Hydrocephalus due to multiple ependymal malformations is caused by mutations in the MPDZ gene

Pascale Saugier-Veber,Thierry Frébourg,François Lecoquierre,Sophie Patrier,Annie Laquerrière,Alice Goldenberg,Homa Adle-Biassette,Yline Capri,Marion Gérard,Marie Brasseur-Daudruy,Florent Marguet,Fabien Guimiot,Valérie Layet,Sara Cipriani

doi:10.1186/s40478-017-0438-4

Abstract

Congenital hydrocephalus is considered as either acquired due to haemorrhage, infection or neoplasia or as of developmental nature and is divided into two subgroups, communicating and obstructive. Congenital hydrocephalus is either syndromic or non-syndromic, and in the latter no cause is found in more than half of the patients. In patients with isolated hydrocephalus, L1CAM mutations represent the most common aetiology. More recently, a founder mutation has also been reported in the MPDZ gene in foetuses presenting massive hydrocephalus, but the neuropathology remains unknown. We describe here three novel homozygous null mutations in the MPDZ gene in foetuses whose post-mortem examination has revealed a homogeneous phenotype characterized by multiple ependymal malformations along the aqueduct of Sylvius, the third and fourth ventricles as well as the central canal of the medulla, consisting in multifocal rosettes with immature cell accumulation in the vicinity of ependymal lining early detached from the ventricular zone. MPDZ also named MUPP1 is an essential component of tight junctions which are expressed from early brain development in the choroid plexuses and ependyma. Alterations in the formation of tight junctions within the ependyma very likely account for the lesions observed and highlight for the first time that primary multifocal ependymal malformations of the ventricular system is genetically determined in humans. Therefore, MPDZ sequencing should be performed when neuropathological examination reveals multifocal ependymal rosette formation within the aqueduct of Sylvius, of the third and fourth ventricles and of the central canal of the medulla.

Highlights

Hydrocephalus which literally means any increase in cerebrospinal fluid (CSF) within the skull has been more precisely defined by the International Hydrocephalus Working Group which describes “an active distension of the ventricular system resulting from inadequate passage of cerebrospinal fluid from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation” [24]
L1CAM pathogenic variants are responsible for a wide spectrum of phenotypes, termed L1, the most severe form being Hydrocephalus with Stenosis of the Aqueduct of Sylvius (HSAS; MIM#307000)
We reviewed the neuropathology of 138 cases genetically tested for X- linked hydrocephalus [1] that allowed us to classify patients who did not display any pathogenic variant in the L1CAM gene into four distinct subgroups

Summary

Introduction

Hydrocephalus which literally means any increase in cerebrospinal fluid (CSF) within the skull has been more precisely defined by the International Hydrocephalus Working Group which describes “an active distension of the ventricular system resulting from inadequate passage of cerebrospinal fluid from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation” [24]. The distinction between them is most of the time difficult, since additional anomalies may be present in apparently non-syndromic forms. No specific cause is found in more than half of the patients they present a syndromic form in 11% of the cases, with only 0.6% of their whole infantile series having an identifiable genetic syndrome [24]. In individuals with apparently isolated hydrocephalus or with no major additional clinical findings, L1CAM mutations represent the most common genetic form with a prevalence of approximately 1:30,000 and account for about 5–10% of males with non-syndromic congenital hydrocephalus [19]. L1CAM pathogenic variants are responsible for a wide spectrum of phenotypes, termed L1, the most severe form being Hydrocephalus with Stenosis of the Aqueduct of Sylvius (HSAS; MIM#307000). In 2013, a founder mutation in this gene was identified in two consanguineous Saudi families in whom the foetuses presented ultrasonographically massive bilateral hydrocephalus [2], but no post-mortem examination could be obtained, so that the underlying mechanism of hydrocephalus remained unknown

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