Research Article: A Homozygous IER3IP1 Mutation Causes Microcephaly With Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome (MEDS)

Date Published: November 18, 2012

Publisher: Wiley Subscription Services, Inc., A Wiley Company

Author(s): Ghada MH Abdel-Salam, Ashleigh E Schaffer, Maha S Zaki, Tracy Dixon-Salazar, Inas S Mostafa, Hanan H Afifi, Joseph G Gleeson.

http://doi.org/10.1002/ajmg.a.35583

Abstract

Wolcott–Rallison syndrome (WRS) and the recently delineated microcephaly with simplified gyration, epilepsy, and permanent neonatal diabetes syndrome (MEDS) are clinically overlapping autosomal recessive disorders characterized by early onset diabetes, skeletal defects, and growth retardation. While liver and renal symptoms are more severe in WRS, neurodevelopmental characteristics are more pronounced in MEDS patients, in which microcephaly and uncontrolled epilepsy are uniformly present. Mutations in the EIF2AK3 gene were described in patients with WRS and defects in this gene lead to increased susceptibility to apoptotic cell death. Mutations in IER3IP1 have been reported in patients with MEDS and similarly, loss of activity results in apoptosis of neurons and pancreatic beta cells in patients. Here we report on a homozygous mutation of the IER3IP1 gene in four patients from two unrelated consanguineous Egyptian families presenting with MEDS who display burst suppression patterns on EEG. All patients presented with mildly elevated liver enzymes, microalbuminuria, and skeletal changes such as scoliosis and osteopenia, leading to repeated bone fractures. We expand the phenotypic spectrum of MEDS caused by IER3IP1 gene mutations and propose that WRS and MEDS are overlapping clinical syndromes, displaying significant gene-dependent clinical variability. © 2012 Wiley Periodicals, Inc.

Partial Text

Microcephaly with simplified gyration is defined as congenital microcephaly associated with a reduced number of gyri, thin or normal cortical thickness, and reduced number and depth of sulci. It may be associated with abnormal myelination or additional brain malformations, and it is classified into five groups according to associated brain imaging findings [Basel-Vanagaite and Dobyns, 2010]. Congenital microcephaly is estimated to affect 1.3–150 per 100,000 live births [Kaindl et al., 2010]. Infantile-onset diabetes mellitus is also a rare disorder, which may be either transient or permanent. The permanent form accounts for approximately 50% of cases and has an estimated incidence of 1 in 260,000 live births [Stanik et al., 2007; Slingerland et al., 2009]. Permanent neonatal diabetes can occur isolated, or accompanied by neurological features such as cerebellar hypoplasia (PTF1A mutations) [Sellick et al., 2004], congenital hypothyroidism (GLIS3 mutations) [Senee et al., 2006], developmental delay (KCNJ11 mutations), and epilepsy (DEND syndrome) [Gloyn et al., 2006].

This study was approved by the Institutional Review Board at the University of California, San Diego and collaborating institutions, all able study participants signed informed consent documents, and the study was performed in accordance with HIPPA privacy rules. DNA was extracted from blood using Qiagen reagents. SNP genotyping was performed using the Sequenom MassARRAY system and iPLEX reagents according to manufacturers recommendations. DNA was subjected to exome capture with the Agilent SureSelect Human All Exome 50 Mb kit, sequenced on an Illumina HiSeq2000 instrument, resulting in ∼94% target coverage at >10× depth. BWA was utilized to align the sequences to the human reference genome (hg19), and GATK [McKenna et al., 2010] was used for variant identification.

In 2005, de Wit et al. described three patients with microcephaly with simplified gyration and skeletal deformities with EIF2AK3 mutations, pointing to the diagnosis of Wolcott–Rallison syndrome in two of the three patients reported [de Wit et al., 2006]. Subsequently, the same group reported homozygous missense IER3IP1 mutations in the previously described patient negative for mutations in EIF2AK3, as well as in an additional unrelated family, concluding the diagnosis of MEDS [Poulton et al., 2011]. The patients with IER3IP1 mutations presented with more severe microcephaly, permanent neonatal diabetes, and skeletal deformities as compared with patients harboring EIF2AK3 mutations. Furthermore, uncontrolled seizures and burst suppression EEG pattern were noticed in all patients with IER3IP1 mutations. Here we describe four patients from two unrelated families showing clinical features of MEDS with burst suppression EEG pattern, skeletal deformity consisting of scoliosis and cortical thinning of long bones leading to multiple fractures, slightly elevated liver enzymes, and microalbuminuria. This report expands the phenotype of MEDS caused by IER3IP1 gene mutations. We therefore conclude that Wolcott–Rallison syndrome and MEDS are clinically overlapping syndromes that display gene-dependent clinical variability.

 

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http://doi.org/10.1002/ajmg.a.35583

 

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