Agenesis of the Mesencephalon and Metencephalon with Cerebellar Hypoplasia: Putative Mutation in theEN2Gene—Report of 2 Cases in Early Infancy

Abstract

Congenital absence of the midbrain and upper pons is a rare human malformation. We describe two unrelated infants with this anomaly and cerebellar hypoplasia who were born at term but died in early infancy from lack of central respiratory drive. MRI in both cases disclosed the lesions during life. Neuropathological examination, performed in one, included immunocytochemical studies of NeuN, synaptophysin, vimentin, and glial fibrillary acidic protein (GFAP). Autopsy revealed a thin midline cord passing through the clivus, in place of the midbrain; it corresponded to hypoplastic and fused corticospinal tracts with ectopic neural tissue in the surrounding leptomeninges. Some ectopia were immunoreactive for synaptophysin and NeuN and others were nonreactive. The neural surfaces facing the subarachnoid fluid-filled space left by the absent midbrain and upper pons were lined by an abnormal villous ependyma. The architecture of the cerebellar cortex was imperfect but generally normal, and Bergmann glial cells had normal radial processes shown by vimentin and GFAP. Structures of the telencephalon, diencephalon, lower brainstem, and spinal cord were generally well formed, but inferior olivary and dentate nuclei were rudimentary and the spinal central canal was dilated at lumbar levels. The cerebral cortex was normally laminated, but pyramidal neurons of layer 5 were sparse in the frontal lobes. The hippocampus, olfactory system, and corpus callosum were formed. An ectopic lingual thyroid was found and had been associated with hypothyroidism during life. A murine model resembling this dysgenesis is demonstrated by homozygous mutations of the organizer genes Wnt1 or En1, also resulting in cerebellar aplasia, and En2, associated with cerebellar hypoplasia. These genes are essential to the formation of the mesencephalic neuromere and rhombomere 1 (metencephalon or upper pons and cerebellum). Pax8 has binding sites in the promoter for En2 and is essential for thyroid development. We speculate that in the human, the failure to form a mesencephalon and metencephalon, with cerebellar hypoplasia, results from a mutation or deletion in the EN2 (Engrailed-2) gene.

Association of the ENGRAILED 2 (EN2) gene with autism in Chinese Han population

“…Deficits in two spatial learning and memory tasks were also observed [Cheh et al, 2006]. Additionally, in human beings cerebellar hypoplasia could result from a mutation or deletion in the EN2 gene [Zec et al, 1997;Sarnat et al, 2002]. All these results supported the possibility that EN2 gene might be involved in the pathogenesis of autism.…”

Integrative classification of morphology and molecular genetics in central nervous system malformations

“…Failure of essential genes to become expressed in specific neuromeres, by contrast, may lead to an absence of those segments. Putative examples are the lack of mesencephalon and metencephalon with cerebellar hypoplasia in mice and humans due to defective Engrailed1 and 2 (EN1 and EN2), or Wingless1 (WNT1) expression [McMahon et al, 1992;Wurst et al, 1994;Joyner, 1996;Mastick et al, 1996;Kuemerle et al, 1997;Sarnat et al, 2002], or the failure of the basal telencephalic nuclei (i.e., basal ganglia) to develop with a putative EMX1 or MASH1 mutation [Casarosa et al, 1999;Sarnat, 2000;Sarnat and Flores-Sarnat, 2001a].…”

Assessment of cortical maturation with prenatal MRI

“…Cerebellar hypoplasia has been described linked to chromosome X [51]. Mutation has also been encountered in agenesis of the mesencephalon [52]. Fig.…”