LAUSR

In 1998, Steinmuller et al. described a previously unrecognized synhemizygous missense variant c.1294C N T in EIF2S3 (p.Pro432Ser) in drome featuring mental retardation, epileptic seizures, hypogonadism, microcephaly, and obesity (MEHMO syndrome; MIM 300148) and mapped the disease locus to Xp22.13-p21 [7]. Interestingly, in addition to the symptoms/signs included in the acronym MEHMO, the proband presentedwith non-autoimmune diabetes at the age of 6months, a condition currently defined as neonatal diabetes [1]. Diabetes was not reported in the other three affected males of the family who died at 7, 2 and 10 months of age. Fourteen years later, Borck [2] identified a hemizygous missense mutation (p.Ile223Thr) in the eukaryotic translation initiation factor 2 subunit 3 (EIF2S3, or eIF2γ) in threemales froma consanguineous family of Moroccan Jewish ancestry that disrupted EIF2 complex formation, resulting in defects in translation initiation, and MEHMO phenotype (Borck however did not associate the mutation with MEHMO syndrome.). Since then, EIF2S3mutations have been described including the Ile465Ser*fs 4 found in the original family reported by Steinmuller, and in two additional individuals with MEHMO and early-onset (b1 year of age), non-autoimmune diabetes [6]. Other two missense mutations, p.Ser108Arg and p.Ile259Met were detected in three patients all exhibiting the main features of MEHMO's phenotype, and other endocrine manifestations such as growth hormone deficiency (GHD) and hypoglycaemia [4]. A study published in the current issue of EBioMedicine has expanded the spectrum of EIF2S3 variants. It describesmonozygotic twin brothers and their maternal cousin, born to a non-consanguineous white European pedigree, that presented with normal head circumferences, mild learning difficulties, severe recurrent hypoglycaemia, short stature with GHD, and thyrotropin (TSH) deficiency. There was also an unusual metabolic phenotype fluctuating between post-prandial hyperglycaemia and hyperinsulinaemic hypoglycaemia that remitted before puberty with persistence of glucose dysregulation characterized by post-prandial hyperglycaemia and variable, fasting hypoglycaemia [3]. Exome sequencing of the X chromosome revealed a novel