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Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations

Research output: Contribution to journalArticle

S Passemard, L Titomanlio, M Elmaleh, A Afenjar, J-L Alessandri, G Andria, T Billette de Villemeur, O Boespflug-Tanguy, L Burglen, E Del Giudice, F Guimiot, C Hyon, B Isidor, A Mégarbané, U Moog, S Odent, K Hernandez, N Pouvreau, I Scala, M Schaer & 3 more P Gressens, B Gerard, Alain Verloes

Original languageEnglish
Article numberN/A
Pages (from-to)962-969
Number of pages8
Issue number12
Publication statusPublished - 22 Sep 2009

King's Authors


Objective: To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations.

Methods: ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family.

Results: We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1).

Conclusions: We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.

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