Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present the two siblings with X-linked hydrocephalus (XLH) and discuss the clinical features and genetical analysis of them. Case 1. The proband, a male, was delivered by the emergency cesarean section because of enlarged head circumference (44cm). His head circumference at 24 years old was 92cm. Neurological examination revealed adducted thumbs, horizontal nystagmus, hyperreflexia and spasticity of legs. He had tonic convulsions. MRI revealed a very thin layer of cerebral cortex. Molecular analysis revealed a deletion of 5 bases in exon 8 of the cell adhesion molecule L1 (L1CAM) gene located at chromosome Xq28. Case 2. The younger maternal half brother of case 1 was also born by the cesarean section, with 48cm in head circumference. A ventriculoatrial shunt was placed at the first month old. Epileptic seizures were seen. At the age of 21 years he had a head circumference of 59cm. A physical examination showed bilateral adducted thumbs, upward deviation of eyes, hyperreflexia and spasticity of legs. CT showed marked generalized ventricular enlargement including the fourth ventricle. Molecular analysis confirmed the same mutations as that of case 1. A maternal uncle had a previous diagnosis of hydrocephalus, and a sister is identified as a heterozygous carrier from molecular genetical analysis. Our results indicate that HLX is caused by the mutations in the gene for neural L1CAM in our family.
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PMID:[A family with X-linked hydrocephalus resulting from mutations in the neural cell adhesion molecule L1]. 874 50

X-linked hereditary spastic paraplegias (HSP) present with two distinct phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (nystagmus, dysarthria, mental retardation) present in the complicated form. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked complicated HSP (SPG2) and PMD. To answer this question, we carried out linkage analysis in a new pedigree with pure HSP (K101) and refined linkage in pedigree K313. The PLP gene was also screened for mutation by direct sequencing and reverse-transcriptase polymerase chain reaction (RT-PCR). In both families, the disease locus mapped to Xq22 with Lod scores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was identified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This finding demonstrates that a form of X-linked pure spastic paraplegia, X-linked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-producing mutation may be in the noncoding portions of PLP or in a nearby gene.
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PMID:Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. 878 Jan 1

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 combination of X-linked mental retardation (XLMR) and neurological disorders occurs in a number of syndromes. Differential diagnosis mostly depends on clinical data and mapping of responsible genes by linkage analysis. We present a Belgian family with severe XLMR and a progressive neurological disorder with ataxia, spasticity and convulsions. Biochemical investigations, neuroimaging and neuropathology were normal. Linkage analysis pointed to region Xq27-28 as the probable locus for the genetic defect. The sequence of the L1CAM cDNA, a possible candidate gene, proved to be normal in the patients. This suggests the presence of a genetic factor on Xq27-28, different from L1CAM, which can lead to severe XLMR and a progressive neurological disorder.
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PMID:X-linked severe mental retardation and a progressive neurological disorder in a Belgian family: clinical and genetic studies. 937 4

Hereditary spastic paraplegia (HSP) is a group of disorders whose primary symptom is insidiously progressive, lower extremity spasticity and weakness. Neuropathological analysis of "pure" HSP reveals axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts (crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis, respectively). HSP may be transmitted as an X-linked, autosomal recessive, or autosomal dominant trait, each of which is genetically heterogeneous: mutations in different genes cause clinically similar disorders. To date, there are at least three genetic loci for X-linked HSP; at least three genetic loci for autosomal recessive HSP; and at least six genetic loci for autosomal dominant HSP. The genetic basis for three of these twelve forms of HSP have been discovered. One form of autosomal recessive HSP (on chromosome 16) is due to mutations in the paraplegin gene, which encodes a mitochondrial protein homologous to metalloproteases. One form of X-linked HSP is caused by mutations in the proteolipoprotein gene, an intrinsic myelin protein. Mutation in this gene also causes the dysmyelinating disorder, Pelizeaus-Merzbacher disease. X-linked spastic paraplegia can be caused also by mutations in the L1CAM gene. This review summarizes our current understanding of genetic heterogeneity and genotype-phenotype correlation in HSP.
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PMID:Hereditary spastic paraplegia: genetic heterogeneity and genotype-phenotype correlation. 1219 86

Loss-of-function mutations of the MECP2 gene at Xq28 are associated with Rett syndrome in females and with syndromic and nonsyndromic forms of mental retardation (MR) in males. By array comparative genomic hybridization (array-CGH), we identified a small duplication at Xq28 in a large family with a severe form of MR associated with progressive spasticity. Screening by real-time quantitation of 17 additional patients with MR who have similar phenotypes revealed three more duplications. The duplications in the four patients vary in size from 0.4 to 0.8 Mb and harbor several genes, which, for each duplication, include the MR-related L1CAM and MECP2 genes. The proximal breakpoints are located within a 250-kb region centromeric of L1CAM, whereas the distal breakpoints are located in a 300-kb interval telomeric of MECP2. The precise size and location of each duplication is different in the four patients. The duplications segregate with the disease in the families, and asymptomatic carrier females show complete skewing of X inactivation. Comparison of the clinical features in these patients and in a previously reported patient enables refinement of the genotype-phenotype correlation and strongly suggests that increased dosage of MECP2 results in the MR phenotype. Our findings demonstrate that, in humans, not only impaired or abolished gene function but also increased MeCP2 dosage causes a distinct phenotype. Moreover, duplication of the MECP2 region occurs frequently in male patients with a severe form of MR, which justifies quantitative screening of MECP2 in this group of patients.
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PMID:Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. 1608 Jan 19

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

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability and recurrent pneumonia. We identified an Xq28 duplication in three families where several male patients had presented with intestinal pseudo-obstruction or bladder distension. The affected boys had similar dysmorphic facial appearances. Subsequently, we ascertained seven further families where the proband presented with similar features. We demonstrated duplications of the Xq28 region in five of these additional families. In addition to MECP2, these duplications encompassed several other genes already known to be associated with diseases including SLC6A8, L1CAM and Filamin A (FLNA). The two remaining families were shown to have intragenic duplications of FLNA only. We discuss which elements of the Xq28 duplication phenotype may be associated with the various genes in the duplication. We propose that duplication of FLNA may contribute to the bowel and bladder phenotype seen in these seven families.
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PMID:Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. 1885 60

L1CAM molecule is a cell adhesion molecule in nervous and enteric systems and is responsible for X-linked hydrocephalus (XLH) spectrum, which is a rare condition with severe congenital hydrocephalus, dysgenesis of the corpus callosum, intellectual disability, spasticity, and adducted thumbs. Several cases of XLH accompanied by Hirschsprung disease (HSCR) have been reported in the literature, but whether HSCR results from a gain-of-function mutation in cases with XLH, i.e., a neomorphic mutation, or the severe end of the L1CAM mutation spectrum remains unclear. The present patient was a Japanese boy with severe congenital hydrocephalus with aqueductal stenosis as well as hypoplasia of the corpus callosum. HSCR had been confirmed by a biopsy. A mutation analysis of the L1CAM gene showed a C61T mutation in exon 1, resulting in a truncating nonsense mutation at amino acid position 21 and producing an extremely short protein that was unlikely to interact with other proteins. These findings suggest that XLH-HSCR represents the severe end of the XLH spectrum, rather than a neomorphic mutation. A thorough abdominal investigation to rule out HSCR should be considered in patients with XLH accompanied by severe constipation.
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PMID:Hydrocephalus with Hirschsprung disease: severe end of X-linked hydrocephalus spectrum. 2235 77

Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic.
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PMID:Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. 2255 90


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