EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO

Impairment of translation initiation and its regulation within the integrated stress response (ISR) and related unfolded-protein response has been identified as a cause of several multisystemic syndromes. Here, we link MEHMO syndrome, whose genetic etiology was unknown, to this group of disorders. MEHMO is a rare X-linked syndrome characterized by profound intellectual disability, epilepsy, hypogonadism and hypogenitalism, microcephaly, and obesity. We have identified a C-terminal frameshift mutation (Ile465Serfs) in the EIF2S3 gene in three families with MEHMO syndrome and a novel maternally inherited missense EIF2S3 variant (c.324T>A; p.Ser108Arg) in another male patient with less severe clinical symptoms. The EIF2S3 gene encodes the gamma subunit of eukaryotic translation initiation factor 2 (eIF2), crucial for initiation of protein synthesis and regulation of the ISR. Studies in patient fibroblasts confirm increased ISR activation due to the Ile465Serfs mutation and functional assays in yeast demonstrate that the Ile465Serfs mutation impairs eIF2gamma function to a greater extent than tested missense mutations, consistent with the more severe clinical phenotype of the Ile465Serfs male mutation carriers. Thus, we propose that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms

Melanocortin-4 Receptor Gene Mutations in Obese Slovak Children

Summary The most common etiology of non-syndromic monogenic obesit

European Laryngological Society position paper on laryngeal dysplasia Part II: diagnosis, treatment, and follow-up

Purpose of review To give an overview of the current knowledge regarding the diagnosis, treatment, and follow-up of laryngeal dysplasia (LD) and to highlight the contributions of recent literature. The diagnosis of LD largely relies on endoscopic procedures and on histopathology. Diagnostic efficiency of endoscopy may be improved using videolaryngostroboscopy (VLS) and bioendoscopic tools such as Narrow Band Imaging (NBI) or Storz Professional Image Enhancement System (SPIES). Current histological classifications are not powerful enough to clearly predict the risk to carcinoma evolution and technical issues such as sampling error, variation in epithelial thickness and inflammation hamper pathological examination. Almost all dysplasia grading systems are effective in different ways. The 2017 World Health Organization (WHO) system should prove to be an improvement as it is slightly more reproducible and easier for the non-specialist pathologist to apply. To optimize treatment decisions, surgeons should know how their pathologist grades samples and preferably audit their transformation rates locally. Whether carcinoma in situ should be used as part of such classification remains contentious and pathologists should agree with their clinicians whether they find this additional grade useful in treatment decisions. Recently, different studies have defined the possible utility of different biomarkers in risk classification. The main treatment modality for LD is represented by transoral laser microsurgery. Radiotherapy may be indicated in specific circumstances such as multiple recurrence or wide-field lesions. Medical treatment currently does not have a significant role in the management of LD. Follow-up for patients treated with LD is a fundamental part of their care and investigations may be supported by the same techniques used during diagnosis (VLS and NBI/SPIES)