Recurrent Fevers as a Prominent and Underrecognized Feature of EPG5-Related Vici Syndrome
Presenter Status
Graduate Student
Abstract Type
Case Report
Primary Mentor or Principal Investigator
Jay L. Vivian, PhD
Presentation Type
Poster
Start Date
20-5-2026 11:00 AM
End Date
20-5-2026 12:00 PM
Abstract Text
Background:
Vici syndrome (EPG5-related neurodevelopmental disorder with multisystem involvement) is a rare pediatric autosomal recessive condition characterized by agenesis of the corpus callosum, cardiomyopathy, cataracts, hypopigmentation, immunodeficiency, microcephaly, myopathy, developmental delay, and failure to thrive. Pathogenic variants in EPG5 disrupt autophagy, a critical cellular homeostatic pathway. As genomic testing becomes more widely available, the clinical spectrum and natural history of Vici syndrome and other EPG5-linked neurodegenerative disorders continue to evolve. While recurrent fevers without an identifiable infectious etiology have been reported in affected individuals, fever has not been well characterized as a significant or defining component of the disease course.
Objectives/Goal:
To describe recurrent fever as a prominent clinical feature in Vici syndrome and to explore its potential relationship to inflammation, immune dysfunction, and disease progression through detailed clinical characterization of two affected infants.
Methods/Design:
We performed comprehensive clinical analyses and additional molecular and functional analysis of two female infants born to nonconsanguineous parents of western European ancestry who were diagnosed with Vici syndrome in early infancy. Genetic testing identified private compound heterozygous pathogenic variants in EPG5, including previously unreported truncating variants predicted to result in premature termination and transcript and protein destabilization. Functional studies using patient-derived cells were conducted to assess autophagy and transcript stability. Clinical data were retrospectively reviewed, with particular focus on febrile episodes, infectious evaluations, immunologic findings, treatments, and multisystem disease progression.
Results:
Both patients were diagnosed with Vici syndrome at approximately three months of age. Patient derived primary cells demonstrated impaired autophagy and destabilized EPG5 transcript, supporting pathogenicity of the identified EPG5 variants. Recurrent febrile episodes of unknown origin began in early infancy and led to repeated hospitalizations. Blood work supported evidence of strong inflammatory condition, but extensive infectious workups failed to identify a consistent microbial cause. Febrile episodes showed partial responsiveness to immunomodulatory therapies, including intravenous immunoglobulin and cytokine-directed treatments. Both patients developed progressive neuromuscular involvement, immunologic abnormalities, and multisystem disease. One patient died from progressive heart failure at 16 months of age, while the second succumbed to acute respiratory failure at 14 months of age.
Conclusions:
These cases highlight recurrent fever as a clinically significant and underrecognized feature of Vici syndrome. The observed fever patterns and lack of an apparent microbial cause suggest a potential role for immune dysregulation, inflammation, and/or hypothalamic dysfunction in disease pathology and progression. Animal models of the disease support a role for inflammation in disease progression. Further studies are needed to elucidate the mechanisms underlying recurrent febrile episodes in Vici syndrome and to inform future clinical management strategies.
Recurrent Fevers as a Prominent and Underrecognized Feature of EPG5-Related Vici Syndrome
Background:
Vici syndrome (EPG5-related neurodevelopmental disorder with multisystem involvement) is a rare pediatric autosomal recessive condition characterized by agenesis of the corpus callosum, cardiomyopathy, cataracts, hypopigmentation, immunodeficiency, microcephaly, myopathy, developmental delay, and failure to thrive. Pathogenic variants in EPG5 disrupt autophagy, a critical cellular homeostatic pathway. As genomic testing becomes more widely available, the clinical spectrum and natural history of Vici syndrome and other EPG5-linked neurodegenerative disorders continue to evolve. While recurrent fevers without an identifiable infectious etiology have been reported in affected individuals, fever has not been well characterized as a significant or defining component of the disease course.
Objectives/Goal:
To describe recurrent fever as a prominent clinical feature in Vici syndrome and to explore its potential relationship to inflammation, immune dysfunction, and disease progression through detailed clinical characterization of two affected infants.
Methods/Design:
We performed comprehensive clinical analyses and additional molecular and functional analysis of two female infants born to nonconsanguineous parents of western European ancestry who were diagnosed with Vici syndrome in early infancy. Genetic testing identified private compound heterozygous pathogenic variants in EPG5, including previously unreported truncating variants predicted to result in premature termination and transcript and protein destabilization. Functional studies using patient-derived cells were conducted to assess autophagy and transcript stability. Clinical data were retrospectively reviewed, with particular focus on febrile episodes, infectious evaluations, immunologic findings, treatments, and multisystem disease progression.
Results:
Both patients were diagnosed with Vici syndrome at approximately three months of age. Patient derived primary cells demonstrated impaired autophagy and destabilized EPG5 transcript, supporting pathogenicity of the identified EPG5 variants. Recurrent febrile episodes of unknown origin began in early infancy and led to repeated hospitalizations. Blood work supported evidence of strong inflammatory condition, but extensive infectious workups failed to identify a consistent microbial cause. Febrile episodes showed partial responsiveness to immunomodulatory therapies, including intravenous immunoglobulin and cytokine-directed treatments. Both patients developed progressive neuromuscular involvement, immunologic abnormalities, and multisystem disease. One patient died from progressive heart failure at 16 months of age, while the second succumbed to acute respiratory failure at 14 months of age.
Conclusions:
These cases highlight recurrent fever as a clinically significant and underrecognized feature of Vici syndrome. The observed fever patterns and lack of an apparent microbial cause suggest a potential role for immune dysregulation, inflammation, and/or hypothalamic dysfunction in disease pathology and progression. Animal models of the disease support a role for inflammation in disease progression. Further studies are needed to elucidate the mechanisms underlying recurrent febrile episodes in Vici syndrome and to inform future clinical management strategies.
Comments
Restricted to Title/Author List/Abstract only as requested by primary author
Poster Board Number: 9