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.",

keywords = "Callosal agenesis, Ectopic P granules autophagy protein 5, EPG5, Neurodegeneration, Neurodevelopment, Vici syndrome",

author = "Susan Byrne and Lara Jansen and U-King-im, {Jean Marie} and Ata Siddiqui and Lidov, {Hart G W} and Istvan Bodi and Luke Smith and Rachael Mein and Thomas Cullup and Carlo Dionisi-Vici and Lihadh Al-Gazali and Mohammed Al-Owain and Zandre Bruwer and {Al Thihli}, Khalid and Rana El-Garhy and Flanigan, {Kevin M.} and Kandamurugu Manickam and Erik Zmuda and Wesley Banks and Ruth Gershoni-Baruch and Hanna Mandel and Efrat Dagan and Annick Raas-Rothschild and Hila Barash and Francis Filloux and Donnell Creel and Michael Harris and Ada Hamosh and Stefan K{\"o}lker and Darius Ebrahimi-Fakhari and Hoffmann, {Georg F.} and David Manchester and Boyer, {Philip J.} and Manzur, {Adnan Y.} and Lourenco, {Charles Marques} and Pilz, {Daniela T.} and Arveen Kamath and Prab Prabhakar and Rao, {Vamshi K.} and Rogers, {R. Curtis} and Ryan, {Monique M.} and Brown, {Natasha J.} and McLean, {Catriona A.} and Edith Said and Ulrike Schara and Anja Stein and Caroline Sewry and Laura Travan and Wijburg, {Frits A.} and Martin Zenker and Shehla Mohammed and Manolis Fanto and Mathias Gautel and Heinz Jungbluth",

year = "2016",

month = mar,

day = "1",

doi = "10.1093/brain/awv393",

language = "English",

volume = "139",

pages = "765--781",

journal = "Brain",

issn = "0006-8950",

publisher = "Oxford University Press",

number = "3",

}

Byrne, S, Jansen, L, U-King-im, JM, Siddiqui, A, Lidov, HGW, Bodi, I, Smith, L, Mein, R, Cullup, T, Dionisi-Vici, C, Al-Gazali, L, Al-Owain, M, Bruwer, Z, Al Thihli, K, El-Garhy, R, Flanigan, KM, Manickam, K, Zmuda, E, Banks, W, Gershoni-Baruch, R, Mandel, H, Dagan, E, Raas-Rothschild, A, Barash, H, Filloux, F, Creel, D, Harris, M, Hamosh, A, Kölker, S, Ebrahimi-Fakhari, D, Hoffmann, GF, Manchester, D, Boyer, PJ, Manzur, AY, Lourenco, CM, Pilz, DT, Kamath, A, Prabhakar, P, Rao, VK, Rogers, RC, Ryan, MM, Brown, NJ, McLean, CA, Said, E, Schara, U, Stein, A, Sewry, C, Travan, L, Wijburg, FA, Zenker, M, Mohammed, S, Fanto, M , Gautel, M & Jungbluth, H 2016, 'EPG5-related Vici syndrome: A paradigm of neurodevelopmental disorders with defective autophagy', Brain, vol. 139, no. 3, pp. 765-781. https://doi.org/10.1093/brain/awv393

TY - JOUR

T1 - EPG5-related Vici syndrome

T2 - A paradigm of neurodevelopmental disorders with defective autophagy

AU - Byrne, Susan

AU - Jansen, Lara

AU - U-King-im, Jean Marie

AU - Siddiqui, Ata

AU - Lidov, Hart G W

AU - Bodi, Istvan

AU - Smith, Luke

AU - Mein, Rachael

AU - Cullup, Thomas

AU - Dionisi-Vici, Carlo

AU - Al-Gazali, Lihadh

AU - Al-Owain, Mohammed

AU - Bruwer, Zandre

AU - Al Thihli, Khalid

AU - El-Garhy, Rana

AU - Flanigan, Kevin M.

AU - Manickam, Kandamurugu

AU - Zmuda, Erik

AU - Banks, Wesley

AU - Gershoni-Baruch, Ruth

AU - Mandel, Hanna

AU - Dagan, Efrat

AU - Raas-Rothschild, Annick

AU - Barash, Hila

AU - Filloux, Francis

AU - Creel, Donnell

AU - Harris, Michael

AU - Hamosh, Ada

AU - Kölker, Stefan

AU - Ebrahimi-Fakhari, Darius

AU - Hoffmann, Georg F.

AU - Manchester, David

AU - Boyer, Philip J.

AU - Manzur, Adnan Y.

AU - Lourenco, Charles Marques

AU - Pilz, Daniela T.

AU - Kamath, Arveen

AU - Prabhakar, Prab

AU - Rao, Vamshi K.

AU - Rogers, R. Curtis

AU - Ryan, Monique M.

AU - Brown, Natasha J.

AU - McLean, Catriona A.

AU - Said, Edith

AU - Schara, Ulrike

AU - Stein, Anja

AU - Sewry, Caroline

AU - Travan, Laura

AU - Wijburg, Frits A.

AU - Zenker, Martin

AU - Mohammed, Shehla

AU - Fanto, Manolis

AU - Gautel, Mathias

AU - Jungbluth, Heinz

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.Met2242Cysfs∗5, 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.

AB - 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.Met2242Cysfs∗5, 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.

KW - Callosal agenesis

KW - Ectopic P granules autophagy protein 5

KW - EPG5

KW - Neurodegeneration

KW - Neurodevelopment

KW - Vici syndrome

UR - http://www.scopus.com/inward/record.url?scp=84964689063&partnerID=8YFLogxK

U2 - 10.1093/brain/awv393

DO - 10.1093/brain/awv393

M3 - Article

AN - SCOPUS:84964689063

SN - 0006-8950

VL - 139

SP - 765

EP - 781

JO - Brain

JF - Brain

IS - 3

ER -

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

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