@article {8313,
	title = {EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy.},
	journal = {Brain},
	volume = {139},
	year = {2016},
	month = {2016 Mar},
	pages = {765-81},
	abstract = {<p>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.</p>},
	keywords = {Agenesis of Corpus Callosum, Animals, Autophagy, Cataract, Child, Preschool, Cross-Sectional Studies, Drosophila melanogaster, Female, Hippocampus, Humans, Male, Mutation, Neurodevelopmental Disorders, Proteins, Retrospective Studies},
	issn = {1460-2156},
	doi = {10.1093/brain/awv393},
	author = {Byrne, Susan and Jansen, Lara and U-King-Im, Jean-Marie and Siddiqui, Ata and Lidov, Hart G W and Bodi, Istvan and Smith, Luke and Mein, Rachael and Cullup, Thomas and Dionisi-Vici, Carlo and Al-Gazali, Lihadh and Al-Owain, Mohammed and Bruwer, Zandre and Al Thihli, Khalid and El-Garhy, Rana and Flanigan, Kevin M and Manickam, Kandamurugu and Zmuda, Erik and Banks, Wesley and Gershoni-Baruch, Ruth and Mandel, Hanna and Dagan, Efrat and Raas-Rothschild, Annick and Barash, Hila and Filloux, Francis and Creel, Donnell and Harris, Michael and Hamosh, Ada and K{\"o}lker, Stefan and Ebrahimi-Fakhari, Darius and Hoffmann, Georg F and Manchester, David and Boyer, Philip J and Manzur, Adnan Y and Lourenco, Charles Marques and Pilz, Daniela T and Kamath, Arveen and Prabhakar, Prab and Rao, Vamshi K and Rogers, R Curtis and Ryan, Monique M and Brown, Natasha J and McLean, Catriona A and Said, Edith and Schara, Ulrike and Stein, Anja and Sewry, Caroline and Travan, Laura and Wijburg, Frits A and Zenker, Martin and Mohammed, Shehla and Fanto, Manolis and Gautel, Mathias and Jungbluth, Heinz}
}
@article {1659,
	title = {Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I.},
	journal = {Eur J Med Genet},
	volume = {53},
	year = {2010},
	month = {2010 Sep-Oct},
	pages = {322-4},
	abstract = {<p>Noonan syndrome (NS) is an autosomal dominant, inherited disorder characterized by facial dysmorphism, congenital heart defects, and reduced postnatal growth. Dysregulated RAS-MAPK signalling is the common molecular basis for NS, a genetically heterogeneous disease. Germline mutations in genes encoding small GTPases of the RAS family (KRAS and NRAS), modulators of RAS function (PTPN11, SOS1 and SHOC2) or downstream signal transducers (RAF1) are causative for NS. SOS1 is the second major gene for NS after PTPN11. Compared to patients with mutations in other genes, SOS1 mutation-positive individuals in general tend to have a more favorable outcome, with less short stature and cognitive impairment. We describe two unrelated patients with NS carrying the same heterozygous SOS1 missense mutation (c.1867T > A/p.F623I). The phenotype of both patients is remarkable as they show uncommon clinical features such as pulmonary lymphangiectasis, congenital pleural effusions, severe feeding problems, and laryngomalacia. These findings may be related to the specific mutation present in our two patients, or be part of the SOS1 phenotype. Detailed clinical assessment of large cohorts of patients with NS and SOS1 mutation is required to clarify this initial observation.</p>},
	keywords = {Child, Preschool, Genes, ras, Germ-Line Mutation, Heterozygote, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Noonan Syndrome, Phenotype, SOS1 Protein},
	issn = {1878-0849},
	doi = {10.1016/j.ejmg.2010.07.011},
	author = {Fabretto, Antonella and Kutsche, Kerstin and Harmsen, May-Britt and Demarini, Sergio and Gasparini, Paolo and Fertz, Maria Cristina and Zenker, Martin}
}
