title: Cerebellar vermis aplasia: patient report and exclusion of the candidate genes EN2 and ZIC1.
abstract: Cerebellar vermis aplasia (ACV, OMIM 117360) is a rare malformation of the cerebellum, with only few familial patients reported so far. Main clinical features of this rare disorder include floppiness and delayed milestones in early infancy, preceding mild cerebellar ataxia, non-progressive clinical course, normal or slightly delayed intelligence, and occasional nystagmus. Neuroimaging reveals selective involvement of the cerebellum, which is prominent in the vermis. Because of the large preponderance of female patients, X-linked dominant transmission was suggested by [Fenichel and Phillips (1989); Arch Neurol 46:582-583], and subsequent reports only concern female patients. Only one family with male-to-male transmission presenting with a generalized atrophy of the cerebellum rather than a more localized vermis aplasia has been reported so far. We report on a family in which father and son are affected by a mild form of ACV, thus confirming an autosomal mode of inheritance of the disease. Our patients showed a progressive improvement of their motor abilities, neurological examination of the father being actually normal except for a mild mental retardation. We also evaluated the potential role of two candidate genes, EN2 and ZIC1, responsible for abnormal cerebellar development in murine knock-out models. However, molecular analysis failed to reveal any causative mutation in the coding sequence of the two genes in our patients. The understanding of the genetic basis of autosomal dominant ACV would allow a better classification of isolate cerebellar malformations and might permit to understand cell differentiation and migration in the developing central nervous system.
authors.affiliation: Clinical Genetics Unit, Hôpital Robert Debré, University Paris VII, France.
authors.forename: Luigi
authors.initials: L
authors.lastname: Titomanlio
authors.forename: Nicola Brunetti
authors.initials: NB
authors.lastname: Pierri
authors.forename: Alfonso
authors.initials: A
authors.lastname: Romano
authors.forename: Floriana
authors.initials: F
authors.lastname: Imperati
authors.forename: Melissa
authors.initials: M
authors.lastname: Borrelli
authors.forename: Valentina
authors.initials: V
authors.lastname: Barletta
authors.forename: Alvaro Antonio
authors.initials: AA
authors.lastname: Diano
authors.forename: Imma
authors.initials: I
authors.lastname: Castaldo
authors.forename: Lucio
authors.initials: L
authors.lastname: Santoro
authors.forename: Ennio
authors.initials: E
authors.lastname: Del Giudice
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000328:Adult; D002524:Cerebellar Ataxia / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002658:Developmental Disabilities / Q000473:pathology; D005192:Family Health; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics; D009759:Nystagmus, Pathologic / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics; D000099266:Engrailed 2 Protein
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D000099266:Engrailed 2 Protein; C492123:ZIC1 protein, human