, Volume 7, Issue 4, pp 259–263

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
Original Article


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 postmortally with Wolcott–Rallison syndrome, after her younger 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 considered 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.


EIF2AK3 Insulin dependent diabetes mellitus Malformation of cortical development Simplified gyral pattern Wolcott–Rallison syndrome 


  1. 1.
    Barkovich AJ, Kuzniecky RI, Jackson GD, Guerrini R, Dobyns WB (2005) A developmental and genetic classification for malformations of cortical development. Neurology 65:1873–1887PubMedCrossRefGoogle Scholar
  2. 2.
    Woods CG, Bond J, Enard W (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76:717–728PubMedCrossRefGoogle Scholar
  3. 3.
    Gloyn AL, Siddiqui J, Ellard S (2006) Mutations in the genes encoding the pancreatic beta-cell Katp channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism. Hum Mutat 27(3):220–231PubMedCrossRefGoogle Scholar
  4. 4.
    Porter JR, Barrett TG (2005) Monogenic syndromes of abnormal glucose homeostasis: clinical review and relevance to the understanding of the pathology of insulin resistance and beta cell failure. J Med Genet 42:893–902PubMedCrossRefGoogle Scholar
  5. 5.
    Iyer S, Korada M, Rainbow L, Kirk J, Brown RM, Shaw N, Barrett TG (2004) Wolcott–Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature. Acta Paediatr 93:1195–1201PubMedCrossRefGoogle Scholar
  6. 6.
    Delepine M, Nicolino M, Barrett T, Golamaully M, Lathrop GM, Julier C (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat Genet 25(4):406–409PubMedCrossRefGoogle Scholar
  7. 7.
    Biason-Lauber A, Lang-Muritano M, Vaccaro T, Schoenle EJ (2002) Loss of kinase activity in a patient with Wolcott–Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. Diabetes 51(7):2301–2305PubMedGoogle Scholar
  8. 8.
    Senée V, Vattem KM, Delépine M, Rainbow LA, Haton C, Lecoq A, Shaw NJ, Robert JJ et al (2004) Wolcott–Rallison syndrome. Clinical, genetic and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes 53:1876–1883PubMedGoogle Scholar
  9. 9.
    Harding HP, Zhang Y, Bertolotti A, Zeng H, Ron D (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5(5):897–904PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang P, McGrath B, Li S, Frank A, Zambito F, Reinert J, Gannon M, Ma K, McNaughton K, Cavener DR (2002) The Perk eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 22:3864–3874PubMedCrossRefGoogle Scholar
  11. 11.
    Owen CR, Kumar R, Zhang P, McGrath BC, Cavener DR, Krause GS (2005) PERK is responsible for the increased phosphorylation of eIF2alpha and the severe inhibition of protein synthesis after transient global brain ischemia. J Neurochem 94(5):1235–1242PubMedCrossRefGoogle Scholar
  12. 12.
    Hao S, Sharp JW, Ross-Inta CM, McDaniel BJ, Anthony TG, Wek RC, Cavener DR, McGrath BC, Rudell JB, Koehnle TJ, Gietzen DW (2006) Uncharged tRNA and sensing of animo acid deficiency in mammalian piriform cortex. Science 307:1776–1778CrossRefGoogle Scholar
  13. 13.
    Carnevalli LS, Pereira CM, Jaqueta CB, Alves VS, Paiva VN, Vattem KM, Wek RC, Mello LEAM, Castilho BA (2006) Phosphorylation of the alpha subunit of translation initiation factor 2 by PKR mediates protein synthesis inhibition in the mouse brain during status epilepticus. Biochem J 397(1):187–194Google Scholar
  14. 14.
    Van der Knaap MS, Leegwater PA, Konst AA et al (2002) Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 51:264–270PubMedCrossRefGoogle Scholar
  15. 15.
    Fogli A, Boespflug-Tanguy O (2006) The large spectrum of eIF2B-related disease. Biochem Soc Trans 34:22–29PubMedGoogle Scholar
  16. 16.
    Brickwood S, Bonthron DT, Al-Gazali LI, Piper K, Hearn T, Wilson DI, Hanley NA (2003) Wolcott–Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 40:685–689PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • M. C. Y. de Wit
    • 1
  • I. F. M. de Coo
    • 1
  • C. Julier
    • 2
  • M. Delépine
    • 3
  • M. H. Lequin
    • 4
  • I. van de Laar
    • 5
  • B. J. Sibbles
    • 6
  • G. J. Bruining
    • 7
  • G. M. S. Mancini
    • 5
  1. 1.Department of Pediatric NeurologyErasmus Medical Center Sophia Children’s HospitalRotterdamThe Netherlands
  2. 2.Génétique des Maladies Infectieuses et Autoimmunes, Institut PasteurParisFrance
  3. 3.Centre National de GénotypageEvryFrance
  4. 4.Department of Pediatric NeuroradiologyErasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands
  5. 5.Department of Clinical GeneticsErasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands
  6. 6.Department of PaediatricsErasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands
  7. 7.Department of DiabetologyErasmus Medical Center, Sophia Children’s HospitalRotterdamThe Netherlands

Personalised recommendations