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EPG5-Related Vici Syndrome: A Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders

  • Shanti Balasubramaniam
  • Lisa G. Riley
  • Anand Vasudevan
  • Mark J. Cowley
  • Velimir Gayevskiy
  • Carolyn M. Sue
  • Caitlin Edwards
  • Edward Edkins
  • Reimar Junckerstorff
  • C. Kiraly-Borri
  • P. Rowe
  • J. Christodoulou
Research Report
Part of the JIMD Reports book series (JIMD, volume 42)

Abstract

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.

Keywords

Autophagy Corpus callosal agenesis EPG5-related Vici syndrome Myopathy Secondary mitochondrial dysfunction 

Notes

Acknowledgements

This research was supported by a New South Wales Office of Health and Medical Research Council Sydney Genomics Collaborative grant (CS and JC). We also gratefully acknowledge donations to JC by the Crane and Perkins families as well as the participation of the research subjects.

References

  1. Al-Owain M, Al-Hashem A, Al-Muhaizea M et al (2010) Vici syndrome associated with unilateral lung hypoplasia and myopathy. Am J Med Genet A 152A(7):1849–1853CrossRefGoogle Scholar
  2. Byrne S, Jansen L, U-King-Im JM et al (2016a) EPG-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain 139(3):765–781CrossRefGoogle Scholar
  3. Byrne S, Vici CD, Smith L et al (2016b) Vici syndrome: a review. Orphanet J Rare Dis 11:21CrossRefGoogle Scholar
  4. Calvo S, Clauser K, Mootha V (2015) MitoCarta2.0: an updated inventory of mammalian proteins. Nucleic Acids Res 44:D1251–D1257CrossRefGoogle Scholar
  5. Chiyonobu T, Yoshihara T, Fukushima Y (2002) Sister and brother with Vici syndrome: agenesis of the corpus callosum, albinism, and recurrent infections. Am J Med Genet 109(1):61–66CrossRefGoogle Scholar
  6. Cullup T, Kho AL, Dionisi-Vici C et al (2013) Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet 45(1):83–87CrossRefGoogle Scholar
  7. del Campo M, Hall BD, Aeby A et al (1999) Albinism and agenesis of the corpus callosum with profound developmental delay: Vici syndrome, evidence for autosomal recessive inheritance. Am J Med Genet 85(5):479–485CrossRefGoogle Scholar
  8. Ebrahimi-Fakhari D, Saffari A, Wahlster L et al (2016) Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain 139(Pt 2):317–337CrossRefGoogle Scholar
  9. Ehmke N, Parvaneh N, Krawitz P et al (2014) First description of a patient with Vici syndrome due to a mutation affecting the penultimate exon of EPG5 and review of the literature. Am J Med Genet A 164A(12):3170–3175CrossRefGoogle Scholar
  10. Fimia GM, Stoykova A, Romagnoli A et al (2007) Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121–1125PubMedGoogle Scholar
  11. Finocchi A, Angelino G, Cantarutti N et al (2012) Immunodeficiency in Vici syndrome: a heterogeneous phenotype. Am J Med Genet A 158A(2):434–439CrossRefGoogle Scholar
  12. Frazier A, Thorburn D (2012) Biochemical analyses of the electron transport chain complexes by spectrophotometry. Methods Mol Biol 837:49–62CrossRefGoogle Scholar
  13. Halama N, Grauling-Halama SA, Beder A et al (2007) Comparative integromics on the breast cancer associated gene KIAA1632: clues to a cancer antigen domain. Int J Oncol 31:205–210PubMedGoogle Scholar
  14. Hedberg-Oldfors C, Darin N, Oldfors A (2017) Muscle pathology in Vici syndrome – a case study with a novel mutation in EPG5 and a summary of the literature. Neuromuscul Disord 27(8):771–776CrossRefGoogle Scholar
  15. Huenerberg K, Hudspeth M, Bergmann S et al (2016) Two cases of Vici syndrome associated with Idiopathic Thrombocytopenic Purpura (ITP) with a review of the literature. Am J Med Genet A 170A(5):1343–1346CrossRefGoogle Scholar
  16. Jiang P, Mizushima N (2014) Autophagy and human diseases. Cell Res 24:69–79CrossRefGoogle Scholar
  17. Jungbluth H, Gautel M (2014) Pathogenic mechanisms in centronuclear myopathies. Front Aging Neurosci 6:339CrossRefGoogle Scholar
  18. Katsetos CD, Koutzaki S, Melvin JJ (2013) Mitochondrial dysfunction in neuromuscular disorders. Semin Pediatr Neurol 20:202–215CrossRefGoogle Scholar
  19. Malicdan MC, Nishino I (2012) Autophagy in lysosomal myopathies. Brain Pathol 22:82–88CrossRefGoogle Scholar
  20. McClelland V, Cullup T, Bodi I et al (2010) Vici syndrome associated with sensorineural hearing loss and evidence of neuromuscular involvement on muscle biopsy. Am J Med Genet A 152A(3):741–747CrossRefGoogle Scholar
  21. Miyata R, Hayashi M, Sato H et al (2007) Sibling cases of Vici syndrome: sleep abnormalities and complications of renal tubular acidosis. Am J Med Genet A 143(2):189–194CrossRefGoogle Scholar
  22. Ozkale M, Erol I, Gumus A, Ozkale Y, Alehan F (2012) Vici syndrome associated with sensorineural hearing loss and laryngomalacia. Pediatr Neurol 47(5):375–378CrossRefGoogle Scholar
  23. Popp MW, Maquat LE (2016) Leveraging rules of nonsense-mediated mRNA decay for genome engineering and personalized medicine. Cell 165(6):1319–1322CrossRefGoogle Scholar
  24. Portbury AL, Willis MS, Patterson C (2011) Tearin’ up my heart: proteolysis in the cardiac sarcomere. J Biol Chem 286:9929–9934CrossRefGoogle Scholar
  25. Ramachandran N, Munteanu I, Wang P et al (2013) VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropathol 125:439–457CrossRefGoogle Scholar
  26. Riley LG, Cowley MJ, Gayevskiy V et al (2017) A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders. J Inherit Metab Dis 40(2):261–269CrossRefGoogle Scholar
  27. Rogers CR, Aufmuth B, Monesson S (2011) Vici syndrome: a rare autosomal recessive syndrome with brain anomalies, cardiomyopathy, and severe intellectual disability. Case Rep Genet 2011:1.  https://doi.org/10.1155/2011/421582 CrossRefGoogle Scholar
  28. Said E, Soler D, Sewry C (2012) Vici syndrome-a rapidly progressive neurodegenerative disorder with hypopigmentation, immunodeficiency and myopathic changes on muscle biopsy. Am J Med Genet A 158A(2):440–444CrossRefGoogle Scholar
  29. Sandri M (2010) Autophagy in skeletal muscle. FEBS Lett 584:1411–1416CrossRefGoogle Scholar
  30. Schmid D, Munz C (2007) Innate and adaptive immunity through autophagy. Immunity 27:11–21CrossRefGoogle Scholar
  31. Sjoblom T, Jones S, Wood LD et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274CrossRefGoogle Scholar
  32. Vici CD, Sabetta G, Gambarara M et al (1988) Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am J Med Genet 29(1):1–8CrossRefGoogle Scholar
  33. Zhang Y, Qi H, Taylor R et al (2007) The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy 3:337–346CrossRefGoogle Scholar
  34. Zhao H, Zhao YG, Wang X, Xu L et al (2013) Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration. J Cell Biol 200:731–741CrossRefGoogle Scholar

Copyright information

© Society for the Study of Inborn Errors of Metabolism (SSIEM) 2017

Authors and Affiliations

  • Shanti Balasubramaniam
    • 1
    • 2
    • 3
    • 4
  • Lisa G. Riley
    • 4
    • 5
  • Anand Vasudevan
    • 6
  • Mark J. Cowley
    • 7
  • Velimir Gayevskiy
    • 7
  • Carolyn M. Sue
    • 7
    • 8
  • Caitlin Edwards
    • 9
  • Edward Edkins
    • 9
  • Reimar Junckerstorff
    • 10
    • 11
  • C. Kiraly-Borri
    • 6
  • P. Rowe
    • 12
    • 13
  • J. Christodoulou
    • 2
    • 3
    • 4
    • 5
    • 14
    • 15
  1. 1.Department of Rheumatology and Metabolic MedicinePrincess Margaret HospitalPerthAustralia
  2. 2.Western Sydney Genetics ProgramThe Children’s Hospital at WestmeadSydneyAustralia
  3. 3.Discipline of Genetic MedicineSydney Medical School, University of SydneySydneyAustralia
  4. 4.Discipline of Child & Adolescent HealthSydney Medical School, University of SydneySydneyAustralia
  5. 5.Genetic Metabolic Disorders Research UnitThe Children’s Hospital at Westmead, KRISydneyAustralia
  6. 6.Genetic Services of Western AustraliaKing Edward Memorial HospitalPerthAustralia
  7. 7.Kinghorn Centre for Clinical GenomicsGarvan Institute of Medical ResearchSydneyAustralia
  8. 8.Department of NeurogeneticsKolling Institute of Medical Research, University of Sydney, Royal North Shore HospitalSydneyAustralia
  9. 9.PathWest Laboratory Medicine WA, Section of Diagnostic GenomicsQEII Medical CentreNedlandsAustralia
  10. 10.PathWest Laboratory Medicine WA, Section of NeuropathologyRoyal Perth HospitalPerthAustralia
  11. 11.School of Pathology and Laboratory MedicineUniversity of Western AustraliaPerthAustralia
  12. 12.Department of NeurologyPrincess Margaret HospitalPerthAustralia
  13. 13.State Child Development CentreWest PerthAustralia
  14. 14.Neurodevelopmental Genomics Research GroupMurdoch Children’s Research InstituteMelbourneAustralia
  15. 15.Department of PaediatricsMelbourne Medical School, University of MelbourneMelbourneAustralia

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