Microcephaly, a commonly documented finding in paediatric neurological practice, confers little diagnostic specificity. Defined by a significant decrease in head circumference, it does not do much to discriminate between the many processes that result in reduced cranial capacity. Given that reduced skull volume reflects the size of the underlying brain, microcephaly is either the consequence of impaired cerebral growth during development or destructive neurological insults. It may be the consequence of environmental, maternal, or genetic aetiologies that include birth asphyxia, intrauterine infections, teratogen exposure, metabolic disease, chromosomal abnormalities, and single gene disorders. Frequently, associated developmental anomalies or neurological findings assist to make specific diagnoses. However, microcephaly may occur in isolation, and when this is extreme (4 or more standard deviations below the population mean), a diagnosis of primary microcephaly (MCPH) is likely. Surprisingly, despite marked reduction in cerebral cortical volume, such patients have mild/moderate intellectual disability without additional neurological deficits. As an autosomal recessive genetic disorder, this condition has been extensively studied in recent years yielding significant insight into the cellular and regulatory mechanisms governing brain growth. Brain volume is reduced to as little as a third of normal in primary microcephaly. This is accompanied by simplified cortical gyration with an otherwise structurally normal brain on neuroimaging. Over the last 3 million years our brains have seen a three-fold increase in size1 and 100-fold increase in surface area through cortical folding (gyrification).2 Evolutionary parallels have consequently been drawn with the expectation that genes identified may provide insight into human brain evolution. Over the last decade seven genes have been identified:3MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ (CPAP), and STIL. All are expressed in the neuroepithelium during embryonic neurogenesis and localize to the centrosomes and mitotic spindle poles. It is therefore thought that primary microcephaly is a disorder of neurogenic mitosis,4 where impaired proliferation of neural progenitor cells results in reduced numbers of neurons and a smaller brain. By determining the orientation of the mitotic spindle, these centrosomal proteins may influence the mode of stem cell division, augmenting the stem cell pool and consequently, brain size. This could provide an explanation for how neurogenesis has been modified during primate evolution to achieve expansion of the cerebral cortex. Intriguingly, comparative genomic sequencing has detected adaptive sequence changes in some of the MCPH genes.5 This raises the possibility that changes in these genes have directly contributed to increasing brain size, though this conjecture remains to be proven. In the last 2 years, the phenotypes associated with the MCPH genes have been substantially extended. Firstly, exome sequencing has identified mutations in WDR62 in a range of severe brain malformations.6,7 These include phenotypes usually thought of as distinct diagnostic entities, such as pachygyria, lissencephaly, schizencephaly, polymicrogyria, and cerebellar hypoplasia. Furthermore, the association of mutations in WDR62 with asymmetric polymicrogyria, unilateral cerebrellar hypoplasia, or open-lipped schizencephaly, suggests that such lesions should not be automatically attributed to vascular-disruptive aetiologies. Secondly, MCPH genes have also been associated with microcephalic primordial dwarfism, a group of autosomal recessive disorders with global growth failure.8 Here, prenatal growth restriction is followed by a marked reduction in postnatal height as well as brain size. Mutations in both CEP152 and CENPJ have been reported9,10 but why mutations in the same genes should cause localized reduction in brain size or global growth failure remains unclear. Maintaining the centrosomal theme, pericentrin is also an established and major disease gene for microcephalic dwarfism. However, centrosomes are not the whole story; the recent identification of multiple genes encoding components of the DNA replication machinery11–13 and an RNA splicing gene14,15 have demonstrated that at least for microcephalic primordial dwarfism other mechanisms are in play. Lastly, progress been made on the most extreme microcephaly phenotype in which profound intellectual disability is accompanied by brain size a tenth of its normal weight. Mutations in the NDE1 gene have been reported by two groups.16,17 This gene encodes a centrosomal protein involved in neuronal migration, as well as mitotic spindle formation, these functions respectively explaining the observed partial deficiency in cortical lamination and extreme microcephaly with grossly simplified cortical gyral structure (microlissencephaly). As well as affording insight into neurobiology and evolution, the burgeoning list of disease genes will have diagnostic utility. Comprehensive molecular testing should soon be a realistic possibility, informing diagnosis and patient management as well as permitting families to make informed reproductive choices. Though screening these large genes with established sequencing technologies has been cumbersome, the advent of next-generation sequencing technologies in diagnostic laboratories will provide the realistic prospect of efficient and cost-effective testing to assist the clinician in dissecting the heterogeneous entity that is microcephaly.
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Dec 1, 2023
Shiming Song + 9
Open Access