G2Cdb::Human Disease report

Disease id
D00000216
Name
L1 syndrome
Nervous system disease
yes

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001881 L1CAM
L1 cell adhesion molecule
Y (15662685) Unknown (?) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (15904436) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (16088863) Deletion (D) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (16650080) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (16816908) Microinsertion (MI) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (17328266) Nonsense (No) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (17328266) Frameshift mutation (FS) Y
G00001881 L1CAM
L1 cell adhesion molecule
Y (17328266) Splice site mutation (SpS) Y

References

  • Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus.

    Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, Kamiguchi H and Yamasaki M

    Institute for Clinical Research and Department of Neurosurgery, Osaka National Hospital, Osaka, Japan.

    Object: Mutations in the gene that codes for the human neural cell adhesion molecule L1 (L1CAM), are known to cause a wide variety of anomalies, now understood as phenotypic expressions of L1 syndrome. The correlations between genotype and phenotype, however, are not fully established. The authors report the results of a nationwide investigation of L1CAM gene mutations that was performed to improve the understanding of L1-mediated molecular mechanisms of X-linked hydrocephalus and to establish neurorimaging criteria for this severe form of L1 syndrome.

    Methods: Ninety-six genomic DNA samples from members of 57 families were obtained from the Congenital Hydrocephalus Research Committee. By using polymerase chain reaction and direct DNA sequencing, the authors identified 25 different L1CAM gene mutations, 20 of them novel, in 26 families with X-linked hydrocephalus. All the mutations were L1CAM loss-of-function mutations, and all the patients had severe hydrocephalus and severe mental retardation. In all cases, specific abnormalities were visible on neuroimaging: a rippled ventricular wall after shunt placement, an enlarged quadrigeminal plate, a large massa intermedia, and hypoplasia of the cerebellar vermis (anterior or total). The patients also had adducted thumbs, spastic paraplegia, and hypoplasia of the corpus callosum, which are characteristic of L1 syndrome.

    Conclusions: The L1CAM loss-of-function mutations cause a severe form of L1 syndrome, unlike the milder form produced by mutations in the L1CAM cytoplasmic domain. We also identified neurorimaging criteria for this severe form of L1 syndrome. These criteria can be used to predict loss-of-function mutations in patients with X-linked hydrocephalus and to help in diagnosing this syndrome.

    Journal of neurosurgery 2006;105;5 Suppl;403-12

  • A novel missense mutation in the L1CAM gene in a boy with L1 disease.

    Simonati A, Boaretto F, Vettori A, Dabrilli P, Criscuolo L, Rizzuto N and Mostacciuolo ML

    Department of Neurological and Visual Science, Section of Clinical Neurology-Child Neurology Unit, Policlinico G. B. Rossi, Verona, and Department of Biology, Laboratory of Human Genetics, University of Pauda, Italy. alessandro.simonati@univr.it

    A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2006;27;2;114-7

  • Expanding the phenotypic spectrum of L1CAM-associated disease.

    Basel-Vanagaite L, Straussberg R, Friez MJ, Inbar D, Korenreich L, Shohat M and Schwartz CE

    Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. basel@post.tau.ac.il

    Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation. Inter- and intrafamilial variability is a well-known feature of the L1CAM spectrum, and several patients have a combination of L1CAM mutations and Hirschsprung's disease (HSCR). We report on two siblings with a missense mutation in exon 7 (p.P240L) of the L1CAM gene. In one of the siblings, congenital dislocation of the radial heads and HSCR were present. Neither patient had hydrocephalus, adducted thumbs, or absent speech, but both had a hypoplastic corpus callosum. We suggest that L1CAM mutation testing should be considered in male patients with a positive family history compatible with X-linked inheritance and either the combination of agenesis of the CC and HSCR or the combination of agenesis of the CC and limb abnormalities, including abnormalities other than adducted thumbs.

    Funded by: NICHD NIH HHS: HD26202

    Clinical genetics 2006;69;5;414-9

  • Prenatal diagnosis in a family with X-linked hydrocephalus.

    Panayi M, Gokhale D, Mansour S and Elles R

    National Genetics Reference Laboratory, Regional Genetics Service, St Mary's Hospital, Manchester, UK. maria.panayi@cmmc.nhs.uk

    The neural cell adhesion molecule L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs). Its expression is essential during embryonic development of the nervous system and it is involved in cognitive function and memory. Mutations in the L1CAM gene are responsible for four related L1 disorders; X-linked hydrocephalus/HSAS (Hydrocephalus as a result of Stenosis of the Aqueduct of Sylvius), MASA (Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs) syndrome, X-linked complicated spastic paraplegia type I (SPG1) and X-linked Agenesis of the Corpus Callosum (ACC). These four disorders represent a clinical spectrum that varies both between and within families. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH syndrome). Since there is no biochemically assayed disease marker, molecular analysis of the L1CAM gene is the only means of confirming a clinical diagnosis. Most L1CAM mutations reported to date are point mutations (missense, nonsense, splice site) and only a few patients with larger rearrangements have been documented. We have characterised a rare intragenic deletion of the L1CAM gene in a sample of DNA extracted from a chorionic villus biopsy (CVB) performed at 12 weeks' gestation. =

    Prenatal diagnosis 2005;25;10;930-3

  • First case of L1CAM gene mutation identified in MASA syndrome in Asia.

    Kanemura Y, Takuma Y, Kamiguchi H and Yamasaki M

    Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka 540-0006, Japan.

    We report here the first case of an L1CAM gene mutation identified in mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome in Japan. The patient was a 10-year-old boy with mild mental retardation, bilateral adducted thumbs and corpus callosum hypoplasia. His family had no history of MASA syndrome. The L1CAM gene contained a nonsense mutation (R1166X) in exon 26 in the cytoplasmic domain. No mutation was found in the extracellular and transmembrane domains of L1CAM. The abnormal development of axon tracts resulting in the corpus callosum hypoplasia and adducted thumbs appears to be caused by malfunction of the cytoplasmic domain of L1CAM.

    Congenital anomalies 2005;45;2;67-9

  • A novel L1CAM mutation with L1 spectrum disorders.

    Silan F, Ozdemir I and Lissens W

    Medical Biology and Genetic Department, Abant Izzet Baysal University, Duzce School of Medicine, Duzce, Turkey. fsilan@yahoo.com

    X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders. X-linked hydrocephalus and associated phenotypes are due to mutations in the L1CAM gene, which has been identified as a coding neural cell adhesion molecule. We report two cases of L1 spectrum disorders within the same family. The first case was diagnosed by ultrasonographic examination prenatally and the second case was diagnosed postnatally. Both patients and their mothers carry a novel mutation of the L1CAM gene. In this family, nine X-linked hydrocephalus and five female carriers were found in three generations, and molecular genetic analysis was performed to detect the asymptomatic carriers.

    Prenatal diagnosis 2005;25;1;57-9

Literature (6)

Pubmed - human_disease

  • Prenatal diagnosis in a family with X-linked hydrocephalus.

    Panayi M, Gokhale D, Mansour S and Elles R

    National Genetics Reference Laboratory, Regional Genetics Service, St Mary's Hospital, Manchester, UK. maria.panayi@cmmc.nhs.uk

    The neural cell adhesion molecule L1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs). Its expression is essential during embryonic development of the nervous system and it is involved in cognitive function and memory. Mutations in the L1CAM gene are responsible for four related L1 disorders; X-linked hydrocephalus/HSAS (Hydrocephalus as a result of Stenosis of the Aqueduct of Sylvius), MASA (Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs) syndrome, X-linked complicated spastic paraplegia type I (SPG1) and X-linked Agenesis of the Corpus Callosum (ACC). These four disorders represent a clinical spectrum that varies both between and within families. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus (CRASH syndrome). Since there is no biochemically assayed disease marker, molecular analysis of the L1CAM gene is the only means of confirming a clinical diagnosis. Most L1CAM mutations reported to date are point mutations (missense, nonsense, splice site) and only a few patients with larger rearrangements have been documented. We have characterised a rare intragenic deletion of the L1CAM gene in a sample of DNA extracted from a chorionic villus biopsy (CVB) performed at 12 weeks' gestation. =

    Prenatal diagnosis 2005;25;10;930-3

  • First case of L1CAM gene mutation identified in MASA syndrome in Asia.

    Kanemura Y, Takuma Y, Kamiguchi H and Yamasaki M

    Institute for Clinical Research, Osaka National Hospital, National Hospital Organization, Osaka 540-0006, Japan.

    We report here the first case of an L1CAM gene mutation identified in mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome in Japan. The patient was a 10-year-old boy with mild mental retardation, bilateral adducted thumbs and corpus callosum hypoplasia. His family had no history of MASA syndrome. The L1CAM gene contained a nonsense mutation (R1166X) in exon 26 in the cytoplasmic domain. No mutation was found in the extracellular and transmembrane domains of L1CAM. The abnormal development of axon tracts resulting in the corpus callosum hypoplasia and adducted thumbs appears to be caused by malfunction of the cytoplasmic domain of L1CAM.

    Congenital anomalies 2005;45;2;67-9

  • A novel L1CAM mutation with L1 spectrum disorders.

    Silan F, Ozdemir I and Lissens W

    Medical Biology and Genetic Department, Abant Izzet Baysal University, Duzce School of Medicine, Duzce, Turkey. fsilan@yahoo.com

    X-linked hydrocephalus, HSAS (hydrocephalus due to stenosis of aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, and adducted thumbs), and CRASH (corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraplegia, and hydrocephalus) syndromes are allelic disorders. X-linked hydrocephalus and associated phenotypes are due to mutations in the L1CAM gene, which has been identified as a coding neural cell adhesion molecule. We report two cases of L1 spectrum disorders within the same family. The first case was diagnosed by ultrasonographic examination prenatally and the second case was diagnosed postnatally. Both patients and their mothers carry a novel mutation of the L1CAM gene. In this family, nine X-linked hydrocephalus and five female carriers were found in three generations, and molecular genetic analysis was performed to detect the asymptomatic carriers.

    Prenatal diagnosis 2005;25;1;57-9

Pubmed - other

  • Molecular mechanisms and neuroimaging criteria for severe L1 syndrome with X-linked hydrocephalus.

    Kanemura Y, Okamoto N, Sakamoto H, Shofuda T, Kamiguchi H and Yamasaki M

    Institute for Clinical Research and Department of Neurosurgery, Osaka National Hospital, Osaka, Japan.

    Object: Mutations in the gene that codes for the human neural cell adhesion molecule L1 (L1CAM), are known to cause a wide variety of anomalies, now understood as phenotypic expressions of L1 syndrome. The correlations between genotype and phenotype, however, are not fully established. The authors report the results of a nationwide investigation of L1CAM gene mutations that was performed to improve the understanding of L1-mediated molecular mechanisms of X-linked hydrocephalus and to establish neurorimaging criteria for this severe form of L1 syndrome.

    Methods: Ninety-six genomic DNA samples from members of 57 families were obtained from the Congenital Hydrocephalus Research Committee. By using polymerase chain reaction and direct DNA sequencing, the authors identified 25 different L1CAM gene mutations, 20 of them novel, in 26 families with X-linked hydrocephalus. All the mutations were L1CAM loss-of-function mutations, and all the patients had severe hydrocephalus and severe mental retardation. In all cases, specific abnormalities were visible on neuroimaging: a rippled ventricular wall after shunt placement, an enlarged quadrigeminal plate, a large massa intermedia, and hypoplasia of the cerebellar vermis (anterior or total). The patients also had adducted thumbs, spastic paraplegia, and hypoplasia of the corpus callosum, which are characteristic of L1 syndrome.

    Conclusions: The L1CAM loss-of-function mutations cause a severe form of L1 syndrome, unlike the milder form produced by mutations in the L1CAM cytoplasmic domain. We also identified neurorimaging criteria for this severe form of L1 syndrome. These criteria can be used to predict loss-of-function mutations in patients with X-linked hydrocephalus and to help in diagnosing this syndrome.

    Journal of neurosurgery 2006;105;5 Suppl;403-12

  • A novel missense mutation in the L1CAM gene in a boy with L1 disease.

    Simonati A, Boaretto F, Vettori A, Dabrilli P, Criscuolo L, Rizzuto N and Mostacciuolo ML

    Department of Neurological and Visual Science, Section of Clinical Neurology-Child Neurology Unit, Policlinico G. B. Rossi, Verona, and Department of Biology, Laboratory of Human Genetics, University of Pauda, Italy. alessandro.simonati@univr.it

    A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G-->A in exon 18 that caused an amino acid change in codon 770. The patient's mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 2006;27;2;114-7

  • Expanding the phenotypic spectrum of L1CAM-associated disease.

    Basel-Vanagaite L, Straussberg R, Friez MJ, Inbar D, Korenreich L, Shohat M and Schwartz CE

    Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel. basel@post.tau.ac.il

    Mutations in the L1CAM gene cause neurological abnormalities of variable severity, including congenital hydrocephalus, agenesis of the corpus callosum, spastic paraplegia, bilaterally adducted thumbs, aphasia, and mental retardation. Inter- and intrafamilial variability is a well-known feature of the L1CAM spectrum, and several patients have a combination of L1CAM mutations and Hirschsprung's disease (HSCR). We report on two siblings with a missense mutation in exon 7 (p.P240L) of the L1CAM gene. In one of the siblings, congenital dislocation of the radial heads and HSCR were present. Neither patient had hydrocephalus, adducted thumbs, or absent speech, but both had a hypoplastic corpus callosum. We suggest that L1CAM mutation testing should be considered in male patients with a positive family history compatible with X-linked inheritance and either the combination of agenesis of the CC and HSCR or the combination of agenesis of the CC and limb abnormalities, including abnormalities other than adducted thumbs.

    Funded by: NICHD NIH HHS: HD26202

    Clinical genetics 2006;69;5;414-9

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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