Abstract
Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0-49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease.
Highlights
Vici syndrome (OMIM 242840) is a severe, early-onset neurodevelopmental disorder characterized by the key features of callosal agenesis, cataracts, cardiomyopathy, generalized hypopigmentation, and combined immunodeficiency
We identified a total of 39 different ectopic P-granules autophagy protein 5 (EPG5) mutations in 38 patients from 30 families of varying ethnicity (Table 1 and Fig. 1)
None of the novel EPG5 mutations identified were found on publically available databases of human genetic variation, except for EPG5 p.Gln336Arg documented in one heterozygous individual on the NCBI SNP database
Summary
Vici syndrome (OMIM 242840) is a severe, early-onset neurodevelopmental disorder characterized by the key features of callosal agenesis, cataracts, cardiomyopathy, generalized hypopigmentation, and combined immunodeficiency. In 2013, our team linked Vici syndrome to recessive mutations in EPG5 on chromosome 18q (Cullup et al, 2013), encoding ectopic P-granules autophagy protein 5 (EPG5) with a key role in autophagy in multicellular organisms (Tian et al, 2010). The autophagy pathway involves several tightly regulated steps, evolving from the initial formation of isolation membranes (or phagophores) to autophagosomes, whose fusion with lysosomes results in the final structures of degradation, autolysosomes. The EPG5 protein has been implicated in the penultimate autophagy stages in Caenorhabditis elegans (Tian et al, 2010) and, more recently, in human cells, suggesting that EPG5 deficiency results in failure of autophagosome-lysosome fusion (Cullup et al, 2013) and, impaired cargo delivery to the lysosome
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