med syndrome ofthe month - journal of medical genetics · kenwnick,jrouet, donnai nerves, b and t...

Syndrome of the month

X linked hydrocephalus and MASA syndrome

Sue Kenwrick, Monique Jouet, Dian Donnai

AbstractX linked hydrocephalus and MASA syn-drome are clinically related, neurologicaldisorders with an X linked recessive modeof inheritance. Although originally de-scribed as distinct entities, their similarityhas become apparent as the number ofreported families has increased and a highdegree ofintra- and interfamilial variationin clinical signs noted for both disorders.Consideration of this clinical overlap to-gether with finding that genes for bothdiseases map to the same chromosomalband (Xq28) led to the hypothesis that theywere caused by mutation at the same locus.This was confirmed by identification ofmutations in patients with X linked hydro-cephalus and MASA syndrome within thegene for neural cell adhesion molecule Li.Here we review the clinical and geneticcharacteristics of these disorders and theunderlying molecular defects in the LIgene.(JrMed Genet 1996;33:59-65)

Key words: hydrocephalus; X linked; MASA syndrome.

University ofCambridgeDepartment ofMedicine, Level 5,Addenbrooke'sHospital, Hills Road,Cambridge CB2 2QQ,UKS KenwrickM Jouet

Department ofClinical Genetics,St Mary's Hospital,Whitworth Park,Manchester M13 OJH,UKD Donnai

Correspondence to:Dr Kenwrick.

X linked hydrocephalusHISTORYX linked recessive hydrocephalus is the mostcommon form of hereditary hydrocephalus(McKusick No 30700), with an incidence ofapproximately 1 in 30 000, and accounting forbetween 2% and 15% of primary idiopathichydrocephalus in newborn males.12 It was firstdescribed in detail in a single large family byBickers and Adams in 19493 and rediscoveredas a sex linked syndrome by Edwards in 1961.14Since then, over 35 families have been reportedand the existence of an X linked recessive formof hydrocephalus is well established.5-'5

CLINICAL FEATURESX linked hydrocephalus is associated with a

wide variation in severity and spectrum of clin-ical signs and symptoms both within and be-tween families. Onset of hydrocephalus oftenoccurs in utero although its appearance may betoo late for detection during routine ultrasoundscanning even at 20 weeks' gestation.10131416Accumulation of cerebrospinal fluid (CSF) isassociated mainly with the lateral and thirdcerebral ventricles and often results in stillbirth

or early mortality. The degree and progressionof hydrocephalus in these families is highlyvariable with some males not presenting withsymptoms of increased intracranial pressureor macrocephaly despite enlargement ofventricles.2 1017 In general, prominent vent-ricular dilatation and progressive hydro-cephalus is associated with early mortality,whereas mild enlargement and arrest is con-sistent with long survival.

Valve insertion is an effective treatment forrelieving high pressure hydrocephalus and im-proving life expectancy; however, survivors arealways late in meeting their developmentalmilestones. They are mentally retarded withhighly variable IQs ranging from "too low totest" to over 701820 and exhibit variable degreesof spasticity with increased tone and hy-perreflexia, particularly in the lower limbs. Re-flexes and tone may be normal in the arms inthe presence of marked lower limb spasticity.1These observations contrast with those de-scribed for non-X linked hydrocephalus wherethe majority of surviving cases have normalintelligence and little motor impairment.2

Flexion-adduction deformities ofthe thumbs(clasped or adducted thumbs) are frequentlybut not always observed (Halliday et al? re-ported clasped thumbs in 44% of cases) andmay be associated with agenesis or hypoplasiaof the abductor or extensor muscles of thethumb.2122 The existence of affected subjectswithout obviously abnormal thumbs, and thepresence of this feature in other syndromes2324means that this cannot be relied upon as adiagnostic sign.A wide variety of brain malformations has

been reported in association with X linkedhydrocephalus including agenesis of the corpuscallosum or septum pellucidum, fusion of thethalamic fornices, colliculi and corpora quad-rigemina, and absence or hypoplasia of thecorticospinal tract (CST), as assessed by histo-logical analysis ofthe pyramids in cross sectionsof the medulla.4825-28 The latter observationprovides an explanation for the observed spas-ticity in this disease as increased tone withhyperreflexia are characteristic signs of CSTdamage. The value of bilateral absence of pyr-amids (BAOP) as an indicator of X linkedhydrocephalus was investigated by Chow25 andHalliday et al.2 They determined that an as-sociation exists between BAOP and X linkedhydrocephalus although the sample size wassmall. Nine out of nine patients with clear or

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"probable" (by clinical criteria) X linked dis-ease were found to have absent pyramidswhereas six out of six control male cases ofcongenital hydrocephalus were not. BAOP'isnot restricted to cases of X linked hydro-cephalus and can be found in other congenitalconditions, such as holoprosencephaly andhydranencephaly. Nevertheless, the un-common nature of BAOP means that it de-serves special attention when assessing isolatedcases ofhydrocephalus for the possibility of thehereditary disorder.

Stenosis of the aqueduct of Sylvius was ori-ginally thought to be the primary cause ofhydrocephalus as it was observed in several ofthe first patients characterised in detail.34 Theacronym HSAS (for hydrocephalus owing tostenosis of the aqueduct of Sylvius) was there-fore adopted. Although the aqueduct has beenfound to be patent in several subsequent ex-amples,5 1422 accurate measurements have rarelybeen obtained. Although a degree ofaqueductalstenosis may well contribute to X linked hydro-cephalus it cannot be considered diagnostic forthe hereditary condition as it is found in up to40% of patients with hydrocephalus.7A variety of ocular, musculoskeletal, and

neurological abnormalities have also beenreported in cases of X linked hydrocephalusincluding nystagmus, ptosis, optic atrophy, sco-liosis, torticollis, lumbar lordosis, and seizures.There are no consistent distinguishingfacial characteristics although prominent earshave been reported.' 18

Thus, X linked hydrocephalus is associatedwith an extremely wide variation in severityand clinical signs. Overall the most consistentfeatures are hydrocephalus, mental retardation,and lower limb spasticity consistent with uppermotor neurone damage (fig 1).

MASA syndromeHISTORYThe term MASA syndrome (McKusick303350), an acronym for Mental retardation,Aphasia, Shuffling gait, and Adducted thumbs,was coined by Bianchine and Lewis30 in 1974to describe the tetrad ofX linked clinical signsobserved in a single large Mexican family. Sincethen several reports have detailed similar famil-ies, although they have been described variouslyas spastic paraplegia type I (SPG1, McKusick312900) or clasped thumb-mental retardationsyndrome, as well as MASA syndrome. Againthere is a high degree of inter- and intrafamilialvariation in clinical presentation.3040

CLINICAL FEATURESThe clinical profiles described for MASA syn-drome patients clearly overlap with those ob-served for X linked hydrocephalus, althoughthe lack of congenital high pressure hydro-cephalus results in a longer life expectancy.Mental retardation, lower limb spasticity, andhyperreflexia are observed in all cases althoughthe degree of impairment can be mild. Flexion-adduction deformities of the thumbs are foundin most, but not all cases and there is a general

deficit in development of expressive relative toreceptive language. Additional clinical signsinclude optic atrophy, lordosis, scoliosis, tor-ticollis, cleft palate, seizures, inguinal hernia,and urinary tract abnormalities. AlthoughMASA is not defined as including hydro-cephalus, imaging in a limited number ofpatients has shown enlargement of cerebralventricles638 and a variety of other brain mal-formations including agenesis of the corpuscallosum.The early suspicion that X linked hydro-

cephalus and MASA syndrome are caused bythe same X linked locus3839 was reinforced bythe observation that both are the result ofgenesin the same subchromosomal band (see below)and reports of single families with both MASAand cotigenital hydrocephalus cases.38"4

GeneticsX linked hydrocephalus and MASA syndromebehave as classical X linked recessive disorderswith very few carrier females showing signs ofdisease. Preferential inactivation of one X inlymphocytes has been shown in manifestingcarriers of one family suggesting that non-ran-dom X inactivation is responsible for thephenotype in females.34The search for a single gene responsible for

X linked hydrocephalus and MASA syndromebegan in earnest when genetic linkage analysisprovided evidence for loci for both syndromesin subchromosomal band Xq28 with little in-dication of genetic heterogeneity.3 35-37 39 42 Fur-ther pedigree analysis allowed refinement ofthe relevant interval to approximately 1 5 me-gabases ofgenomic DNAbetween polymorphicmarkers DXS52 and DXS605,71"538 a regioncontaining the gene for neural cell adhesionmolecule LI.4 Assessment of this gene in Xlinked hydrocephalus and MASA syndromefamilies provided the final proof that the twodisorders are indeed caused by mutation at asingle locus in Xq28.

Neural cell adhesion molecule LINeural cell adhesion molecule Li is a multi-domain, highly conserved cell surface glyco-protein expressed primarily on the axons ofdeveloping neurones. It is a member of theimmunoglobulin superfamily consisting of sixdomains with core structural motifs similar tothose found in immunoglobulins (Ig type C2),five domains similar to type III repeats foundin the extracellular matrix protein fibronectin(Fn type III), a short transmembrane region,and a cytoplasmic region. Results of in vitroassays and antibody perturbation experimentsindicate that Li is involved in neuronalmigration and neurite (for example, axon)extension as well as fasciculation.44-46 Duringdevelopment Li is located on subsets of mi-grating neurones, at the surface of long axons,and on growth cones and it continues to beexpressed in the adult nervous system on un-myelinated axons. Although mainly neuronal,expression at other sites suggests that it mayalso play a part in myelination of peripheral

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Figure 1 Examples of clinical signs in patients with X linked hydrocephalus or MASA syndrome. For all subjectsmutations within the Ll gene have been detected. (A) Axial CT scan of a neonate from an X linked hydrocephalusfamily showing gross lateral and third ventricle dilatation and extreme thinning of the cortical mantle. Appearances arecompatible with aqueductal stenosis. (B) An infant with X linked hydrocephalus: note the enlarged head and claspedthumbs. (C) A view of an adducted right thumb in the infant shown in (B). (D) Spastic lower limbs in a subjectdescribed as having AISA syndrome.

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nerves, B and T lymphocyte function, andmigration of intestinal crypt cells.47"9Li can interact at the cell surface with a

number of different glycoproteins, includingother members of the immunoglobulin super-family, and proteoglycans either on the surfaceof cells or in the extracellular environment.Homophilic binding is probably its principlemode of interaction,50 although LI (or closerelatives in other species) has also been shownto undergo heterophilic interactions.5-56 Thisvariety of binding partners suggests that LImay have different functions at different timesand locations during development.

In order to promote neuronal migration oraxon extension, binding of LI at the neuronalsurface must initiate downstream events thatresult in a reorganisation of the cytoskeleton.Experiments in vitro have begun to unravelsome of the signalling events that may be in-volved. For example, Li homophilic bindinginduces changes in intracellular levels ofsecondmessengers, such as inositol phosphates andCa2 +, and affects phosphorylation of tu-bulin.5760 Furthermore, Li promotion of neur-ite outgrowth in vitro may involve cis-interaction ofLi with members ofthe fibroblastgrowth factor receptor family which initiate asecond messenger cascade via their cytoplasmictyrosine kinase domains.6' Li may also directlyinteract with the cytoskeleton via binding of itscytoplasmic domain to ankyrin.6" The relevanceof these interactions to LI function in vivo, thepurpose of different Li ligands, and the roleof individual domains of the protein have yetto be determined. In view of the role of Li inthe morphogenesis of the nervous system andthe common occurrence of brain malformationin patients with X linked hydrocephalus orMASA syndrome, the Li gene was considereda prime candidate for the locus involved inthese disorders.

Mutation analysisDetection of mutations in families sufferingfrom MASA syndrome as well as X linkedhydrocephalus confirmed that these disorders(including SPG1 and clasped thumb-mentalretardation) are allelic and caused by hetero-geneous mutations within the LI locus.89 63-70The 143 kDa human Li protein is encoded

by an open reading frame of 3771 bp containedwithin a 4-5 kb messenger RNA.7172 Low levelexpression of this transcript in B cell linesenabled complete sequencing of LI cDNAfrom patients resulting in the first evidence thatLi corresponds to the X linked hydrocephaluslocus.6667 More flexibility in the approach tomutation searching has been provided by res-olution of the genomic structure of the Li geneand determination of sequences at intron-exonboundaries (A Rosenthal, EMBL databaseHSNCAMX). The gene consists of 28 exonsdistributed across 15 kb of genomic DNA andconditions have been established for amp-lification of each exon.'To date, 25 different Li mutations have been

reported in as many families and these are

represented in fig 2. Virtually every form ofmutation has been found with the notable ex-ception of whole gene deletion. Missense mut-ations are the most common, representing overhalf of those reported (14), although splicing(5), frameshift (2), nonsense (2), deletion (1),and duplication (1) events have been described.Mutations are distributed across the Li geneaffecting many different domains ofthe protein.Although this wide variation in position andtype of mutation may in part explain the wideclinical spectrum observed for these disorders,intrafamilial variation coupled with a lack ofclustering of mutations confounds strict geno-type/phenotype correlations.Three mutations have been described (H23,

H44, H24) that would truncate Li before thetransmembrane domain, eliminating the po-tential for cell surface expression ofthe protein.As no Li isoforms have been described withouta transmembrane domain, subjects bearingthese mutations presumably lack Li functioncompletely. Predictably, these mutations areassociated with severe congenital hydro-cephalus and early mortality.89 By contrast,three mutations (H29, H 13, MASA3) thattruncate the protein in the cytoplasmic domain,allowing cell surface presentation, were foundin families described as having MASA syn-drome.To date, five mutations described affect pro-

cessing of Li hnRNA. In all of these casesproduction of normal as well as aberrantlyspliced mRNA is apparent from studies oncDNA from B cell lines. If these results canbe extrapolated to the nervous system, theyindicate that Li splicing mutations act in adominant negative fashion at the cellular level,although they appear recessive in heterozygousfemales.As little is known about the roles ofindividual

domains of LI, it is not possible to predict theoutcome of specific mutations on Li functionand neural development. The distribution ofmutations across many domains, however, sug-gests that they may affect interaction with avariety of different ligands (for the extracellulardomain), signal transduction, as well as in-teractions with cytoskeletal proteins (in-tracellular domain). Some insight into thepotential effects of mutations on Li proteincan be gained from interspecies sequence com-parisons and protein modelling. For example,several of the missense mutations described todate affect residues that are highly conservedbetween like domains within Li as well asbetween Ll-like proteins in different species(for example, C264Y, G121S, R184Q, andG452R). That these mutations are likely toaffect the structural integrity of individual do-mains is borne out by comparison with modelsof immunoglobulin domains related to thosepresent in LI7" (C Chothia, personal com-munication). Those affecting less conservedresidues (for example, D598N, H210Q, andE309K) are more likely to affect ligand re-cognition or quatemary folding of the matureprotein (for a comparison of residues affectedby missense mutations see ref 8).

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Ig type C2 Fn type ll TM

NH2 - COOH

W9S(H3) G452R(H6) V768F(H5) S 14L(M SA~l)G121 S(H7) G370R(F2) FD598N(MASA5) Y17O7C(H1)

1179S(F1) |E309K(H38) P941L(H39) 0

R184Q(H18)|H210Q(H12)|

C264Y(H2)xHx x

H40OHSAS13 H19xH4

bArg485STOP (H23)-_ Gln586STOP (H44)

xIH29

* 1163 + 7 novel AAS (H13)1

||1180 (MASA3)

-O 122 + 75 novel aas (HSAS1)

Figure 2 Published mutations in the LI gene in relation to Ll protein structure. Protein domains: Ig type C2(immunoglobulin-like domains), Fn type III (fibronectin type III domains), TM (transmembrane region). H, HSAS,MASA, and F numbers represent the names given to individual families by authors. Boxed family numbers indicatefamilies described as MASA syndrome (or clasped thumb-mental retardation or SPGJ). Underlined numbers highlightfamilies with examples ofHSAS as well as MASA syndrome (or SPGJ). For all mutations numbering of residueswithin Ll uses the first methionine as amino acid number 1. Missense mutations are given using the single letter aminoacid code. Positions affected by splicing mutations are indicated by scissors. For all other mutations the solid linerepresents intact Ll protein up to the point affected by mutation. For deletion MASA 3 the C-tertninal 77 residues of Llwould be deleted and for a DNA duplication in HSASI the terminal 35 amino acids would be replaced by 75 newresidues.

Several explanations can be put forward forthe observed lack ofwhole gene deletion. Largedeletions may incorporate additional geneswhose function is essential for viability or whoseabsence would give rise to a different pheno-type. In this regard it is interesting that thechromosomal region surrounding Li is rich inexpressed sequences.74 This may be coupledwith a lack of sequences predisposing to de-letion in the immediate vicinity of the Li geneand the relatively small size of genomic Li.Alternatively, complete deletion of Li itselfmay be lethal or give rise to a phenotype notrecognisable as X linked hydrocephalus or

MASA syndrome.

Pathology in relation to LI functionIdentification of the LI gene as a disease locusprovides an opportunity for examining its func-tion in human development. Despite the factthat Li expression is found throughout thenervous system and is implicated in neuronalmigration and neurite extension, CNS andPNS architecture is grossly preserved even incases where the gene mutation would eliminatecell surface expression of Li. Normal lam-ination of the cortices of the cerebrum andcerebellum, for example, is maintained.32728This is not unexpected as Li is one componentof a highly complex network of interacting, andoften related, cell adhesion molecules some ofwhich may have overlapping functions. Perhapsthe most dramatic distinguishable mor-

phological sign in cases of X linked hydro-cephalus is hypoplasia of the corticospinal tract(CST). That this is not secondary to raisedintracranial pressure is implied by the fact thatCST absence is not a general feature of con-

genital hydrocephalus.2 A prominent role forLi in the development of this tract of neurones

is consistent with the high levels of expressionobserved during rat CST genesis.75

In summary, neuropathological investiga-tions in patients with LI mutations indicatethat the protein must have a prominant rolein the development of the corticospinal tract,which is consistent with the spasticity observedin patients. No explanation can be providedat present for other features such as mentalretardation, adducted thumbs, or ventriculardilatation. Furthermore, the precise functionof LI in some areas of high expression, suchas the cerebellum, is not illuminated by existingneuropathology.

DiagnosisFrom a clinical point of view identification ofthe gene for this group of disorders enablesaccurate diagnosis and early detection inutero.65 This is particularly relevant for smallpedigrees or families with isolated cases. Apriori the recurrence risk for male sibs of a

hydrocephalic boy is 4%,2 76 which rises to 50%where the X linked disease is identified. Theproblem is therefore one of having to recognisethe small proportion of hydrocephalic maleswith a mutation in LI when X linked in-heritance is not apparent. Unfortunately, rou-tine mutation screening of all hydrocephalicboys is impractical (primary idiopathic hydro-cephalus occurs in about 0-6 per 1000 livebirths2) and no absolutely reliable method ofdiagnosing X linked hydrocephalus in sporadiccases has yet been developed. However, wheresurvival is long enough for additional signs,such as spasticity, mental retardation, and flex-ion deformities of the thumbs, to be observed,screening for an Li mutation should be con-

sidered.65 Where possible, suitable imagingshould be used to assess pyramidal tract status

Missense

Splicing

Nonsense

Frameshift

Deletions

Duplication

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in view of the association of BAOP with Xlinked disease. The wide variation in clinicalsigns observed in subjects with a proven LImutation means that inevitably sporadic caseswill be hard to diagnose and some will escapeattention.For families with a clear X linked pattern of

inheritance of hydrocephalus or MASA syn-drome there is very little indication of hetero-geneity. There are only two published examplesof families with a disorder that recombines withan Xq28 haplotypel577 and an LI mutationthat segregates completely with hydrocephalushas been identified for one of these families (MJouet, unpublished data).

ConclusionsIn summary, X linked hydrocephalus andMASA syndrome represent a clinical spectrumowing to a heterogeneous group of mutationsin the gene for neural cell adhesion moleculeLi. These naturally occurring mutations serve

to highlight regions of LI that must be criticalfor correct function of the protein. Therefore,continued mutation analysis in these disorderscombined with thorough neuropathology andassessment of the functional consequences ofmutation promises to provide valuable insightinto the function of this cell adhesion moleculeduring human development as well as providetools for accurate diagnosis.

SK and MJ are supported by the Medical Research Counciland the Wellcome Trust with generous contributions from theRoyal Society. We thank John Xuereb, Wayney Squier forneuropathology, and Jian-Sheng Du, John MacFarlane, andCyrus Chothia for helpful discussions.

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