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  Jun ZhangMichael A. WilliamsDaniele Rigamonti Genetics of human hydrocephalus Received: 27 July 2005Received in revised form: 24 March 2006Accepted: 1 April 2006Published online: 13 June 2006 j  Abstract  Human hydrocephalusis a common medical conditionthat is characterized by abnormal-ities in the flow or resorption of cerebrospinalfluid(CSF),resultingin ventricular dilatation. Humanhydrocephalus can be classifiedinto two clinical forms, congenitaland acquired. Hydrocephalus isone of the complex and multifac-torial neurological disorders.A growing body of evidenceindicates that genetic factors play amajor role in the pathogenesis of hydrocephalus. An understandingof the genetic components andmechanism of this complex disor-dermayofferussignificantinsightsinto the molecular etiology of impaired brain development andan accumulation of the cerebro-spinal fluid in cerebral compart-ments during the pathogenesis of hydrocephalus. Genetic studies inanimalmodelshavestartedtoopenthe way for understanding theunderlying pathology of hydro-cephalus. At least 43 mutants/locilinked to hereditaryhydrocephalushave been identified in animalmodels and humans. To date, 9genes associated with hydrocepha-lus have been identified in animalmodels. In contrast, only one suchgene has been identified in hu-mans. Most of the known hydro-cephalus gene products are theimportant cytokines, growth fac-tors or related molecules in thecellular signal pathways duringearly brain development. The cur-rent molecular genetic evidencefrom animal models indicates thatin the early development stage,impaired and abnormal braindevelopment caused by abnormalcellular signaling and functioning,all these cellular and developmen-tal events would eventually lead tothe congenital hydrocephalus.Owing to our very primitiveknowledge of the genetics andmolecular pathogenesis of humanhydrocephalus, it is difficult toevaluate whether data gained fromanimal models can be extrapolatedto humans. Initiation of a largepopulation genetics study in hu-mans will certainly provideinvaluable information about themolecular and cellular etiology and the developmental mecha-nisms of human hydrocephalus.This review summarizes therecent findings on this issueamong human and animal models,especially with reference to themolecular genetics, pathological,physiological and cellular studies,and identifies future researchdirections. j  Key words  hydrocephalus  Æ congenital  Æ  acquired  Æ genetic of   Æ  multifactorial disorder REVIEW J Neurol (2006) 253:1255–1266DOI 10.1007/s00415-006-0245-5   J    O N2  2  4   5   J. Zhang, Sc.D., Ph.D. ( & )  Æ M.A. Williams  Æ  D. RigamontiDept. of Neurosurgery The Johns Hopkins University School of Medicine600 N. Wolfe Street, Phipps 100Baltimore, MD 21287, USATel.: +1-410/955-2259Fax.: +1-410/955-9126E-Mail: jhzhang@jhmi.eduM.A. WilliamsAdult Hydrocephalus ProgramDept. of Neurology The Johns Hopkins University School of MedicineBaltimore, MD 21205, USA  Introduction Human hydrocephalus is a significant medical con-dition with an estimated incidence of 1 in 1500 births[1]. Hydrocephalus is characterized by abnormalitiesin the flow or resorption of cerebrospinal fluid (CSF),resulting in ventricular dilatation. However, hydro-cephalus is far more complicated than a simple dis-order of CSF circulation [2]. Although commonly considered a single disorder, human hydrocephalus isa collection of a heterogeneous complex and multi-factorial disorders [3]. Genetic factors are involved inthe pathogenesis of hydrocephalus [4–6]. For the purposes of this review, we categorize hydrocephalusas congenital, which is present at birth and oftenassociated with developmental defects; and acquired,which occurs after development of the brain andventricles [7–12]. The development and progression of congenitalhydrocephalus is a dynamic process that is not yetwell understood. It is thought that it may develop atan important and specific embryonic time period of neural stem cell proliferation and differentiation inthe brain [13, 14]. Congenital hydrocephalus may  occur alone (non-syndromic) or as part of a syn-drome with other anomalies (syndromic) [15, 16]. In syndromic forms, it is hard to define the defectivegene because of the association with other anomalies.We will mainly focus on isolated forms of hydro-cephalus. In genetic terms, the isolated (non-syndro-mic) form of hydrocephalus is a primary and majorphenotype caused by a specific faulty gene.It is estimated that about 40% of hydrocephaluscases have a possible genetic etiology [10]. In humans,X-linked hydrocephalus (HSAS1, OMIM) comprisesapproximately 5–15% of the congenital cases with agenetic cause [10, 17–20]. Although there is strong evidence for genetic causes, only one hydrocephalusgene (X-linked) has been identified in humans.Besidesgeneticfactors,manyotherfactorsinfluencethe development of congenital hydrocephalus, such ascongenital malformations, intracerebral hemorrhage,maternal alcohol use [21, 22], infection [6, 23–25], and X-ray radiation during pregnancy [26, 27]. Genetics in hydrocephalus Congenital hydrocephalus is the more common of thetwo forms of hydrocephalus, and is probably theconsequence of abnormal brain development andperturbed cellular function, which emphasizes theimportant roles that congenital hydrocephalus genesplay during brain development. In general, therecurrence risk for congenital hydrocephalusexcluding X-linked hydrocephalus is low. Empiric riskrates range from <1% to 4% [28–30], indicating the rarity of autosomal recessive congenital hydrocepha-lus [10, 20, 31, 32]. However, multiple human kin- dreds with congenital hydrocephalus have beenreported [10, 15, 20, 32–43]. The loci or genes for human autosomal recessive congenital hydrocephalushave not yet been identified, but there is at least onelocus for this trait. Furthermore, like animal models,since there is heterogeneity among clinical pheno-types, there may be more genetic loci in humanautosomal recessive congenital hydrocephalus.One kindred was reported in which congenitalhydrocephalus was transmitted in an autosomaldominant fashion. This condition was associatedwith aqueductal stenosis but was not associatedwith mental retardation or pyramidal tract dys-function. The lack of mental retardation and pyra-midal tract dysfunction was in contrast to X-linkedor recessive congenital hydrocephalus with stenosisof the aqueduct of Sylvius (HSAS), in which theseabnormalities are commonly seen [44]. Anotherstudy identified a kindred with a microdeletion of 8q12.2-q21.2 which subsequently developed hydro-cephalus. This trait was also transmitted in anautosomal dominant fashion [45]. Molecular geneticstudies have revealed that the responsible gene forX-linked human congenital hydrocephalus is atXq28 encoding for  L1CAM   (L1 protein) [46]. Themutations are distributed over the functional pro-tein domains. The exact mechanisms by which thesemutations cause a loss of L1 protein function arestill under investigation.Another form of this disorder, acquired or adult-onset hydrocephalus is mostly sporadic and charac-terized by ventricular enlargement in the absence of significant elevations of intracranial pressure; there-fore this form is termed normal pressure hydro-cephalus (NPH). Definite changes in CSF flow,resorption, and associated dynamics have been foundin NPH patients, and these changes may represent apathogenic mechanism or a secondary phenomenon[47]. Adult-onset hydrocephalus may develop eitheras a result of decompensation of a ‘‘compensated’’congenital hydrocephalus, or it may arise de novo inadult life secondary to an acquired disturbance of normal CSF dynamics. The latter may be due to late-onset aqueductal stenosis or disruption of normalCSF absorptive pathways [11, 48]. Acquired (adult- onset, or NPH) form of inherited hydrocephalus isvery rare. Recently, an X-linked adult-onset NPH [49]and a form of familial NPH that is transmitted inautosomal dominant fashion [50] have been reported,but detailed genetic linkage studies have not beencarried out yet. The genetic etiology of this form istherefore totally unknown. 1256  Hydrocephalus has been observed in many mam-mals [51–59]. Animal hydrocephalus models have many histopathological similarities to humans andcan be used to understand the genetics and patho-genesis of brain damage [59–64]. It has been well documented in the animal models that in the majority of cases, congenital hydrocephalus is a genetic dis-ease. Furthermore, many congenital hydrocephalusloci have been mapped and identified in the animalmodels.Hydrocephalic Texas strain (HTX) rat model of inherited congenital hydrocephalus is characterizedby onset in late gestation, a complex mode of inher-itance, and ventricular dilatation associated withabnormalities in the cerebral aqueduct and subcom-missural organ (SCO), a structure that is importantfor the patency of the aqueduct of Sylvius and normalCSF flow in the brain. Quantitative trait locus (QTL)genetic mapping has been performed from the prog-eny of a backcross of HTX rat with the non-hydro-cephalic Fischer F344 strain. The disease has beenlinked with loci on chromosome (Chr) 9 (peakmarkers D9Rat2), 10 (between markers D10Rat136and D10Rat135), 11 (peak markers D11Arb2 andD11Rat46) and 17 (peak markers D17mit4 andD17Rat154) respectively. The severity of hydroceph-alus in HTX rat seems to be influenced by differentgenetic loci [65–68]. Another study suggested that the HTX strain is homozygous carrier of an autosomalrecessive hydrocephalus gene with incomplete pene-trance [69]. The genetics of another hydrocephalusinbred strain, Wistar-Lewis rats (LEW/Jms) whichdemonstrate inherited congenital hydrocephalus, isless clear with possible traits as an autosomal reces-sive [70] or semidominant or multigenic (possibleQTL) with a possible locus on sex chromosomes [71],but none of the loci has been localized.In mouse models, three QTL loci associated withcongenital hydrocephalus have been identified andlabeled as Vent8a, Vent4b, and Vent7c. As a majorQTL controlling variance in ventricular size, Vent8a islocated on Chr 8 (near the markers D8Mit94 andD8Mit189). The Other two loci, Vent4b and Vent7c,show strong epistatic interactions affecting ventricu-lar size in the developing embryo. Vent4b is locatedon Chr 4 (near D4Mit237 and D4Mit214), and Vent7cis located on Chr 7 (between D7Mit178 andD7Mit191) [72].The autosomal recessive congenital hydrocepha-lus-1 (hy1) mouse has been characterized phenotyp-ically by a dome-shaped head that is sometimes seenat birth or develops during the first 2 weeks. Inter-nally, dilatation of the entire ventricular system isobserved [73,74]. A more severe phenotypic form, hydrocephalus-2 (hy2) mouse [75, 76], and an obstructive hydrocephalus (oh) mouse with commu-nicating hydrocephalus and secondary aqueductalstenosis have also been described [77, 78]. Unfortu- nately subsequent efforts to identify genetic loci havenot been done on these non-inbred mouse strains.In mouse targeted insertional mutagenesis, theaccidental insertion of a transgene into a crucialgenomic locus could yield important information,which has happened twice in hydrocephalus geneticstudies. The transgenic mouse line OVE459 demon-strates autosomal recessive congenital hydrocephalus.This is caused by a Bdnf transgene-induced insertionalmutation on a single locus on mouse Chromosome 8(near marker D8Mit152). The OVE459 insertion locusis overlapped with that of autosomal recessivehydrocephalus-3 (hy3) mouse that phenotypically shows lethal communicating hydrocephalus withperinatal onset [79, 80]. The transgene insertion re- sulted as a rearrangement of Hydin exons in OVE459mice. Subsequently, a single CG base-pair deletion inexon 15 of Hydin was also discovered in hy3 micecarrying the spontaneous hy3 mutant allele [81, 82]. In another targeted insertional mutagenesisresulting in congenital hydrocephalus, the CYP2J2transgene interferes with the expression of a brain-specific isoform of the regulatory factor X4 (RFX4),which belongs to the winged helix transcription factorfamily. This brain specific isoform is called varianttranscript 3 or RFX4_v3 and is crucial for normalbrain development as well as for the genesis of theSCO. Loss of a single allele prevents formation of theSCO and leads to an autosomal dominant congenitalhydrocephalus. This obstructive hydrocephalus ap-peared to be secondary to failure of development of the SCO [83].The autosomal recessive congenital hydrocephalus(ch) mouse was reported decades ago [79]. Recently this mouse has been shown to have a mutation onanother winged helix/forkhead transcription factorgene, Foxc1 (Mf1) on mouse Chromosome 13 [84, 85]. There is a recent report of 6 children with hydro-cephalus from 3 different families with subtelomericdeletions from chromosome 6p. Three forkhead geneswithin this region (FOXF1 and FOXQ1) or proximalto it (FOXC1) were evaluated as potential candidatedisease genes but no disease causing mutations wereidentified [86].The autosomal recessive hydrocephalus with hopgait (hyh) mouse exhibits dramatic dilation of theventricles at birth and invariably develops hoppinggait. The hyh mouse shows a markedly small cerebralcortex at birth and dies postnatally from progressiveenlargement of the ventricular system. The smallcortex in hyh mouse reflects altered development of the neuronal cells. In this mouse, it is postulated thatneural progenitor cells withdraw prematurely fromthe cell cycle, producing more early-born, deep-layer 1257  cerebral cortical neurons but depleting the corticalprogenitor pool, and creating a small cortex. Geneticlinkage analysis localized the hyh locus betweenmarkers D7Mit75 and D7Mit56 on mouse Chr 7. La-ter, the hyh gene was identified as  a -SNAP (solubleNSF attachment protein  a ) [87]. Homozygous mutantmice harbor a missense mutation M105I in a con-served residue in one of the  a -helical domains. Thehyh mutant was not a null allele and is expressed;however, the mutant protein is 40% less abundant inhyh mice.The autosomal recessive hemorrhagic hydroceph-alus (hhy) homozygous mutant mouse has dilatedlateral ventricles and a patent aqueduct, with no his-tological abnormalities either in the subarachnoidspace or in the choroid plexus. Multiple hemorrhagesin the meninges and throughout the brain paren-chyma can be observed in the advanced stages of hydrocephalus. The hhy locus has been localized onmouse Chr 12 [88].Recently, several new congenital hydrocephalusmodels have emerged in zebra fish mutagenesisscreening. These models have been shown to have thedefects in embryogenesis and early developmentleading to enlarged brain ventricles. However, geneticloci for these models have not been identified yet [89,90].Genetic studies in animal models have started toopen the way for understanding the underlyingpathology of hydrocephalus. In contrast to researchwith animal models, human hydrocephalus geneticresearch has lagged far behind. To date, at least 43mutants of hydrocephalus have been described, and10 congenital hydrocephalus genes have been identi-fied. Among them, only one hydrocephalus gene hasbeen identified in humans (see Table 1). Developmental, physiological and anatomicalpathology of hydrocephalus The neuropathology of hydrocephalus has been ade-quately elucidated. Cerebral ventricle dilatation sec-ondary to disturbed CSF flow has been observed as aninheritable trait in a variety of laboratory animals (aswell as in humans). In most cases, defective devel-opment of the cerebral aqueduct or the subarachnoidspace has been observed [61]. Affected individualsmay have severe developmental delay and radio-graphic findings of hydrocephalus [91].The morphological and developmental changesin the ventricular system have been well studied inthree major rat models of congenital hydrocephalus:6-aminonicotinamide (6-AN)-induced, LEW/Jms andHTX mutant rats. Comparative morphological stud-ies revealed that 6-AN-induced hydrocephalus wascomparable to the Dandy-Walker syndrome. TheLEW/Jms and HTX mutant models were identicalwith regard to the form of presentation and pro-gression of hydrocephalus in the postnatal period;but the pathogenesis of these two conditions in thefetal period was different. The LEW/Jms rats showedprimary congenital aqueductal stenosis in early prenatal life and the hydrocephalic state appearedbefore pulmonary maturation was completed. How-ever, although the model has been considered to beof congenital communicating hydrocephalus [64],the HTX fetuses demonstrated secondary closure of the aqueduct in the perinatal period. This secondary closure of the aqueduct in HTX rats is believed to bedue to retrograde degeneration of the thalamuscaused by apoptotic cell death [92, 93] and failure in cell proliferation [94, 95]. The HTX rat also shows a reduction in the secretory cells of the SCO.Regarding the role of the SCO in hydrocephaluspathogenesis, serial brain sections through aqueductregions containing the SCO from HTX rats, incomparison with normal Fischer F344 strain, havebeen studied and found that reduced SCO glyco-protein immunoreactivity precedes both aqueductclosure and expansion of the lateral ventricles in theHTX rate (as it’s redundant) [96, 97]. Although some studies have addressed the activa-tion of macrophages and microglia (the residentmononuclear phagocytes of the brain) within thebrain in animal hydrocephalus models, little is knownof their state of activation or regional distribution inhuman congenital hydrocephalus. In one experiment,brain tissue samples of 10 human fetal cases withhydrocephalus and 10 non-hydrocephalic controlswere stained immunohistochemically with antibodiesdirected against MHC class II and CD68 antigens, andlectin histochemistry was done with tomato lectin.Hydrocephalus cases showed focal collections of CD68 and tomato lectin-positive macrophages alongthe ependymal lining of the lateral ventricles, partic-ularly within the occipital horn. By comparison, braintissue samples from controls showed few or noependymal or supraependymal macrophages and thefew macrophages that were present were not as in-tensely immunoreactive as in the hydrocephaluscases. The macrophage response detected at theependymal lining of the ventricles and within theperiventricular area in hydrocephalus may be relatedboth to the severity of hydrocephalus and the age of the fetus [98]. Microglia that are normally inter-spersed throughout the intermediate zone and cir-cumscribing the basal ganglia were within normalconfines in all cases examined. Unexpectedly, hydro-cephalic cases also showed focal regions of hypovas-cularization or alterations in the structure and 1258
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