Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum

Saqib Mahmood,Muhammad J Hassan,Wasim Ahmad

doi:10.1186/1750-1172-6-39

Abstract

Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, and STIL) identified from different world populations. Contribution of ASPM and WDR62 gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations in MCPH1, WDR62 and ASPM genes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder.

Highlights

In this article, we have reviewed the clinical and molecular genetics studies of autosomal recessive primary microcephaly (MCPH)
Molecular genetics of autosomal recessive primary microcephaly including a comprehensive appraisal of the seven mapped loci (MCPH1 - MCPH7), their corresponding genes, protein products of the genes, their likely role in normal brain development and the details of the mutations reported in these genes, especially with reference to Pakistan, have been
The results shown by Montgomery et al (2011) [120] have suggested that primate brain size may have at least a partially conserved genetic basis, and have contradicted previous studies that linked adaptive evolution of ASPM to changes in relative cortex size

Summary

Introduction

We have reviewed the clinical and molecular genetics studies of autosomal recessive primary microcephaly (MCPH). A recent study has clinically evaluated patients with ASPM mutations and showed several additional phenotypes They include border-line microcephaly and intelligence quotient (IQ) scores, mild epilepsy, late-onset seizures, simplified gyral pattern, ventricle enlargement, partial corpus callosum agenesis, and mild cerebellar hypoplasia [8]. In case of MCPH2 gene (WDR62) mutations, a broad clinical phenotype in MCPH patients has been observed by three independent research groups [21,26,27]. It includes microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum.

Canadian families and 1 Arab Family

Conclusion

Findings

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