title: Abnormal spindle-like microcephaly-associated (ASPM) mutations strongly disrupt neocortical structure but spare the hippocampus and long-term memory.
abstract: Autosomal recessive primary microcephaly results from abnormal brain development linked to proliferation defects in neural progenitors. The most frequent form, caused by ASPM mutations, is usually defined by a reduced brain volume and is associated with intellectual disability. Although many ASPM cases have now been reported, structural brain abnormalities and their link with cognitive disabilities have rarely been investigated. In this study, we used high resolution T1-weighted magnetic resonance imaging in seven patients with ASPM mutations and 39 healthy age-matched controls to quantify regional volumes, thickness, surface area, gyrification index and white matter volumes of 30 cortical regions. We observed a consistent reduction of 50% or more in the volume and surface area of all cortical regions except for the hippocampus and surrounding medial temporal structures, which were significantly less reduced. Neuropsychologic assessment indicated significant impairments of cognitive abilities. However, these impairments were associated with normal mnesic abilities, in keeping with the relative preservation of the hippocampus and medial temporal structures. These results show that, contrary to current opinion, the cortical volume and surface area of patients with ASPM mutations is reduced depending on a regionally specific fashion and their cognitive profile reflects this heterogeneity. The precise characterization of the cortical map and cognitive abilities of patients with ASPM mutations should allow developing more focused reeducative interventions well-suited to their real abilities.
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France; Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France; Service de Neuropédiatrie, Hôpital Robert Debré, AP-HP, Paris, France. Electronic address: sandrine.passemard@inserm.fr.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Passemard
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France; Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Sorbonne Universités, UPMC Université Paris 06, Paris, France; Service de Neuropédiatrie, Hôpital Trousseau, AP-HP, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Billette de Villemeur
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France; Service de Neuropédiatrie, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Boespflug-Tanguy
authors.affiliation: Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Karen
authors.initials: K
authors.lastname: Hernandez
authors.affiliation: Service de Psychopathologie, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Laurent
authors.affiliation: Service de Génétique, Hôpital Mère-Enfant, Nantes, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Isidor
authors.affiliation: Université Paris Diderot - Sorbonne Paris Cité, Paris, France; Inserm CIC-EC1426, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Alberti
authors.affiliation: Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pouvreau
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Drunat
authors.affiliation: Département de Génétique, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Gérard
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: El Ghouzzi
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gallego
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France; Service de Radiopédiatrie, Hôpital Robert Debré, AP-HP, Paris, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Elmaleh-Bergès
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Wieland B
authors.initials: WB
authors.lastname: Huttner
authors.affiliation: Office Médico-Pédagogique, Département de psychiatrie, Université de Genève, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Eliez
authors.affiliation: Inserm, U1141, Hôpital Robert Debré, Paris, France; Université Paris Diderot - Sorbonne Paris Cité, Paris, France; Service de Neuropédiatrie, Hôpital Robert Debré, AP-HP, Paris, France; Center for Developing Brain, King's College, St. Thomas' Campus, London, United Kingdom.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Office Médico-Pédagogique, Département de psychiatrie, Université de Genève, Switzerland; Stanford Cognitive & Systems Laboratory, Stanford University School of Medicine, Palo Alto, CA, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Schaer
mesh_terms: D000293:Adolescent; D002648:Child; D003071:Cognition / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008297:Male; D057567:Memory, Long-Term / Q000502:physiology*; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D019579:Neocortex / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009483:Neuropsychological Tests; D066127:White Matter / Q000473:pathology; D055815:Young Adult
chemical_list: C467202:ASPM protein, human; D009419:Nerve Tissue Proteins
keywords: Brain development; Hippocampus; Human cerebral cortex; MCPH; Memory