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.
Lisa G. Riley and Anand Vasudevan contributed equally to this work.
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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.
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Communicated by: Saskia Brigitte Wortmann, M.D., Ph.D.
Appendices
Key Messages
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A male patient presented with clinical features resembling a mitochondrial disorder including profound developmental delay, visual impairment, epilepsy and skeletal myopathy
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Two novel EPG5 variants identified on WGS
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Muscle morphological studies showed increased variability of fibre size, rare internalised nuclei, mitochondrial abnormalities and aggregates of autophagosomes
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Considerable overlap exists between EPG5-related Vici syndrome and mitochondrial disorders
Details of the Contributions of Individual Authors
SB drafted the manuscript and was involved in the clinical management and diagnostic workup of the patient with AV, CK-B and PR. LR, MC, VG, CS, CE, EE and JC performed/supervised/interpreted molecular workup. All authors have read/critically revised the manuscript.
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SB, LR, AV, MC, VG, TR, CS, RJ, CK and PR declare they have no conflict of interest. JC is a communicating editor of the Journal of Inherited Metabolic Disease.
Ethics
All procedures followed in this study were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, and its later amendments, and this project was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee (reference number 10/CHW/113). Informed consent was obtained for all participants included in the study.
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Balasubramaniam, S. et al. (2017). EPG5-Related Vici Syndrome: A Primary Defect of Autophagic Regulation with an Emerging Phenotype Overlapping with Mitochondrial Disorders. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 42. JIMD Reports, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_71
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DOI: https://doi.org/10.1007/8904_2017_71
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