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

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.

EPG5 c.1007A > G mutation in a sibling pair with rapidly progressing Vici syndrome

“…In addition to these phenotypic features, cardiomyopathy, developmental delay, microcephaly, and failure to thrive were described as typical consequences (Byrne et al., ; Chiyonobu et al., ; del Campo et al., ). Since the first description, more than 40 families have been published with Vici syndrome (VICIS), who were compatible with an autosomal recessive transmission and have extended the variable clinical spectrum with myopathy, epilepsy, elevated aminotransferases, thymus aplasia, thrombocytopenic purpura, sensorineural hearing loss, and renal tubular acidosis (Aggarwal, Tandon, Bhowmik, & Dalal, ; Al‐Owain et al., ; Alzahrani, Alghamdi, & Waggass, ; Balasubramaniam et al., ; Byrne et al., ; Chiyonobu et al., ; Cullup et al., ; del Campo et al., ; Demiral, Sen, Esener, Ceylaner, & Tekedereli, ; El‐Kersh, Jungbluth, Gringras, & Senthilvel, ; Hedberg‐Oldfors, Darin, & Oldfors, ; Hori et al., ; Huenerberg et al., ; Maillard et al., ; McClelland et al., ; Miyata et al., ; Ozkale, Erol, Gümüs, Ozkale, & Alehan, ; Rogers, Aufmuth, & Monesson, ; Said, Soler, & Sewry, ; Shimada et al., ; Waldrop et al., ). The prognosis was found to be poor with a median survival of 42 months (Byrne, Dionisi‐Vici, Smith, Gautel, & Jungbluth, ).…”

Seave: a comprehensive web platform for storing and interrogating human genomic variation

“…As a component of Australia’s first clinically accredited whole genome pathology service, Seave has met the rigorous demands of ISO 15189 clinical accreditation. In a research setting, it has been successfully used to discover novel disease genes and variants, as well as rapidly supporting the diagnosis of patients with previously reported pathogenic variants (Balasubramaniam et al , 2017a,b; De Sousa et al , 2017; Ewans et al , 2018; Heimer et al , 2016; Kumar et al , 2016; Riley et al , 2017). Cancer research requires the comprehensive interrogation of large numbers of somatic variants of all sizes and types at differing variant allele frequencies.…”

Impaired proteostasis in rare neurological diseases

“…is a key autophagic modulator involved in the formation of autolysosomes that is mutated in Vici syndrome, a rare autosomal recessively inherited multisystemic disorder [128]. Nevertheless, the formation of autolysosomes and subsequent cargo degradation As mentioned before, autophagy serves as a mechanism for removal of not only misfolded or aggregated proteins, but also defective organelles such as mitochondria.…”

“…mutant genes have been linked with over a dozen distinct RNDs in which either formation and/or maturation of autophagosomes is impaired [9,18,69,70,119,121,[126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141]. For instance, lysosomal-associated membrane glycoprotein 2 (LAMP2), which is involved in autophagosome maturation, cause Danon disease, a rare genetic condition characterized by muscle weakening and intellectual disability [127].…”