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)

Leukoencephalopathy with swelling and a discrepantly mild clinical course is a recently identified syndrome described by van der Knaap et al. It is characterised by macrocephaly occurring during the first year of life, initially normal or nearly normal development, slowly progressive ataxia and spasticity with initial preservation of intellectual functions. MRI shows diffuse abnormality of signal intensity in the hemisphere white matter with subcortical cyst-like spaces in the fronto-parietal and anterior temporal areas. The case of a 5-year-old boy whose clinical and neuroimaging findings are consistent with this syndrome is reported. The clinical and neuroimaging findings of this case may provide further information about this new syndrome which could possibly be useful also for genetic counselling.
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PMID:[Leukoencephalopathy with swelling, megalencephalopathy and surprisingly mild course. A case report]. 1076 5

Alexander disease is a rare disorder of the central nervous system of unknown etiology. Infants with Alexander disease develop a leukoencephalopathy with macrocephaly, seizures and psychomotor retardation, leading to death usually within the first decade; patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. The pathological hallmark of all forms of Alexander disease is the presence of Rosenthal fibers, cytoplasmic inclusions in astrocytes that contain the intermediate filament protein GFAP in association with small heat-shock proteins. We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers. These results suggested that a primary alteration in GFAP may be responsible for Alexander disease. Sequence analysis of DNA samples from patients representing different Alexander disease phenotypes revealed that most cases are associated with non-conservative mutations in the coding region of GFAP. Alexander disease therefore represents the first example of a primary genetic disorder of astrocytes, one of the major cell types in the vertebrate CNS.
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PMID:Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease. 1113 88

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder characterized by macrocephaly, deterioration of motor functions with ataxia, and spasticity, eventuating in mental decline. The brain appears swollen on magnetic resonance imaging, with diffuse white-matter abnormalities and the invariable presence of subcortical cysts. MLC was recently localized on chromosome 22q(tel). We have narrowed down the critical region by linkage analysis of 11 informative families with MLC to a region of approximately 250 kb, containing four known genes. One family with two patients who were siblings did not display linkage between the MLC phenotype and any of the analyzed microsatellite markers on chromosome 22q(tel), suggesting genetic heterogeneity and the existence of at least a second MLC locus. The maximum two-point LOD score for the 11 families was 6.6 at recombination fraction .02. Twelve different mutations in seven informative and six uninformative families were found in one of the candidate genes, KIAA0027, which we renamed "MLC1." The gene encodes a putative membrane protein with eight predicted transmembrane domains. The patients of one family were compound heterozygotes for mutations that both introduced stop codons. The mutations further included frameshifts, splice-acceptor mutations, a putative splice-donor mutation, and amino acid substitutions of residues in predicted transmembrane domains. These data provide strong evidence that mutations of MLC1 cause the disease.
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PMID:Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. 1125 42

Leukoencephalopathy with swelling and a discrepantly mild clinical course ("van der Knaap disease") is a recently identified syndrome. It is characterised by macrocephaly occurring during the first year of life, initially normal or nearly normal development, and slowly progressive ataxia and spasticity with initial preservation of intellectual functions. MRI shows diffuse abnormality in signal intensity, as well as swelling of the hemispheral white matter with subcortical cyst-like spaces in the fronto-parietal and anterior temporal areas. It is thought to have an autosomal recessive mode of inheritance, since many patients have consanguineous parents and more than one affected patient is often present within the same family. We report on two sibs: a 5-year old boy affected with "van der Knaap disease" and his macrocephalic sister whose first MRI (2 years 6 months) showed delayed myelination, which led us to suspect the same disease as her brother, however with subsequent normalisation at the second MRI (3 years 6 months).
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PMID:Presence of delayed myelination and macrocephaly in the sister of a patient with vacuolating leukoencephalopathy with subcortical cysts. 1150 54

Hydrocephalus-stenosis of the acqueduct of Sylvius sequence (HSAS) is characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, agenesis of the corpus callosum and mental retardation. X-linked hydrocephalus is known to be due to mutations in the gene coding for the neural cell adhesion molecule L1 (L1-CAM) and diagnosis is made by identification of a mutation in the L1-CAM gene. Prenatal diagnosis of HSAS is usually suggested on ultrasound examination showing hydrocephalus in a male fetus associated with bilateral adducted thumbs. Mutation screening of the L1-CAM gene is indicated when neuropathological examination shows hypoplasia of the corticospinal tract associated with aqueductal stenosis. We report here two cases of HSAS diagnosed within the same family by ultrasound examination in the first trimester of pregnancy when bilateral adducted thumbs were the only early ultrasound marker.
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PMID:Prenatal diagnosis of hydrocephalus-stenosis of the aqueduct of Sylvius by ultrasound in the first trimester of pregnancy. Report of two cases. 1178 37

Alexander disease is a rare, degenerative disorder of the central nervous system. It is characterized clinically by spasticity, seizures, dementia, loss of developmental milestones, and macrocephaly. Here we describe a 13-year-old boy with Alexander disease and severe scoliosis. The patient initially presented at 9 months of age, with profound mental retardation and a history of seizures. When he was 7 years old, a pediatrician had diagnosed Alexander disease (hypotonia, macrocephaly, and progressive low-density white matter predominantly in the frontal region on computed tomography examination). From the age of 10, thoracolumbar scoliosis had gradually become severe. Because treatment using a corrective brace would have produced major problems because of the patient's mental retardation, the scoliosis was successfully treated surgically, by careful posterior spinal fusion with instrumentation, and an autologous iliac crest bone graft. A 64 degrees curve was corrected to 18 degrees (72% correction). Scoliosis with Alexander disease is considered to be very rare because patients with the disease seldom survive long enough to develop spinal deformities.
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PMID:Scoliosis in a patient with Alexander disease. 1213 31

Serial neuroimaging studies in Alexander's disease were obtained on an African-American girl who died at 4z\x years of age. She presented with macrocephaly, psychomotor retardation, spasticity, a seizure disorder, and hydrocephalus. A thorough metabolic evaluation of defined leukodystrophies, including Krabbe's disease, adrenoleukodystrophy, metachromatic leukodystrophy, Canavan's disease, and Leigh disease, was negative. A diagnosis of Alexander's disease was made based on the clinical features and ruling out all other possible causes. It was confirmed by pathologic findings of numerous subpial, subependymal, and perivascular Rosenthal fibers throughout the entire cerebrum. Interestingly, autopsy also identified the stenotic sylvian aqueduct owing to Rosenthal fiber accumulation, explaining the origin of hydrocephalus. The evolution of magnetic resonance imaging findings appears to be unique in this disease.
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PMID:Infantile Alexander's disease: serial neuroradiologic findings. 1217 72

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive disorder characterized by macrocephaly, deterioration of motor function with ataxia, spasticity and mental decline. It has been revealed that the mutations in the gene, KIAA0027, were responsible for MLC and the gene was renamed subsequently 'MLC1'. A 41-year-old Japanese male with MLC, in whom a homozygous missense mutation, TCG to TTG at codon 93 resulting in S93L, was detected in the MLC1 gene, was described. MRI revealed marked cerebral atrophy and enlargement of the ventricular system. The subject's motor function had severely deteriorated, while his cognitive function had maintained at the level of a 2-year-old for the past 10 years. The mutation in the MLC1 gene of the patient is considered to be a common mutation responsible for MLC in Japanese patients because the same mutation had been detected in two other Japanese patients with MLC.
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PMID:A case of megalencephalic leukoencephalopathy with subcortical cysts (van der Knaap disease): molecular genetic study. 1285 May 17

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.
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PMID:Canavan disease: a monogenic trait with complex genomic interaction. 1456 59

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The deficiency of aspartoacylase leads to increased concentration of N-acetylaspartic acid in brain and body fluids. The failure to hydrolyze N-acetylaspartic acid causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia in early life, which changes to spasticity, macrocephaly, head lag, and progressive severe mental retardation. Although Canavan's disease is panethnic, it is most prevalent in the Ashkenazi Jewish population. Research at the molecular level led to the cloning of the gene for aspartoacylase and development of a knockout mouse for Canavan's disease. These developments have afforded new tools for research in the attempts to understand the pathophysiology of Canavan's disease, design new therapies, and explore methods for gene transfer to the central nervous system.
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PMID:Molecular basis of Canavan's disease: from human to mouse. 1457 38


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