Neuropediatrics 2019; 50(04): 257-261
DOI: 10.1055/s-0039-1692129
Short Communication
Georg Thieme Verlag KG Stuttgart · New York

EPG5 Variants with Modest Functional Impact Result in an Ameliorated and Primarily Neurological Phenotype in a 3.5-Year-Old Patient with Vici Syndrome

Megan S. Kane
1   Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, United States
,
Jia Zhao
1   Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, United States
,
Julie Muskett
1   Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, United States
,
Amelia Diplock
2   Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Siddharth Srivastava
2   Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Natalie Hauser
1   Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, United States
,
John F. Deeken
3   Inova Schar Cancer Institute, Inova Health System, Fairfax, Virginia, United States
4   Department of Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, United States
,
John E. Niederhuber
1   Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, United States
5   Genomics and Bioinformatics Research Institute, Fairfax, Virginia, United States
6   Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
7   Department of Public Health Sciences, School of Medicine, University of Virginia, Charlottesville, Virginia, United States
,
Wendy E. Smith
8   Department of Pediatrics, The Barbara Bush Children’s Hospital, Main Medical Center, Portland, Maine, United States
,
Thierry Vilboux
1   Inova Translational Medicine Institute, Inova Health System, Fairfax, Virginia, United States
,
2   Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
› Author Affiliations
Further Information

Publication History

02 January 2019

23 April 2019

Publication Date:
21 June 2019 (online)

Abstract

Congenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 (EPG5)-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of EPG5 variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous EPG5 variants [NM_020964.2: c.772G > T/c.5943–9_5943–5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the EPG5 variants present would be milder with a higher amount of residual EPG5 expression. Analyses of EPG5 messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing; mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of EPG5 expression.

Corresponding authors.


Supplementary Material

 
  • References

  • 1 Byrne S, Dionisi-Vici C, Smith L, Gautel M, Jungbluth H. Vici syndrome: a review. Orphanet J Rare Dis 2016; 11: 21
  • 2 Byrne S, Jansen L, U-King-Im JM. , et al. EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy. Brain 2016; 139 (Pt 3): 765-781
  • 3 Dionisi Vici C, Sabetta G, Gambarara M. , et al. Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers. Am J Med Genet 1988; 29 (01) 1-8
  • 4 Ebrahimi-Fakhari D, Saffari A, Wahlster L. , et al. Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain 2016; 139 (Pt 2): 317-337
  • 5 Ebrahimi-Fakhari D. Congenital disorders of autophagy: what a pediatric neurologist should know. Neuropediatrics 2018; 49 (01) 18-25
  • 6 Cullup T, Kho AL, Dionisi-Vici C. , et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat Genet 2013; 45 (01) 83-87
  • 7 Shimada S, Hirasawa K, Takeshita A. , et al. Novel compound heterozygous EPG5 mutations consisted with a missense mutation and a microduplication in the exon 1 region identified in a Japanese patient with Vici syndrome. Am J Med Genet A 2018; 176 (12) 2803-2807
  • 8 Waldrop MA, Gumienny F, Boue D. , et al. Low-level expression of EPG5 leads to an attenuated Vici syndrome phenotype. Am J Med Genet A 2018; 176 (05) 1207-1211
  • 9 Wang Z, Miao G, Xue X. , et al. The Vici syndrome protein EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. Mol Cell 2016; 63 (05) 781-795
  • 10 Kane MS, Vilboux T, Wolfe LA. , et al. Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome. Brain 2016; 139 (Pt 9): e52
  • 11 Hori I, Otomo T, Nakashima M. , et al. Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement. Sci Rep 2017; 7 (01) 3552