title: RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.
abstract: Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.
authors.affiliation: APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', Paris, France.|APHP, GHUEP, Hôpital Armand-Trousseau, Service de Neuropédiatrie, Paris, France.|Sorbonne Universités, UPMC Université Paris 06, GRC-UPMC ConCer-LD, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Valence
authors.affiliation: APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', Paris, France.|APHP, GHUEP, Hôpital Armand-Trousseau, Service de Radiologie, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Garel
authors.affiliation: Service de Génétique, CHU d'Angers, Angers, France.
authors.forename: M
authors.initials: M
authors.lastname: Barth
authors.affiliation: Service de Génétique, CHU de Tours, and UMR_INSERM U930, Faculté de Médecine, Université François Rabelais, Tours, France.
authors.forename: A
authors.initials: A
authors.lastname: Toutain
authors.affiliation: Service de Neurologie Pédiatrique, CHU J Minjoz, Besançon, France.
authors.forename: C
authors.initials: C
authors.lastname: Paris
authors.affiliation: Service de Neurologie Pédiatrique, CHU J Minjoz, Besançon, France.
authors.forename: D
authors.initials: D
authors.lastname: Amsallem
authors.affiliation: Service de Neurologie Pédiatrique, CHU de Tours, Tours, France.
authors.forename: M-A
authors.initials: MA
authors.lastname: Barthez
authors.affiliation: APHP, GHUEP, Hôpital Armand-Trousseau, Service de Neuropédiatrie, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Mayer
authors.affiliation: APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', Paris, France.|APHP, GHUEP, Hôpital Armand-Trousseau, Service de Neuropédiatrie, Paris, France.|Sorbonne Universités, UPMC Université Paris 06, GRC-UPMC ConCer-LD, Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Rodriguez
authors.affiliation: APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', Paris, France.|Neuroprotection du cerveau en développement, INSERM U1141, Paris, France.|APHP, GHUEP, Hôpital Armand-Trousseau, Département de Génétique, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Burglen
mesh_terms: D000293:Adolescent; D000328:Adult; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009421:Nervous System Malformations / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics*; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D011973:Receptors, LDL; D000091042:Reelin Protein; C036053:VLDL receptor; C000717127:RELN protein, human; D012697:Serine Endopeptidases
keywords:  VLDLR; CAMRQ1; RELN; intellectual disability; lissencephaly; nonprogressive cerebellar ataxia; pontocerebellar hypoplasia