Autosomal recessive primary microcephaly due to ASPM mutations: An update

Area of Science:

• Genetics
• Neurodevelopmental disorders
• Molecular biology

Background:

• Primary hereditary microcephaly (MCPH) is a genetically diverse neurodevelopmental condition.
• It is characterized by reduced brain volume (occipitofrontal circumference -2SD at birth, -3SD after 6 months) and intellectual disability.
• The abnormal spindle-like microcephaly gene (ASPM) is crucial for neurogenesis, and its mutations cause MCPH5, the most common form of MCPH.

Purpose of the Study:

• To report new ASPM mutations and analyze a large cohort of MCPH patients.
• To comprehensively review molecular, clinical, neuroradiological, and neuropsychological data from previously reported families.
• To investigate the relationship between ASPM mutations, brain structure, and cognitive abilities.

Main Methods:

• Genetic analysis of 47 new patients from 39 families, identifying 28 novel ASPM mutations.
• Exhaustive literature review of 282 previously reported families with 161 distinct ASPM mutations.
• Correlation of molecular findings with clinical, neuroradiological, and neuropsychological data.

Main Results:

• Identification of 28 new ASPM mutations in 47 patients, adding to the 161 known mutations.
• Analysis of a large cohort reveals that ASPM-related microcephaly is not invariably linked to intellectual deficiency.
• Structural brain defects, including reduced cortical volume and surface area, are associated with cognitive abilities.

Conclusions:

• ASPM mutations are a significant cause of primary hereditary microcephaly.
• The phenotypic spectrum of ASPM-related microcephaly is broader than previously recognized, with variable intellectual outcomes.
• Understanding the link between brain structure and cognitive function in MCPH is crucial for patient management.