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

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.

[1]  M. Leppert,et al.  Microcephaly with simplified gyral pattern in six related children. , 1999, American journal of medical genetics.

[2]  William C Earnshaw,et al.  Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling , 2008, Nature Genetics.

[3]  M. Fichera,et al.  The molecular landscape of ASPM mutations in primary microcephaly , 2008, Journal of Medical Genetics.

[4]  C. Woods,et al.  Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. , 2005, American journal of human genetics.

[5]  Philippe David,et al.  Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero‐posterior gradient pre‐ and post‐natally , 2008, American journal of medical genetics. Part A.

[6]  C. Walsh,et al.  Protein-truncating mutations in ASPM cause variable reduction in brain size. , 2003, American journal of human genetics.

[7]  W. Ahmad,et al.  NOVEL PROTEIN-TRUNCATING MUTATIONS IN THE ASPM GENE IN FAMILIES WITH AUTOSOMAL RECESSIVE PRIMARY MICROCEPHALY , 2007, Journal of neurogenetics.

[8]  N. Tommerup,et al.  Compound heterozygous ASPM mutations in Pakistani MCPH families , 2009, American journal of medical genetics. Part A.

[9]  G. Pfeifer,et al.  Microcephalin Encodes a Centrosomal Protein , 2006, Cell cycle.

[10]  K. Devriendt,et al.  Mutations in the Pericentrin (PCNT) Gene Cause Primordial Dwarfism , 2008, Science.

[11]  C. Woods,et al.  Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation , 2002, Journal of medical genetics.

[12]  Alexander F. Markham,et al.  ASPM is a major determinant of cerebral cortical size , 2002, Nature Genetics.

[13]  D. Glover,et al.  A requirement for the Abnormal Spindle protein to organise microtubules of the central spindle for cytokinesis in Drosophila. , 2002, Journal of cell science.

[14]  Christopher A. Walsh,et al.  Molecular genetics of human microcephaly , 2001, Current opinion in neurology.

[15]  W. Dobyns.  Primary microcephaly: new approaches for an old disorder. , 2002, American journal of medical genetics.

[16]  J. Scholey,et al.  Spindle pole organization in Drosophila S2 cells by dynein, abnormal spindle protein (Asp), and KLP10A. , 2005, Molecular biology of the cell.

[17]  R. Kuzniecky,et al.  A developmental and genetic classification for malformations of cortical development , 2005, Neurology.

[18]  C. Walsh,et al.  ASPM mutations identified in patients with primary microcephaly and seizures , 2005, Journal of Medical Genetics.

[19]  A. Kumar,et al.  Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations , 2004, Clinical genetics.

[20]  Vladimir Larionov,et al.  The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein. , 2005, Human molecular genetics.

[21]  R. Saunders,et al.  The Drosophila Gene abnormal spindle Encodes a Novel Microtubule-associated Protein That Associates with the Polar Regions of the Mitotic Spindle , 1997, The Journal of cell biology.

[22]  K. Sperling,et al.  The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype , 2005, Human mutation.

[23]  T. Siddique,et al.  Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene , 2006, Neurogenetics.

[24]  C. Woods,et al.  What primary microcephaly can tell us about brain growth. , 2006, Trends in molecular medicine.

[25]  C. Truwit,et al.  Microlissencephaly: A Heterogeneous Malformation of Cortical Development , 1998, Neuropediatrics.