Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 1972, Fried described a large Scottish family affected by X linked mental retardation (XLMR), hydrocephalus, and mild facial dysmorphism. The phenotype has considerable similarity to the MASA syndrome, which results from mutations of the L1CAM gene in Xq28, and this family has since been assumed to be an example of this condition. We have reinvestigated the family for linkage to X chromosome markers, and obtained additional clinical information on surviving affected subjects. The phenotype in these patients has evolved into a distinctive syndrome, with severe mental retardation (MR), spastic diplegia, ventricular dilatation, and calcification of the basal ganglia. Linkage to Xq28 markers has been excluded, suggesting that Fried syndrome is not allelic with MASA syndrome. Two point and multipoint linkage analysis indicates that the gene for this condition lies within the interval KAL-DXS989 in Xp22. We propose the designation Fried syndrome to emphasise the disorder's distinctive phenotype.
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PMID:Fried syndrome is a distinct X linked mental retardation syndrome mapping to Xp22. 922 59

X-linked hydrocephalus, MASA syndrome and certain forms of X-linked spastic paraplegia and agenesis of corpus callosum are now known to be due to mutations in the gene for the neural cell adhesion molecule L1 (19, 30). As a result, these syndromes have recently been reclassified as CRASH syndrome, an acronym for Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spasticity and Hydrocephalus (8). A comparison of existing case reports with molecular genetic analysis reveals a striking correlation between the type of mutation in the L1CAM gene and the severity of the disease. Mutations that produce truncations in the extracellular domain of the L1 protein are more likely to produce severe hydrocephalus, grave mental retardation or early death than point mutations in the extracellular domain or mutations affecting only the cytoplasmic domain of the protein. While less severe than extracellular truncations, point mutations in the extracellular domain do produce more severe neurologic problems than mutations in just the cytoplasmic domain.
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PMID:CRASH syndrome: mutations in L1CAM correlate with severity of the disease. 926 56

The neuronal cell adhesion molecule L1 (L1CAM) is a transmembrane glycoprotein belonging to the immunoglobulin superfamily and is essential in the development of the nervous system. It is mainly expressed on neurons and Schwann cells, and plays a key role in axon outgrowth and pathfinding through interactions with various extracellular ligands and intracellular second messenger systems. Mutations in L1 are responsible for a wide spectrum of neurologic abnormalities and mental retardation. This spectrum includes X-linked hydrocephalus, MASA syndrome, X-linked complicated spastic paraplegia type 1 and X-linked agenesis of the corpus callosum. These four diseases were initially described as distinct clinical entities with an overlapping clinical spectrum, but can now be lumped into one syndrome caused by mutations in the L1 gene. The main clinical features of this spectrum are Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus, which has led to the acronym CRASH syndrome.
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PMID:L1-associated diseases: clinical geneticists divide, molecular geneticists unite. 930 Jun 53

Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.
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PMID:L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling. 944 Aug 2

The L1 cell adhesion molecule (L1CAM) is a neuronal gene involved in the development of the nervous system. Mutations in L1CAM are known to cause several clinically overlapping X linked mental retardation conditions: X linked hydrocephalus (HSAS), MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), spastic paraplegia type I (SPG1), and X linked agenesis of the corpus callosum (ACC). In an analysis of a family with HSAS, we identified a C-->T transition (C924T) in exon 8 that was initially thought to have no effect on the protein sequence as the alteration affected the third base of a codon (G308G). Extensive analysis of the other 27 exons showed no other alteration. A review of the sequence surrounding position 924 indicated that the C-->T transition created a potential 5' splice site consensus sequence, which would result in an in frame deletion of 69 bp from exon 8 and 23 amino acids of the L1CAM protein. RT-PCR of the RNA from an affected male fetus and subsequent sequence analysis confirmed the use of the new splice site. This is the first report of a silent nucleotide substitution in L1CAM giving rise to an alteration at the protein level. Furthermore, it shows that as mutation analysis plays an ever more important role in human genetics, the identification of a synonymous base change should not be routinely discounted as a neutral polymorphism.
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PMID:A silent mutation, C924T (G308G), in the L1CAM gene results in X linked hydrocephalus (HSAS). 964 85

The L1CAM gene, which is located in Xq28 and codes for a neuronal cell adhesion molecule, is involved in three distinct conditions: HSAS (hydrocephalus-stenosis of the aqueduct of Sylvius), MASA (mental retardation, aphasia, shuffling gait, adductus thumbs), and SPG1 (spastic paraplegia). Molecular analysis of the L1CAM gene is labor-intensive because of the size of the coding region, which is fragmented in numerous exons, and because of the great allelic heterogeneity and distribution of the mutations. The FAMA (fluorescent assisted mismatch analysis) method combines the excellent sensitivity of the chemical cleavage method for scanning PCR fragments larger than 1 kb and the power of automated DNA sequencers. In order to optimize this method for L1CAM, we divided the gene into nine genomic fragments, each including three to four exons. These fragments were PCR-amplified using nine sets of primers containing additional rare universal sequences. A second-stage PCR, per formed with the two dye-labeled universal primers, allowed us to generate 1-kb-labeled fragments, which were then submitted to the chemical cleavage analysis. Among 12 French families with HSAS and/or MASA, we identified nine distinct L1CAM mutations, seven of which were novel, and an intronic variation. This study demonstrates that FAMA allows rapid and reliable detection of mutations in the L1CAM gene and thus represents one of the most appropriate methods to provide diagnosis for accurate genetic counseling in families with HSAS, MASA, or SPG1.
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PMID:Identification of novel L1CAM mutations using fluorescence-assisted mismatch analysis. 974 77

L1 disease is a group of overlapping clinical phenotypes including X-linked hydrocephalus, MASA syndrome, spastic paraparesis type 1, and X-linked agenesis of corpus callosum. The patients are characterized by hydrocephalus, agenesis or hypoplasia of corpus callosum and corticospinal tracts, mental retardation, spastic paraplegia, and adducted thumbs. The responsible gene, L1CAM, encodes the L1 protein which is a member of the immunoglobulin superfamily of neuronal cell adhesion molecules. The L1 protein is expressed in neurons and Schwann cells and seems to be essential for nervous system development and function. The patients' gene mutations are distributed over the functional protein domains. The exact mechanisms by which these mutations cause a loss of L1 protein function are unknown. There appears to be a relationship between the patients' clinical phenotype and the genotype. Missense mutations in extracellular domains or mutations in cytoplasmic regions cause milder phenotypes than those leading to truncation in extracellular domains or to non-detectable L1 protein. Diagnosis of patients and carriers, including prenatal testing, is based on the characteristic clinical picture and DNA mutation analyses. At present, there is no therapy for the prevention or cure of patients' neurological disabilities.
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PMID:Genetic and clinical aspects of X-linked hydrocephalus (L1 disease): Mutations in the L1CAM gene. 1143 88

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.
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PMID:A novel L1CAM mutation with L1 spectrum disorders. 1566 85

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. =
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PMID:Prenatal diagnosis in a family with X-linked hydrocephalus. 1608 63

Mutations in the X-chromosomal gene (L1CAM) for cell adhesion molecule L1 are associated with a heterogeneous group of conditions that include agenesis of the corpus callosum, hydrocephalus, spastic paraplegia, adducted thumbs and mental retardation (L1-spectrum disease, CRASH or MASA syndrome). Although L1CAM is expressed during renal development and L1cam-deficient mice have congenital malformations of the kidney and the urinary tract, L1CAM mutations have not been associated with renal anomalies in men. We report on a boy with prenatally detected hydrocephalus. After his birth, bilateral duplex kidneys and ureters, with a unilateral mega-ureter serving a hydronephrotic upper pole, as well as agenesis of the corpus callosum, adducted thumbs, spasticity, and mental retardation were recognized, fulfilling the criteria of an L1-spectrum disease. Genetic testing of the patient and his mother identified a 2 bp deletion in the invariant splice consensus sequence of intron 18 of L1CAM, predicting a largely truncated or absent protein. At the age of 9 years, 7 years after heminephrectomy, the boy has normal renal function. This observation suggests that patients with L1CAM mutations may have renal abnormalities as seen in the L1cam-deficient mouse model. L1CAM might, therefore, also be considered a possible candidate gene for renal malformations.
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PMID:L1CAM mutation in a boy with hydrocephalus and duplex kidneys. 1729 22


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