Large Phenotypic Variation of Individuals from a Family with a Novel ASPM Mutation Associated with Microcephaly, Epilepsy, and Behavioral and Cognitive Deficits.

Randi Von Wrede,Rainer Surges,Gábor Zsurka,Anja Ivo,Theodor Rüber,Tobias Baumgartner,Christoph Helmstaedter,Wolfram S Kunz,Martin Schidlowski,Kerstin Hallmann,Hans-Jürgen Huppertz

doi:10.3390/genes13030429

Abstract

Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations.

Highlights

Disabled patients suffering from epilepsy, and especially from drug-resistant epilepsy, need an exact and widespread work up, including genetic testing, as clear diagnosis helps the patients and their caregivers to understand and accept the diagnosis.it helps the treating clinician to find appropriate treatment regimens as well as prevents initiation of useless treatments [1,2].Microcephaly, primary hereditary (MCPH), is a rare neurodevelopmental disorder characterized by microcephaly and intellectual disability [3] in absence of other congenital abnormalities [3,4]
Three scales were used for assessing severity of disability: the Global Assessment of Severity of Epilepsy Scale (GASE) [10], the SINGER scale [11] and the modified Rankin scale [12]. mRS is a single-item, seven-point ordinal scale for clinicians ranging from zero to six
The authors propose an evolutionary mechanism by which ASPM regulates cortical expansion during evolution by controlling the affinity of ventricular radial glial cells for the ventricular surface, modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor

Summary

Introduction

Disabled patients suffering from epilepsy, and especially from drug-resistant epilepsy, need an exact and widespread work up, including genetic testing, as clear diagnosis helps the patients and their caregivers to understand and accept the diagnosis. Primary hereditary (MCPH), is a rare neurodevelopmental disorder characterized by microcephaly and intellectual disability [3] in absence of other congenital abnormalities [3,4]. ASPM (abnormal spindle-like microcephaly-associated) gene mutations (almost exclusively nonsense, frame-shift or splice site mutations) are the most frequent underlying genetic cause for autosomal recessive MCPH [3]. The ASPM gene maps at the locus 1q31.3.; it consists of 28 exons and encodes a protein that consists of 3477 amino acids. Seizures are found in up to 15% of ASPM-MCPH patients [6,7] and should lead to a diligent MRI work up

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Discussion

Conclusion