Neuropathological review of 138 cases genetically tested for X-linked hydrocephalus: evidence for closely related clinical entities of unknown molecular bases.

Abstract

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.

• Authors: Homa Adle-Biassette, Pascale Saugier-Veber, Catherine Fallet-Bianco, Anne-Lise Delezoide, Férecheté Razavi, Nathalie Drouot, Anne Bazin, Anne-Marie Beaufrère, Bettina Bessières, Sophie Blesson, Martine Bucourt, Dominique Carles, Louise Devisme, Frédérique Dijoud, Blandine Fabre, Carla Fernandez, Dominique Gaillard, Marie Gonzales, Frédérique Jossic, Madeleine Joubert, Nicole Laurent, Brigitte Leroy, Laurence Loeuillet, Philippe Loget, Pascale Marcorelles, Jelena Martinovic, Marie-José Perez, Daniel Satge, Martine Sinico, Mario Tosi, Jacques Benichou, Pierre Gressens, Thierry Frebourg, Annie Laquerrière
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 126 Issue 3 Pg. 427-42 (Sep 2013) ISSN: 1432-0533 [Electronic] Germany
• PMID: 23820807 (Publication Type: Journal Article)

Chemical References

• Neural Cell Adhesion Molecule L1

Topics

• Abnormalities, Multiple (genetics, pathology)
• Cerebral Aqueduct (abnormalities, pathology)
• Female
• Genetic Diseases, X-Linked (pathology)
• Humans
• Hydrocephalus (pathology)
• Infant, Newborn
• Mutation (genetics)
• Nervous System Diseases (genetics, pathology)
• Neural Cell Adhesion Molecule L1 (genetics)
• Pedigree
• Phenotype
• Pregnancy