Abstract
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency. Profound developmental delay, progressive failure to thrive and acquired microcephaly are almost universal, suggesting an evolving (neuro) degenerative component. In most patients there is additional variable multisystem involvement that may affect virtually any organ system, including lungs, thyroid, liver and kidneys. A skeletal myopathy is consistently associated, and characterized by marked fibre type disproportion, increase in internal nuclei, numerous vacuoles, abnormal mitochondria and glycogen storage. Life expectancy is markedly reduced.Vici syndrome is due to recessive mutations in EPG5 on chromosome 18q12.3, encoding ectopic P granules protein 5 (EPG5), a key autophagy regulator in higher organisms. Autophagy is a fundamental cellular degradative pathway conserved throughout evolution with important roles in the removal of defective proteins and organelles, defence against infections and adaptation to changing metabolic demands. Almost 40 EPG mutations have been identified to date, most of them truncating and private to individual families.The differential diagnosis of Vici syndrome includes a number of syndromes with overlapping clinical features, neurological and metabolic disorders with shared CNS abnormalities (in particular callosal agenesis), and primary neuromuscular disorders with a similar muscle biopsy appearance. Vici syndrome is also the most typical example of a novel group of inherited neurometabolic conditions, congenital disorders of autophagy.Management is currently largely supportive and symptomatic but better understanding of the underlying autophagy defect will hopefully inform the development of targeted therapies in future.
Highlights
Vici syndrome [OMIM242840] is a severe, recessively inherited congenital disorder characterized by the principal features of callosal agenesis, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, and a combined immunodeficiency
Definition Vici syndrome [OMIM242840, ORPHA1493] is a severe congenital multisystem disorder characterized by the principal features of agenesis of the corpus callosum, cataracts, oculocutaneous hypopigmentation, cardiomyopathy, a combined immunodeficiency and additional, more variable multisystem involvement
Abnormal findings reported to date include lymphopenia with variable T cell subset defects, neutropenia, leucopenia, hypogammaglobulinaemia, lack of response to recall antigens and a defect of memory B cells with lack of specific antibody response to certain immunizations such as those with tetanus and pneumococcal vaccine. These findings suggest prominent impairment of the humoral immune response with a milder defect of the T cell compartment, further prospective studies will be required to delineate the immunological phenotype further
Summary
A recently generated conditional drosophila knockout shows a marked autophagy defect and evidence of progressive neurodegeneration in retinal photoneurons [14] Taken together, these findings indicate Vici syndrome as a paradigm of a disorder linking neurodevelopment and neurodegeneration in the same pathway. Following the genetic resolution of Vici syndrome in 2013, a number of disorders associated with defects in primary autophagy regulators have been identified– for example, Static Encephalopathy in childhood with NeuroDegeneration in Adulthood (SENDA) due to Xlinked recessive mutations in WDR45, and early-onset syndromic ataxia due to recessive mutations in SNX14, suggesting congenital disorders of autophagy as a novel group of neurometabolic disorders with recognizable features, mechanistically linked in the same pathway (reviewed in, [25]).
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