ORIGINAL ARTICLE Microcephaly and simplified gyral pattern of the brain associated with early onset insulin-dependent diabetes mellitus M. C. Y. de Wit & I. F. M. de Coo & C. Julier & M. Delépine & M. H. Lequin & I. van de Laar & B. J. Sibbles & G. J. Bruining & G. M. S. Mancini Received: 23 April 2006 / Accepted: 10 August 2006 / Published online: 14 September 2006 # Springer-Verlag 2006 Abstract Two families are presented with a child suffering from microcephaly with a simplified gyral pattern of the brain (SGP) and early onset insulin dependent diabetes mellitus (IDDM). The first patient was diagnosed post- mortally with Wolcott–Rallison syndrome, after her youn- ger brother developed IDDM, and a homozygous mutation in the eukaryotic translation initiation factor 2-alpha kinase 3 was found. The younger brother did not undergo magnetic resonance imaging (MRI). The patient from the second family has no EIF2AK3 mutation. SGP is consid- ered to arise from decreased neuronal proliferation or increased apoptosis at an early stage of embryonal development, but insight into the pathways involved is minimal. EIF2AK3 is involved in translation initiation. It has been proposed that loss of function mutations reduce the ability of the cell to respond to endoplasmic reticulum stress, resulting in apoptosis of pancreatic Langerhans cells. Our findings suggest that in some cases, early onset IDDM and SGP can arise from common mechanisms leading to increased apoptosis. Keywords EIF2AK3 . Insulin dependent diabetes mellitus . Malformation of cortical development . Simplified gyral pattern . Wolcott–Rallison syndrome Introduction In congenital microcephaly, magnetic resonance imaging (MRI) of the brain may reveal a relatively normal looking cortex (true microcephaly) or a diverse spectrum of brain malformations. One of those malformations is a simplified gyral pattern (SGP). in which the number of gyri and sulci is reduced, while cortex thickness is normal. This differ- entiates SGP from pachygyria or microlissencephaly with abnormally thick cortex. The same phenotype is also described in the literature as microcephaly with simplified gyration (MSG). SGP is thought to arise from decreased proliferation and/or increased apoptosis during embryogen- Neurogenetics (2006) 7:259–263 DOI 10.1007/s10048-006-0061-1 M. C. Y. de Wit : I. F. M. de Coo Department of Pediatric Neurology, Erasmus Medical Center Sophia Children’ s Hospital, Rotterdam, The Netherlands C. Julier Génétique des Maladies Infectieuses et Autoimmunes, Institut Pasteur, Paris, France M. Delépine Centre National de Génotypage, Evry, France M. H. Lequin Department of Pediatric Neuroradiology, Erasmus Medical Center, Sophia Children’ s Hospital, Rotterdam, The Netherlands I. van de Laar : G. M. S. Mancini (*) Department of Clinical Genetics, Erasmus Medical Center, Sophia Children’ s Hospital, Westzeedijk 112, 3016 Rotterdam, The Netherlands e-mail: g.mancini@erasmusmc.nl B. J. Sibbles Department of Paediatrics, Erasmus Medical Center, Sophia Children’ s Hospital, Rotterdam, The Netherlands G. J. Bruining Department of Diabetology, Erasmus Medical Center, Sophia Children’ s Hospital, Rotterdam, The Netherlands