ASPM-Related Primary Microcephaly Presenting with Severe Gyral Simplification and Cerebellar Hypoplasia: A Case
Ali Gülen1, Fahrettin Duymuş2, Hasibe Nesligül Gönen3
1Department of Medical Genetics, Uşak Training and Research Hospital, Uşak, Türkiye.
Introduction:
Biallelic loss-of-function variants in the abnormal spindle-like, microcephaly-associated ASPM (OMIM *605481) are the most common cause of autosomal recessive primary microcephaly, specifically microcephaly 5, primary, autosomal recessive MCPH5 (OMIM # 608716), typically characterized by congenital or early-onset microcephaly with variable intellectual disability and a simplified gyral pattern on brain magnetic resonance imaging (MRI), rather than classic lissencephaly due to neuronal migration failure.
Case Presentations:
We report a 16-year-old male with prenatally detected microcephaly, severe global developmental delay, and intellectual disability. Brain MRI demonstrated markedly reduced sulcation reported as lissencephaly, white-matter and cerebellar volume loss (vermian and tonsillar hypoplasia), enlarged retrocerebellar extra-axial cerebrospinal fluid space, colpocephaly, and fourth ventricle dilatation. Exome sequencing identified two truncating ASPM variants: NM_018136.5:c.349C>T (p.(Arg117Ter), rs137852996) and a novel frameshift NM_018136.5:c.4973_4974del (p.(Ser1658CysfsTer14)); these were classified as pathogenic/likely pathogenic under the ACMG criteria.
Conclusion:
We report a male adolescent with severe prenatal-onset microcephaly and a neuroimaging phenotype reported as lissencephaly with cerebellar hypoplasia, in whom exome sequencing identified truncating ASPM variants including a novel frameshift allele. This case highlights a critical diagnostic pitfall where extreme gyral simplification in MCPH5 mimics lissencephaly. It underscores the need to recognize an expanded ASPM phenotype that includes complex posterior fossa and ventricular malformations, preventing misdiagnosis and ensuring accurate genetic counseling.
