Autosomal recessive primary microcephaly due to ASPM mutations: An update
Pascaline Létard1,2,3, Séverine Drunat1,4, Yoann Vial1,4
1PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Abstract:
Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities.
Insights
Primary hereditary microcephaly (MCPH) is a neurodevelopmental disorder caused by mutations in the abnormal spindle-like microcephaly gene (ASPM). This study identifies new ASPM mutations and reveals that ASPM-related microcephaly does not always cause intellectual deficiency.
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.
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