Prenatal molecular diagnosis of a severe type of L1 syndrome (X-linked hydrocephalus)

Clinical article

Restricted access


The aim of this study was to evaluate the feasibility of prenatal L1CAM gene testing for X-linked hydrocephalus (XLH).


In a nationwide study conducted in Japan between 1999 and 2009, the authors identified 51 different L1CAM gene mutations in 56 families with XLH. Of these 56 families, 9 obligate carriers requested prenatal gene mutation analysis for the fetal L1CAM gene in 14 pregnancies.


In 2004, new clinical guidelines for genetic testing were established by 10 Japanese genetic medicine–related societies. These guidelines stated that the genetic testing of carriers should be done only with their consent and with genetic counseling. Therefore, because females are carriers, since 2004, L1CAM gene analysis has not been performed for female fetuses. The authors report on 7 fetal genetic analyses that were performed at the request of families carrying L1CAM mutations, involving 3 female (prior to 2004) and 4 male fetuses. Of the 7 fetuses, 3 (1 male and 2 female) carried L1CAM mutations. Of these 3, 1 pregnancy (the male fetus) was terminated; in the other cases, the pregnancies continued, and 3 female and 3 male babies without the XLH phenotype were born.


Prenatal L1CAM gene testing combined with genetic counseling was beneficial for families carrying L1CAM mutations.

Abbreviations used in this paper: AC = amniocentesis; CVS = chorionic villous sampling; PCR = polymerase chain reaction; XLH = X-linked hydrocephalus.

Article Information

Address correspondence to: Mami Yamasaki, M.D., Ph.D., Department of Neurosurgery, Osaka National Hospital, National Hospital Organization, 2-1-14 Hoenzaka, Chuo-ku, Osaka City, 540-0006, Japan. email:

© AANS, except where prohibited by US copyright law.



  • View in gallery

    Flow chart showing the protocol for prenatal L1CAM mutation analysis used at Osaka National Hospital.

  • View in gallery

    A: Pedigree of family HC27. B: Postnatal CT scan of the patient (III-1) showing bilateral severe ventricular dilation. C: Result of L1CAM gene analysis showing the position of the G to C transition in intron 14. This L1CAM mutation was reported previously by Kanemura et al. in 2005.

  • View in gallery

    A: Pedigree of family HC45. B: Fetal MR imaging of fetus (II-3) at 20 weeks of gestation showing bilateral severe ventricular dilation. C: Result of L1CAM gene analysis showing the deletion of ACC, which is a novel L1CAM mutation. fd = fetal death due to twisting of the umbilical cord; GW = gestational weeks; sa = spontaneous abortion; TOP = termination of pregnancy.

  • View in gallery

    Case summary of HC53. Left: Pedigree of family HC53. Right: Result of L1CAM gene analysis showing the C to A transition, which is a novel L1CAM mutation.



Finckh UGal A: Prenatal molecular diagnosis of L1-spectrum disorders. Prenat Diagn 20:7447452000


Fransen EVan Camp GD'Hooge RVits LWillems PJ: Genotype-phenotype correlation in L1 associated diseases. J Med Genet 35:3994041998


Genetic-Medicine-Related Societies: Guidelines for Genetic Testing (


Gu SMOrth UZankl MSchröder JGal A: Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait. Am J Med Genet 71:3363401997


Hlavin MLLemmon V: Molecular structure and functional testing of human L1CAM: an interspecies comparison. Genomics 11:4164231991


Jouet MKenwrick S: Gene analysis of L1 neural cell adhesion molecule in prenatal diagnosis of hydrocephalus. Lancet 345:1611621995


Jouet MRosenthal AArmstrong GMacFarlane JStevenson RPaterson J: X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene. Nat Genet 7:4024071994


Kanemura YOkamoto NSakamoto HShofuda TKamiguchi HYamasaki M: Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus. J Neurosurg 105:5 Suppl4034122006


Kanemura YTakuma YKamiguchi HYamasaki M: First case of L1CAM gene mutation identified in MASA syndrome in Asia. Congenit Anom (Kyoto) 45:67692005


MacFarlane JRDu JSPepys MERamsden SDonnai DCharlton R: Nine novel L1 CAM mutations in families with X-linked hydrocephalus. Hum Mutat 9:5125181997


Michaelis RCDu YZSchwartz CE: The site of a missense mutation in the extracellular Ig or FN domains of L1CAM influences infant mortality and the severity of X linked hydrocephalus. J Med Genet 35:9019041998


Panayi MGokhale DMansour SElles R: Prenatal diagnosis in a family with X-linked hydrocephalus. Prenat Diagn 25:9309332005


Piccione MMatina FFichera MLo Giudice MDamiani GJakil MC: A novel L1CAM mutation in a fetus detected by prenatal diagnosis. Eur J Pediatr 169:4154192010


Pineda-Alvarez DEDubourg CDavid VRoessler EMuenke M: Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients. Am J Med Genet C Semin Med Genet 154C:931012010


Publishing Committee for Guideline of Fetal Hydrocephalus: [Guideline for Fetal Hydrocephalus Diagnosis and Management.] KinpodoKyoto, Japan2005. (Jpn)


Renier DSainte-Rose CPierre-Kahn AHirsch JF: Prenatal hydrocephalus: outcome and prognosis. Childs Nerv Syst 4:2132221988


Rosenthal AJouet MKenwrick S: Aberrant splicing of neural cell adhesion molecule L1 mRNA in a family with X-linked hydrocephalus. Nat Genet 2:1071121992


Senat MVBernard JPDelezoide ASaugier-Veber PHillion YRoume J: Prenatal diagnosis of hydrocephalusstenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy. Report of two cases. Prenat Diagn 21:112911322001


Van Camp GFransen EVits LRaes GWillems PJ: A locus-specific mutation database for the neural cell adhesion molecule L1CAM (Xq28). Hum Mutat 8:3911996


Vos YJde Walle HEBos KKStegeman JATen Berge AMBruining M: Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis. J Med Genet 47:1691752010


Wilson PLKaltman BBMulvihill JJWilkins JWagner AFGoodman JR: Prenatal identification of a novel R937P L1CAM missense mutation. Genet Test Mol Biomarkers 13:5155192009


Yamasaki MArita NHiraga SIzumoto SMorimoto KNakatani S: A clinical and neuroradiological study of X-linked hydrocephalus in Japan. J Neurosurg 83:50551995




All Time Past Year Past 30 Days
Abstract Views 7 7 7
Full Text Views 13 13 9
PDF Downloads 54 54 44
EPUB Downloads 0 0 0


Google Scholar