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

JIMD Rep. 2018;42:19-29. doi: 10.1007/8904_2017_71.

Shanti Balasubramaniam ¹ ² ³ ⁴, Lisa G Riley ⁵ ⁶, Anand Vasudevan ⁷, Mark J Cowley ⁸, Velimir Gayevskiy ⁸, Carolyn M Sue ⁸ ⁹, Caitlin Edwards ¹⁰, Edward Edkins ¹⁰, Reimar Junckerstorff ¹¹ ¹², C Kiraly-Borri ⁷, P Rowe ¹³ ¹⁴, J Christodoulou ¹⁵ ¹⁶ ⁵ ⁶ ¹⁷ ¹⁸

Affiliations

1 Department of Rheumatology and Metabolic Medicine, Princess Margaret Hospital, Perth, WA, Australia. saras329@hotmail.com.
2 Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia. saras329@hotmail.com.
3 Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. saras329@hotmail.com.
4 Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. saras329@hotmail.com.
5 Discipline of Child & Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
6 Genetic Metabolic Disorders Research Unit, The Children's Hospital at Westmead, KRI, Sydney, NSW, Australia.
7 Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, Australia.
8 Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, NSW, Australia.
9 Department of Neurogenetics, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.
10 PathWest Laboratory Medicine WA, Section of Diagnostic Genomics, QEII Medical Centre, Nedlands, WA, Australia.
11 PathWest Laboratory Medicine WA, Section of Neuropathology, Royal Perth Hospital, Perth, WA, Australia.
12 School of Pathology and Laboratory Medicine, University of Western Australia, Perth, WA, Australia.
13 Department of Neurology, Princess Margaret Hospital, Perth, WA, Australia.
14 State Child Development Centre, West Perth, WA, Australia.
15 Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
16 Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
17 Neurodevelopmental Genomics Research Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
18 Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia.

PMID: 29159459 DOI: 10.1007/8904_2017_71

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.

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