X-linked hydrocephalus: Clinical heterogeneity at a single gene locus

Abstract

X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence (H-SAS, MIM number 30007) is a rare genetic disorder characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, agenesis of corpus callosum and mental retardation. We confirm here the localisation of the mutant gene on Xq (Xq 2.8) by linkage analysis in a 5-generation pedigree (maximum lod score of Z = 4.57 at theta = 0.04 with probe St14 at locus DXS52) and emphasise the phenotypic variability of the disease. Ventricular dilatation in affected males was either severe and diagnosed antenatally or moderate and consistent with a long survival with little or no macrocephaly. Since other X-linked syndromes of mental retardation with spasticity and flexion deformities of the thumbs have previously been shown to map to the Xq 2.8 region as well (e.g. MASA syndrome and spastic paraplegia), the present results raise the question of whether H-SAS syndrome, MASA syndrome and spastic paraplegia with mental retardation might represent different phenotypic expression of various mutations at the same locus.

Spectrum of X‐linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): Clinical review with six additional families

“…In young or even prepubertal boys, spastic paraplegia i?, not reported in general. Edwards, 1961;Visekul et al, 1975;Willems et al, 1987;Kelley et al, 1988;Serville et al, 1992. of patients, spastic paraplegia andlor adducted thumbs are absent, indicating that the condition can present as nonspecific X-linked mental retardation (XLMR). In this respect, the families reported by Gedeon et al [19911 and by Nordstrom et al [1992] are of possible importance.…”

“…In families with HSAS, inter-and intrafamilial clinical variability is well-known [Edwards, 1961;Fried, 1972;Willems et al, 1987;Serville et al, 19921. Linkage analysis in HSAS families placed the locus a t Xq28 as well [Willems et al, 1990[Willems et al, , 1992Serville et al, 1992;Lyonnet et al, 1992;Jouet et al, 1993al. Some years ago, reports appeared of 2 families in which males had both MASA syndrome and HSAS; DNA linkage analysis in these families also placed the locus a t Xq28, leading to the hypothesis that MASA syndrome and X-linked hydrocephalus, due to stenosis of the aqueduct of Sylvius (HSAS), may be variable expressions of the same gene a t Xq28 [Schrander-Stumpel et al, 1990;Fryns et al, 19911. A further family, reported as a MASA syndrome family, supported this observation [Kaepernick et al, 19941.…”

Refining the genetic location of the gene for X linked hydrocephalus within Xq28.

“…A lod score of 4X26 with polymorphic marker DXS52 (Stl4) confirms the linkage of HSAS to Xq28. Identification of a recombination event between the HSAS gene and Xq28 loci F8C and DXS605 (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) reduces the size of the interval likely to contain the disease locus to about 1-5 megabases, the distance between DXS605 and DXS52. The locus for neural cell adhesion molecule, LICAM, maps within this interval and therefore represents a candidate gene for HSAS.…”

Impaired neural differentiation and glymphatic CSF flow in the Ccdc39 rat model of neonatal hydrocephalus: genetic interaction with L1cam

“…Furthermore, CRISPR/Cas9 offers the opportunity to test genetic modifiers and possible genetic interactions that determine disease severity in congenital hydrocephalus. For instance, X-linked hydrocephalus (XLH), which can result from mutations in the L1 cell adhesion molecule ( L1cam ) gene in mice (Dahme et al, 1997; Demyanenko et al, 1999), rats (Emmert et al, 2019) and humans (Adle-Biassette et al, 2013; Dahme et al, 1997; Rosenthal et al, 1992), varies in severity from hydrocephalus with multiple structural abnormalities and prenatal death to a milder phenotype with cognitive impairment or isolated symptoms even within the same family (Fryns et al, 1991; Serville et al, 1992). CRISPR/Cas9-generated rodent models of congenital hydrocephalus resulting from mutations in different hydrocephalus-related genes, such as L1cam and Ccdc39 , can be interbred to investigate epistatic interactions previously believed to affect mutation penetrance and ventricular size in other models of hydrocephalus (Weller and Gärtner, 2001; Zhang et al, 2006).…”