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NEUROLOGY 2009;73:962-969
© 2009 American Academy of Neurology

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

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

From the Department of Genetics (S.P., L.T., C.H., K.H., N.P., B.G., A.V.), Service de Neuropédiatrie (S.P., L.T., P.G.), Service de Radiologie (M.E.), Service de Foëtopathologie (F.G.), and INSERM (S.P., P.G., A.V.), U676, Hôpital Robert Debré, APHP, Paris, France; Department of Pediatrics (L.T., G.A., E.D., I.S.), Federico II University, Naples, Italy; Service de Génétique Clinique (A.A., L.B.) and Service de Neuropédiatrie (T.B.d.V.), Hôpital Trousseau, APHP, Paris; Universités Paris VI/XII (T.B.d.V.); Service de Réanimation Néonatale et Pédiatrique (J.-L.A.), CHD Félix Guyon, Saint Denis de la Réunion; Service de Génétique Clinique (O.B.-T.), Université de Clermont Ferrand; Service de Génétique Clinique (B.I.), Université de Nantes, France; Unité de Génétique Médicale (A.M.), Faculté de Médecine, Université de Saint Joseph, Beirut, Lebanon; Institute of Human Genetics (U.M.), Heidelberg University, Germany; Service de Génétique Clinique (S.O.), Université de Rennes, France; and Department of Psychiatry (M.S.), University of Geneva School of Medicine, Switzerland.

Address correspondence and reprint requests to Pr. Alain Verloes, Department of Clinical Genetics, Robert Debré University Hospital, 48 Bd Sérurier, 75019 Paris, France alain.verloes{at}rdb.aphp.fr

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.

Abbreviations: MCPH = primary hereditary microcephaly; MR = mental retardation; MSG = microcephaly with simplified gyral pattern; MV = microcephalia vera; OFC = occipital-frontal circumference.

*These authors contributed equally.

Supported by the GIS-Maladies Rares, Fondation Lejeune, Fondation pour la Recherche Medicale, and Mariani Foundation (4 nonprofit organizations).

Disclosure: Author disclosures are provided at the end of the article.

Received March 11, 2009. Accepted in final form June 25, 2009.






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