Two New Cases of Primary Microcephaly with Neuronal Migration Defect Caused by Truncating Mutations in the ASPM Gene
Ayberk Türkyılmaz1, Safiye Gunes Sager2
1Department of Medical Genetics, Karadeniz Technical University Faculty of Medicine, Trabzon, Turkey.
Abstract:
Autosomal recessive primary microcephaly (MCPH) is a uncommon disorder due to congenital deficiency in the development of the cerebral cortex, characterized by a head circumference below 2 SD. MCPH is a group of diseases with genetic heterogeneity and has been reported by the Online Mendelian Inheritance In Man® (OMIM) database and associated with 25 different genes. It is known that MCPH cases are most frequently associated with abnormal spindle-like, microcephaly-associated (ASPM) gene mutations. The ASPM protein consists of an N-terminal 81 IQ (isoleucine-glutamine) domain, a calponin-homology domain, and a C-terminal domain. It interacts with calmodulin and calmodulin-related proteins via the IQ domain and acts as a part in mitotic spindle function. The basic characteristics of cases with ASPM gene mutations are microcephaly (below -3 SD) present before 1 year of age, intellectual disability, and the absence of other congenital anomalies. Macroscopic organization of the brain is preserved in cases with ASPM mutation, and a decrease in brain volume, particularly gray matter volume loss and a simplified gyral pattern are observed. Cortical migration defects are a very rare finding in patients with ASPM mutations. In the present study, we aimed to discuss the clinical and genetic findings in 2 cases with cortical dysplasia in which truncated variants in the ASPM gene were detected, particularly in terms of genotype-phenotype correlation in comparison with the literature.
Insights
Primary microcephaly (MCPH) is a rare brain development disorder. This study examines two cases with rare cortical dysplasia linked to the abnormal spindle-like, microcephaly-associated (ASPM) gene, exploring genotype-phenotype correlations.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a rare congenital disorder affecting cerebral cortex development, characterized by a head circumference below -2 SD.
- MCPH exhibits genetic heterogeneity, with mutations in 25 different genes identified, most commonly involving the abnormal spindle-like, microcephaly-associated (ASPM) gene.
Observation:
- ASPM protein plays a role in mitotic spindle function, interacting with calmodulin via its IQ domain.
- Typical clinical features of ASPM mutations include severe microcephaly (<-3 SD) before age one, intellectual disability, and absence of other congenital anomalies.
- Brain imaging in ASPM-related MCPH reveals preserved macroscopic organization but reduced brain volume, particularly gray matter loss and simplified gyral patterns.
Findings:
- Cortical migration defects are exceptionally rare in patients with ASPM mutations.
- This study presents two cases of MCPH with cortical dysplasia associated with truncated variants in the ASPM gene.
- The findings emphasize the importance of genotype-phenotype correlation in understanding ASPM-related microcephaly.
Implications:
- The study expands the known spectrum of phenotypes associated with ASPM gene mutations.
- Understanding these genotype-phenotype correlations can aid in diagnosing and managing MCPH.
- Further research into ASPM variants may uncover novel insights into brain development and microcephaly pathogenesis.
