_f Med Genet 1996;33: 59-65 59 Syndrome of the month J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from

X linked and MASA syndrome

Sue Kenwrick, Monique Jouet, Dian Donnai

Abstract or early mortality. The degree and progression X linked hydrocephalus and MASA syn- of hydrocephalus in these families is highly drome are clinically related, neurological variable with some males not presenting with disorders with an X linked recessive mode symptoms of increased intracranial pressure of inheritance. Although originally de- or despite enlargement of scribed as distinct entities, their similarity ventricles.21017 In general, prominent vent- has become apparent as the number of ricular dilatation and progressive hydro- reported families has increased and a high cephalus is associated with early mortality, degree ofintra- and interfamilial variation whereas mild enlargement and arrest is con- in clinical signs noted for both disorders. sistent with long survival. Consideration of this clinical overlap to- Valve insertion is an effective treatment for gether with finding that genes for both relieving high pressure hydrocephalus and im- diseases map to the same chromosomal proving life expectancy; however, survivors are band (Xq28) led to the hypothesis that they always late in meeting their developmental were caused by mutation at the same locus. milestones. They are mentally retarded with This was confirmed by identification of highly variable IQs ranging from "too low to mutations in patients with X linked hydro- test" to over 701820 and exhibit variable degrees cephalus and MASA syndrome within the of spasticity with increased tone and hy- gene for neural cell adhesion molecule Li. perreflexia, particularly in the lower limbs. Re- Here we review the clinical and genetic flexes and tone may be normal in the arms in characteristics of these disorders and the the presence of marked lower limb spasticity.1 underlying molecular defects in the LI These observations contrast with those de- gene. scribed for non-X linked hydrocephalus where

(JrMed Genet 1996;33:59-65) the majority of surviving cases have normal http://jmg.bmj.com/ intelligence and little motor impairment.2 Key words: hydrocephalus; X linked; MASA syndrome. Flexion-adduction deformities ofthe thumbs (clasped or adducted thumbs) are frequently but not always observed (Halliday et al? re- X linked hydrocephalus ported clasped thumbs in 44% of cases) and HISTORY may be associated with agenesis or hypoplasia

X linked recessive hydrocephalus is the most of the abductor or extensor muscles of the on September 30, 2021 by guest. Protected copyright. common form of hereditary hydrocephalus thumb.2122 The existence of affected subjects (McKusick No 30700), with an incidence of without obviously abnormal thumbs, and the approximately 1 in 30 000, and accounting for presence of this feature in other syndromes2324 between 2% and 15% of primary idiopathic means that this cannot be relied upon as a hydrocephalus in newborn males.12 It was first diagnostic sign. described in detail in a single large family by A wide variety of brain malformations has Bickers and Adams in 19493 and rediscovered been reported in association with X linked as a sex linked syndrome by Edwards in 1961.14 hydrocephalus including agenesis ofthe corpus University of Since then, over 35 families have been reported callosum or septum pellucidum, fusion of the Cambridge and the existence of an X linked recessive form thalamic fornices, colliculi and corpora quad- Department of of Medicine, Level 5, hydrocephalus is well established.5-'5 rigemina, and absence or hypoplasia of the Addenbrooke's corticospinal tract (CST), as assessed by histo- Hospital, Hills Road, logical analysis ofthe pyramids in cross sections Cambridge CB2 2QQ, UK CLINICAL FEATURES of the medulla.4825-28 The latter observation S Kenwrick X linked hydrocephalus is associated with a provides an explanation for the observed spas- M Jouet wide variation in severity and spectrum of clin- ticity in this disease as increased tone with Department of ical signs and symptoms both within and be- hyperreflexia are characteristic signs of CST Clinical Genetics, tween families. Onset of hydrocephalus often damage. The value of bilateral absence of pyr- St Mary's Hospital, occurs in utero although its appearance may be amids (BAOP) as an indicator of X linked Whitworth Park, Manchester M13 OJH, too late for detection during routine ultrasound hydrocephalus was investigated by Chow25 and UK scanning even at 20 weeks' gestation.10131416 Halliday et al.2 They determined that an as- D Donnai Accumulation of (CSF) is sociation exists between BAOP and X linked Correspondence to: associated mainly with the lateral and third hydrocephalus although the sample size was Dr Kenwrick. cerebral ventricles and often results in stillbirth small. Nine out of nine patients with clear or 60 Kenwrick, _rouet, Donnai "probable" (by clinical criteria) X linked dis- deficit in development of expressive relative to ease were found to have absent pyramids receptive language. Additional clinical signs whereas six out of six control male cases of include optic atrophy, lordosis, scoliosis, tor-

congenital hydrocephalus were not. BAOP'is ticollis, cleft palate, seizures, inguinal hernia, J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from not restricted to cases of X linked hydro- and urinary tract abnormalities. Although cephalus and can be found in other congenital MASA is not defined as including hydro- conditions, such as holoprosencephaly and cephalus, imaging in a limited number of hydranencephaly. Nevertheless, the un- patients has shown enlargement of cerebral common nature of BAOP means that it de- ventricles638 and a variety of other brain mal- serves special attention when assessing isolated formations including agenesis of the corpus cases ofhydrocephalus for the possibility of the callosum. hereditary disorder. The early suspicion that X linked hydro- Stenosis of the aqueduct of Sylvius was ori- cephalus and MASA syndrome are caused by ginally thought to be the primary cause of the same X linked locus3839 was reinforced by hydrocephalus as it was observed in several of the observation that both are the result ofgenes the first patients characterised in detail.34 The in the same subchromosomal band (see below) acronym HSAS (for hydrocephalus owing to and reports of single families with both MASA stenosis of the aqueduct of Sylvius) was there- and cotigenital hydrocephalus cases.38"4 fore adopted. Although the aqueduct has been found to be patent in several subsequent ex- amples,5 1422 accurate measurements have rarely Genetics been obtained. Although a degree ofaqueductal X linked hydrocephalus and MASA syndrome stenosis may well contribute to X linked hydro- behave as classical X linked recessive disorders cephalus it cannot be considered diagnostic for with very few carrier females showing signs of the hereditary condition as it is found in up to disease. Preferential inactivation of one X in 40% of patients with hydrocephalus.7 lymphocytes has been shown in manifesting A variety of ocular, musculoskeletal, and carriers of one family suggesting that non-ran- neurological abnormalities have also been dom X inactivation is responsible for the reported in cases of X linked hydrocephalus phenotype in females.34 including nystagmus, ptosis, optic atrophy, sco- The search for a single gene responsible for liosis, torticollis, lumbar lordosis, and seizures. X linked hydrocephalus and MASA syndrome There are no consistent distinguishing began in earnest when genetic linkage analysis facial characteristics although prominent ears provided evidence for loci for both syndromes have been reported.' 18 in subchromosomal band Xq28 with little in- Thus, X linked hydrocephalus is associated dication ofgenetic heterogeneity.3 35-37 39 42 Fur- with an extremely wide variation in severity ther pedigree analysis allowed refinement of and clinical signs. Overall the most consistent the relevant interval to approximately 1 5 me- features are hydrocephalus, mental retardation, gabases ofgenomic DNA between polymorphic and lower limb spasticity consistent with upper markers DXS52 and DXS605,71"538 a region http://jmg.bmj.com/ motor neurone damage (fig 1). containing the gene for neural cell adhesion molecule LI.4 Assessment of this gene in X linked hydrocephalus and MASA syndrome MASA syndrome families provided the final proof that the two HISTORY disorders are indeed caused by mutation at a The term MASA syndrome (McKusick single locus in Xq28.

303350), an acronym for Mental retardation, on September 30, 2021 by guest. Protected copyright. , Shuffling gait, and Adducted thumbs, was coined by Bianchine and Lewis30 in 1974 Neural cell adhesion molecule LI to describe the tetrad of X linked clinical signs Neural cell adhesion molecule Li is a multi- observed in a single large Mexican family. Since domain, highly conserved cell surface glyco- then several reports have detailed similar famil- protein expressed primarily on the axons of ies, although they have been described variously developing neurones. It is a member of the as spastic paraplegia type I (SPG1, McKusick immunoglobulin superfamily consisting of six 312900) or clasped thumb-mental retardation domains with core structural motifs similar to syndrome, as well as MASA syndrome. Again those found in immunoglobulins (Ig type C2), there is a high degree of inter- and intrafamilial five domains similar to type III repeats found variation in clinical presentation.3040 in the extracellular matrix protein fibronectin (Fn type III), a short transmembrane region, and a cytoplasmic region. Results of in vitro CLINICAL FEATURES assays and antibody perturbation experiments The clinical profiles described for MASA syn- indicate that Li is involved in neuronal drome patients clearly overlap with those ob- migration and neurite (for example, axon) served for X linked hydrocephalus, although extension as well as fasciculation.44-46 During the lack of congenital high pressure hydro- development Li is located on subsets of mi- cephalus results in a longer life expectancy. grating neurones, at the surface of long axons, Mental retardation, lower limb spasticity, and and on growth cones and it continues to be hyperreflexia are observed in all cases although expressed in the adult nervous system on un- the degree of impairment can be mild. Flexion- myelinated axons. Although mainly neuronal, adduction deformities of the thumbs are found expression at other sites suggests that it may in most, but not all cases and there is a general also play a part in myelination of peripheral X linked hydrocephalus and MASA syndrome 61 J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from

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Figure 1 Examples of clinical signs in patients with X linked hydrocephalus or MASA syndrome. mutations within For all subjects the Ll gene have been detected. (A) Axial CT scan of a neonate from an X linked hydrocephalus family showing gross lateral and dilatation and extreme thinning of the cortical mantle. Appearances are compatible with aqueductal stenosis. (B) An infant with X linked hydrocephalus: note the enlarged head and clasped thumbs. (C) A view of an adducted right thumb in the infant shown in (B). (D) Spastic lower limbs in a subject described as having AISA syndrome. 62 Kenwnick, Jrouet, Donnai

nerves, B and T lymphocyte function, and represented in fig 2. Virtually every form of migration of intestinal crypt cells.47"9 mutation has been found with the notable ex- Li can interact at the cell surface with a ception of whole gene deletion. Missense mut- number of different glycoproteins, including ations are the most common, representing over J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from other members of the immunoglobulin super- half of those reported (14), although splicing family, and proteoglycans either on the surface (5), frameshift (2), nonsense (2), deletion (1), of cells or in the extracellular environment. and duplication (1) events have been described. Homophilic binding is probably its principle Mutations are distributed across the Li gene mode of interaction,50 although LI (or close affecting many different domains ofthe protein. relatives in other species) has also been shown Although this wide variation in position and to undergo heterophilic interactions.5-56 This type of mutation may in part explain the wide variety of binding partners suggests that LI clinical spectrum observed for these disorders, may have different functions at different times intrafamilial variation coupled with a lack of and locations during development. clustering of mutations confounds strict geno- In order to promote neuronal migration or type/phenotype correlations. axon extension, binding of LI at the neuronal Three mutations have been described (H23, surface must initiate downstream events that H44, H24) that would truncate Li before the result in a reorganisation of the cytoskeleton. transmembrane domain, eliminating the po- Experiments in vitro have begun to unravel tential for cell surface expression ofthe protein. some of the signalling events that may be in- As no Li isoforms have been described without volved. For example, Li homophilic binding a transmembrane domain, subjects bearing induces changes in intracellular levels ofsecond these mutations presumably lack Li function messengers, such as inositol phosphates and completely. Predictably, these mutations are Ca2 +, and affects phosphorylation of tu- associated with severe congenital hydro- bulin.5760 Furthermore, Li promotion ofneur- cephalus and early mortality.89 By contrast, ite outgrowth in vitro may involve cis- three mutations (H29, H13, MASA3) that interaction ofLi with members ofthe fibroblast truncate the protein in the cytoplasmic domain, growth factor receptor family which initiate a allowing cell surface presentation, were found second messenger cascade via their cytoplasmic in families described as having MASA syn- tyrosine kinase domains.6' Li may also directly drome. interact with the cytoskeleton via binding of its To date, five mutations described affect pro- cytoplasmic domain to ankyrin.6" The relevance cessing of Li hnRNA. In all of these cases of these interactions to LI function in vivo, the production of normal as well as aberrantly purpose of different Li ligands, and the role spliced mRNA is apparent from studies on of individual domains of the protein have yet cDNA B to be determined. In view of the role of Li in from cell lines. If these results can the morphogenesis of the nervous system and be extrapolated to the nervous system, they the common occurrence ofbrain malformation indicate that Li splicing mutations act in a in patients with X linked hydrocephalus or dominant negative fashion at the cellular level, http://jmg.bmj.com/ MASA syndrome, the Li gene was considered although they appear recessive in heterozygous a prime candidate for the locus involved in females. these disorders. As little is known about the roles ofindividual domains of LI, it is not possible to predict the outcome of specific mutations on Li function and neural development. The distribution of mutations across Mutation analysis many domains, however, sug- on September 30, 2021 by guest. Protected copyright. Detection of mutations in families suffering gests that they may affect interaction with a from MASA syndrome as well as X linked variety of different ligands (for the extracellular hydrocephalus confirmed that these disorders domain), signal transduction, as well as in- (including SPG1 and clasped thumb-mental teractions with cytoskeletal proteins (in- retardation) are allelic and caused by hetero- tracellular domain). Some insight into the geneous mutations within the LI locus.89 63-70 potential effects of mutations on Li protein The 143 kDa human Li protein is encoded can be gained from interspecies sequence com- by an open reading frame of 3771 bp contained parisons and protein modelling. For example, within a 4-5 kb messenger RNA.7172 Low level several of the missense mutations described to expression of this transcript in B cell lines date affect residues that are highly conserved enabled complete sequencing of LI cDNA between like domains within Li as well as from patients resulting in the first evidence that between Ll-like proteins in different species Li corresponds to the X linked hydrocephalus (for example, C264Y, G121S, R184Q, and locus.6667 More flexibility in the approach to G452R). That these mutations are likely to mutation searching has been provided by res- affect the structural integrity of individual do- olution of the genomic structure ofthe Li gene mains is borne out by comparison with models and determination of sequences at intron-exon of immunoglobulin domains related to those boundaries (A Rosenthal, EMBL database present in LI7" (C Chothia, personal com- HSNCAMX). The gene consists of 28 exons munication). Those affecting less conserved distributed across 15 kb of genomic DNA and residues (for example, D598N, H210Q, and conditions have been established for amp- E309K) are more likely to affect ligand re- lification of each exon.' cognition or quatemary folding of the mature To date, 25 different Li mutations have been protein (for a comparison of residues affected reported in as many families and these are by missense mutations see ref 8). X linked hydrocephalus and MASA syndrome 63

Ig type C2 Fn type ll TM

NH2 - COOH J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from W9S(H3) G452R(H6) V768F(H5) S 14L(M SA~l) G121 S(H7) G370R(F2) FD598N(MASA5) Y17O7C(H1)

Missense 1179S(F1) |E309K(H38) P941L(H39) 0 R184Q(H18) |H210Q(H12)| C264Y(H2) Splicing xHx x x x H40OHSAS13 H19 H4 IH29 bArg485STOP (H23) Nonsense -_ Gln586STOP (H44)

Frameshift * 1163 + 7 novel AAS (H13)1

Deletions ||1180 (MASA3)

Duplication -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 indicate families described as MASA syndrome (or clasped thumb-mental retardation or SPGJ). Underlined numbers highlight families with examples of HSAS as well as MASA syndrome (or SPGJ). For all mutations numbering of residues within Ll uses the first methionine as amino acid number 1. Missense mutations are given using the single letter amino acid code. Positions affected by splicing mutations are indicated by scissors. For all other mutations the solid line represents intact Ll protein up to the point affected by mutation. For deletion MASA 3 the C-tertninal 77 residues of Ll would be deleted and for a DNA duplication in HSASI the terminal 35 amino acids would be replaced by 75 new residues.

Several explanations can be put forward for is consistent with the high levels of expression the observed lack ofwhole gene deletion. Large observed during rat CST genesis.75 deletions may incorporate additional genes In summary, neuropathological investiga- whose function is essential for viability or whose tions in patients with LI mutations indicate absence would give rise to a different pheno- that the protein must have a prominant role type. In this regard it is interesting that the in the development of the corticospinal tract, chromosomal region surrounding Li is rich in which is consistent with the spasticity observed expressed sequences.74 This may be coupled in patients. No explanation can be provided with a lack of sequences predisposing to de- at present for other features such as mental letion in the immediate vicinity of the Li gene retardation, adducted thumbs, or ventricular http://jmg.bmj.com/ and the relatively small size of genomic Li. dilatation. Furthermore, the precise function Alternatively, complete deletion of Li itself of LI in some areas of high expression, such may be lethal or give rise to a phenotype not as the cerebellum, is not illuminated by existing recognisable as X linked hydrocephalus or neuropathology. MASA syndrome.

Diagnosis on September 30, 2021 by guest. Protected copyright. Pathology in relation to LI function From a clinical point of view identification of Identification of the LI gene as a disease locus the gene for this group of disorders enables provides an opportunity for examining its func- accurate diagnosis and early detection in tion in human development. Despite the fact utero.65 This is particularly relevant for small that Li expression is found throughout the pedigrees or families with isolated cases. A nervous system and is implicated in neuronal priori the recurrence risk for male sibs of a migration and neurite extension, CNS and hydrocephalic boy is 4%,2 76 which rises to 50% PNS architecture is grossly preserved even in where the X linked disease is identified. The cases where the gene mutation would eliminate problem is therefore one of having to recognise cell surface expression of Li. Normal lam- the small proportion of hydrocephalic males ination of the cortices of the cerebrum and with a mutation in LI when X linked in- cerebellum, for example, is maintained.32728 heritance is not apparent. Unfortunately, rou- This is not unexpected as Li is one component tine mutation screening of all hydrocephalic of a highly complex network ofinteracting, and boys is impractical (primary idiopathic hydro- often related, cell adhesion molecules some of cephalus occurs in about 0-6 per 1000 live which may have overlapping functions. Perhaps births2) and no absolutely reliable method of the most dramatic distinguishable mor- diagnosing X linked hydrocephalus in sporadic phological sign in cases of X linked hydro- cases has yet been developed. However, where cephalus is hypoplasia of the corticospinal tract survival is long enough for additional signs, (CST). That this is not secondary to raised such as spasticity, mental retardation, and flex- intracranial pressure is implied by the fact that ion deformities of the thumbs, to be observed, CST absence is not a general feature of con- screening for an Li mutation should be con- genital hydrocephalus.2 A prominent role for sidered.65 Where possible, suitable imaging Li in the development of this tract of neurones should be used to assess pyramidal tract status 64 Kenwrick, J7ouet, Donnai

17 Kuzniecky RI, Watters GV, Watters L, Meagher-Villemure in view of the association of BAOP with X K. X-linked hydrocephalus. Can Neurol Sci 1986;13: linked disease. The wide variation in clinical 344-6. 18 Fried K. X-linked mental retardation and/or hydrocephalus. signs observed in subjects with a proven LI Clin Genet 1972;3:258-63. mutation means that inevitably sporadic cases 19 Opitz JM, Segal AT, Klove H, Mathews CH, Lehreke RC. J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from will to some escape X-linked mental retardation. Study of a large kindred with be hard diagnose and will 20 affected members. Pediatr 1965;67:713-14. attention. 20 Renpenning H, Gerrard JW, Zaleski WA, Tabata T. Familial a sex-linked mental retardation. Can Med Assoc .7 1962;87: For families with clear X linked pattern of 954-6. inheritance of hydrocephalus or MASA syn- 21 Holtzman RNN, Garcia L, Koenigsberger R. Hydro- drome there is very little indication of hetero- cephalus and congenital clasped thumbs: a case report with electromyographic evaluation. Dev Med Child Neurol geneity. There are only two published examples 1976;18:521-7. of families with a disorder that recombines with 22 Landrieu P, Ninane J, Ferriere G, Lyon G. Aqueductal stenosis in X-linked hydrocephalus; a secondary phe- an Xq28 haplotypel577 and an LI mutation nomenon? Dev Med Child Neurol 1979;21:637-52. that segregates completely with hydrocephalus 23 Fitch N, Levy EP. Adducted thumb syndromes. Clin Genet 1975;8: 190-8. has been identified for one of these families (M 24 Weckesser EC, Reed JR, Heiple KG. Congenital clasped Jouet, unpublished data). thumb (congenital flexion-adduction deformity of the thumb). _7 Bone joint Surg (Am) 1968;50:1417-28. 25 Chow CW, HallidayJL, Anderson RM, Danks DM, Fortune DW. Congenital absence of pyramids and its significance in genetic diseases. Acta Neuropathol 1985;65:313-17. Conclusions 26 Holmes LB, Nash A, ZuRhein GM, Levin M, Opitz J. X- In summary, X linked hydrocephalus and linked aqueductal stenosis: clinical and neuropathological findings in two families. Pediatrics 1973;51:697-704. MASA syndrome represent a clinical spectrum 27 Sovik 0, Van der Hagen CB, Loken AC. X-linked aque- owing to a heterogeneous group of mutations ductal stenosis. Clin Genet 1977;11:416-20. 28 Warren MC, Lu AT, Zierig WH. Sex-linked hydrocephalus in the gene for neural cell adhesion molecule with aqueductal stenosis. Pediatr 1963;63: 1104-10. Li. These naturally occurring mutations serve 29 Stevenson RE, Hall JG, Goodman RM. Human mal- formations and related anomalies. Oxford Monograms on to highlight regions of LI that must be critical Medical Genetics 1993;27:68. for correct function of the protein. Therefore, 30 Bianchine JW, Lewis RC. The MASA syndrome: a new heritable mental retardation syndrome. Clin Genet 1974; continued mutation analysis in these disorders 5:298-306. combined with thorough neuropathology and 31 Boyd E, Schwartz CE, Schroer RJ, et al. Agenesis of the associated with MASA syndrome. Clin assessment of the functional consequences of Dysmorphol 1993;2:332-41. mutation promises to provide valuable insight 32 Fryns JP, Schrander-Stumpel C, De Die-Smulders C, Borghgraef M, Van Den Berghe H. MASA syndrome: into the function of this cell adhesion molecule delineation of the clinical spectrum at prepubertal age. during human development as well as provide Am JMed Genet 1992;43:402-7. 33 Gareis FJ, Mason JD. X-linked mental retardation as- tools for accurate diagnosis. sociated with bilateral clasp thumb anomaly. Am _7 Med Genet 1984;17:333-8. SK and MJ are supported by the Medical Research Council 34 Kapernick L, Legius E, Higgins J, Kapur S. Clinical aspects and the Wellcome Trust with generous contributions from the of the MASA syndrome in a large family, including ex- Royal Society. We thank John Xuereb, Wayney Squier for pressing females. Clin Genet 1994;45:181-5. neuropathology, and Jian-Sheng Du, John MacFarlane, and 35 Kenwrick SJ, Ionasescu V, Ionasescu G, et al. Linkage Cyrus Chothia for helpful discussions. studies of X-linked recessive spastic paraplegia using DNA probes. Hum Genet 1986;73:264-6. 36 Macias Wilson GN. The of sex-linked VR, Day DW, King TE, Clasped- 1 Edwards JH. syndrome hydrocephalus. thumb mental retardation. Am .7 Med Genet 1992;43: Arch Dis Child 1961;36:486-93. 408-14. http://jmg.bmj.com/ 2 Halliday J, Chow CW, Wallace D, Danks DM. X linked 37 Rietschel M, Freidl W, Uhlhaas S, et al. MASA syndrome: a of a 20 in hydrocephalus: survey year period Victoria, clinical variability and linkage analysis. Am .7 Med Genet Australia. Med Genet 1986;23:23-3 1. 199 1;41:10-14. 3 Bickers DS, Adams RD. 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Clin Ultrasound 1993;21: linked complicated spastic paraplegia, MASA syndrome, 211-14. and X linked to stenosis 7 Feldman Yates et al. the hydrocephalus owing congenital Jouet M, E, J, Refining genetic of the of a variable of the location of the gene for X linked hydrocephalus within aqueduct Sylvius: expression Med Genet same mutation at Xq28. .7 Med Genet 1991;28:429-31. Xq28. 1993;30:214-17. Van Der Auwera et al. 8 Jouet M, Moncla A, Paterson J, et al. New domains of 42 Willems PJ, Dijkstra I, BJ, Assignment cell-adhesion molecule LI in X-linked of X linked hydrocephalus to Xq28 by linkage analysis. neural implicated Genomics hydrocephalus and MASA syndrome. Am 7 Hum Genet 1990;8:367-70. 1995;56:1304-14. 43 Dietrich A, Kom B, Poustka A. Completion of the physical of Mamm Genome 9 Jouet M, Rosenthal A, Armstrong G, et al. X-linked spastic map Xq28. 1992;3:168-72. paraplegia (SPG1), MASA syndrome and X-linked hydro- 44 Grumet M. Cell adhesion molecules and their subgroups cephalus result from mutations in the Li gene. Nature in the nervous system. Curr Opin Neurobiol 1991;1:370-6. Genet 1994;7:402-7. 45 Sonderegger P, Rathjen FG. Regulation of axonal growth in the vertebrate nervous interactions between 10 Kelley RI, Mennuti MT, Hiskey WF, Zackai EH. X-linked system by recessive aqueductal stenosis without macrocephaly. Clin glycoproteins belonging to two subgroups of the im- Genet 1988;33:390-4. munoglobulin superfamily. .7 Cell Biol 1992;119:1387-94. 46 Kenwrick Willems Lemmon V. Mutations 11 Lyonnet S, Pelet A, Royer G, et al. The gene for X-linked Wong EV, S, P, hydrocephalus maps to Xq28, distal to DXS52. Genomics in the cell adhesion molecule Li cause mental retardation. 1992;14:508-10. Trends Neurosci 1995;18:168-72. 12 Schrander-Stumpel C, Meyer H, Merckx D, et al. The 47 Bixby JL, Lilien, J, Reichardt F. 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52 Felsenfeld DP, Hynes MA, Skoler KM, Furley AJ, Jessell 64 Fransen E, Schrander-Stumpel C, Vits L, et al. X-linked TM. Tag-I can mediate homophilic binding, but neurite hydrocephalus and MASA syndrome present in one family outgrowth on Tag-I requires an Ll-like molecule and Bi are due to a single missense mutation in exon 28 of the integrins. Neuron 1994;12:675-90. LlCAM gene. Humn Molec Genet 1994;3:2255-6. 53 Grumet M, Friedlander DR, Edelman GM. Evidence for 65 Jouet M, Kenwrick S. Gene analysis of LI neural cell

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