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

Abstract : 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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Contributor : Hervé de Villemeur <>
Submitted on : Monday, September 28, 2009 - 6:43:32 PM
Last modification on : Wednesday, August 19, 2020 - 11:16:36 AM



Sandrine Passemard, Luigi Titomanlio, Monique Elmaleh, Alexandra Afenjar, Jean-Luc Alessandri, et al.. Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.. Neurology, American Academy of Neurology, 2009, 73 (12), pp.962-9. ⟨10.1212/WNL.0b013e3181b8799a⟩. ⟨inserm-00420406⟩



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