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

Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower extremities. Among eight loci linked with autosomal-dominant (AD)-HSP, the SPG4 locus on chromosome 2p22 accounts for about 40% of all patients. Recently, mutations in a new member of the AAA protein family, called spastin, have been identified as responsible for SPG4-linked AD-HSP. Here, we describe a novel missense mutation (c.1031T>A; I344K) in exon 7 of the SPG4 gene identified in a Korean family with typical clinical features of pure AD-HSP. The mutation affects the third amino acid of the highly conserved AAA cassette domain, which is the most fore part of the domain altered by a missense mutation reported so far. Clinical presentations of affected individuals carrying the I344K mutation were not different from those of pure AD-HSP with SPG4 mutations reported previously. However, it is noteworthy that neither urinary dysfunction nor involvement of upper extremities was noticed in this family. To our knowledge, this is the first report of genetically confirmed AD-HSP in Korea.
 ...
PMID:A novel missense mutation (I344K) in the SPG4gene in a Korean family with autosomal-dominant hereditary spastic paraplegia. 1220 86

A large Italian pedigree from southern Italy with autosomal dominant uncomplicated spastic paraplegia is reported. The clinical picture was uniform and characterized by insidiously progressive lower extremity weakness and spasticity. The mean age at onset of symptoms was 8.3 years. Significant linkage to the SPG3 locus on chromosome 14 was detected. The authors also report their search for mutations in a gene located in the region and its exclusion as a candidate for SPG3.
 ...
PMID:A large family with pure autosomal dominant hereditary spastic paraplegia from southern Italy mapping to chromosome 14q11.2-q24.3. 1238 59

Hereditary spastic paraplegia (HSP) is a heterogeneous condition characterised in its pure form by progressive lower limb spasticity. Mutations in SPG4 (encoding spastin) may be responsible for up to 40% of autosomal dominant (AD) cases. A cohort of 41 mostly pure HSP patients from Britain and Austria, 30 of whom displayed AD inheritance, was screened for mutations in SPG4 by single strand conformation polymorphism (SSCP) analysis followed by sequencing of samples with mobility shifts. We identified eight SPG4 mutations in pure AD HSP patients, seven of which were novel: one missense mutation within the AAA cassette (1633G>T), two splice site mutations (1130-1G>T, 1853+2T>A) and four frameshift mutations (190_208dup19, 1259_1260delGT, 1702_1705delGAAG, 1845delG). A novel duplication in intron 11 (1538+42_45dupTATA) was also detected. We report the HUGO-approved nomenclature of these mutations as well. Furthermore, we detected a silent change (1004G>A; P293P), previously reported as a mutation, which was also present in controls. The frequency of SPG4 mutations detected in pure AD HSP was 33.3%, suggesting that screening of such patients for SPG4 mutations is worthwhile. Most patients will have unique mutations. Screening of SPG4 in apparently isolated cases of HSP may be of less value.
 ...
PMID:Screening of patients with hereditary spastic paraplegia reveals seven novel mutations in the SPG4 (Spastin) gene. 1255 68

This report describes a 36-year-old female with bilateral optic atrophy. Physical examination was normal except for subclinical signs of lower limbs spasticity. Her father was affected of Strumpell-Lorrain disease. The clinical characteristics of Hereditary Spastic Paraplegia or Strumpell-Lorrain disease are: progressive spasticity of the lower limbs and pathological reflexes. Pathologically, this disease is characterized by a degeneration or demyelinization of the cortico-spinal system and, to a lesser extent, of the posterior cord and the spino-cerebellar system. Optic neuropathy and dyschromatopsy have already been reported in a small group of patients. Visual acuity ranged from 20/20 to 20/200. Visual field alterations consisted of superior bitemporal amputation. Fundus examination showed optic atrophy. The incidence of optic neuropathy in Strumpell-Lorrain disease is quite high but its presence is often overlooked. Most patients are asymptomatic, but signs of optic nerve dysfunction are evident at clinical examination. According to some authors, there is an inverse relationship between the impairment of walking and the visual dysfunction. This was also noted in our case.
 ...
PMID:[Optic neuropathy in Strumpell-Lorrain disease: presentation of a clinical case and literature review]. 1256 12

Hereditary spastic paraplegia is a rare disorder with gait disturbance due to a degeneration of the corticospinal tract, sometimes accompanied by involvement of other systems. Out of the 20 loci known so far, eight genes have now been identified, allowing the first molecular and cell studies in the pathophysiology of the disorder. These should also help to understand the function of the corticospinal tract at the molecular level and design strategies to prevent and treat spasticity due to more common causes. The proteins encoded by these genes play a role in development, in signal transduction between axons and myelinating cells, in cellular, particularly axonal trafficking or in energy metabolism. Some of them have actions in several areas of cellular function. Here we review the present knowledge about the genes involved in hereditary spastic paraplegia, a field presently undergoing rapid change.
 ...
PMID:Hereditary spastic paraplegia: clues from a rare disorder for a common problem? 1293 37

Hereditary spastic paraplegias comprise a group of clinically heterogeneous syndromes characterized by lower extremity spasticity and weakness, with distal axonal degeneration in the long ascending and descending tracts of the spinal cord. The early onset hereditary spastic paraplegia SPG3A is caused by mutations in the atlastin/human guanylate-binding protein-3 gene (renamed here atlastin-1), which codes for a 64-kDa member of the dynamin/Mx/guanylate-binding protein superfamily of large GTPases. The atlastin-1 protein is localized predominantly in brain, where it is enriched in pyramidal neurons in the cerebral cortex and hippocampus. In cultured cortical neurons, atlastin-1 co-localized most prominently with markers of the Golgi apparatus, and immunogold electron microscopy revealed a predominant localization of atlastin-1 to the cis-Golgi. Yeast two-hybrid analyses and co-immunoprecipitation studies demonstrated that atlastin-1 can self-associate, and gel-exclusion chromatography and chemical cross-linking studies indicated that atlastin-1 exists as an oligomer in vivo, most likely a tetramer. Membrane fractionation and protease protection assays revealed that atlastin-1 is an integral membrane protein with two predicted transmembrane domains; both the N-terminal GTP-binding and C-terminal domains are exposed to the cytoplasm. Together, these findings indicate that the SPG3A protein atlastin-1 is a multimeric integral membrane GTPase that may be involved in Golgi membrane dynamics or vesicle trafficking.
 ...
PMID:Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. 1450 57

Hereditary spastic paraplegias (HSP) comprise a genetically and clinically heterogeneous group of neurodegenerative disorders characterised by progressive spasticity and hyperreflexia of the lower limbs. Autosomal dominant hereditary spastic paraplegia linked to the SPG3A locus on chromosome 14q11-21 accounts for approximately 10% of autosomal dominant hereditary spastic paraplegia (ADHSP). It is caused by mutations in the SPG3A gene encoding the protein atlastin. To date, only five disease-causing mutations in the SPG3A gene have been described. We analysed 13 SPG4-negative families for mutations in the SPG3A gene and identified a mutation in 38% (5/13). Two of the mutations are novel, c.481G>C (p.A161P) and c.740A>C (p.H247P). One of the novel mutations was found both in a family with early onset of symptoms and in a late onset family. Furthermore, we report on numerous polymorphisms detected in the SPG3A gene.
 ...
PMID:Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. 1469 38

Hereditary spastic paraplegias (HSPs) are characterized by progressive lower extremity spasticity due to an axonal degeneration of motor and sensory neurons. We report a four-generation pedigree segregating an autosomal dominant phenotype for HSP and showing a linkage to the SPG10 locus, coding for Kinesin family member 5A. Subsequent to a denaturing high performance liquid chromatography (dHPLC) mutation screening we found a new missense mutation 838C>T (R280C) at an invariant arginine residue in a region involved in the microtubule binding activity.
 ...
PMID:Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. 1545 12

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. The major features of HSP are a marked phenotypic variability both among and within families and an extended genetic heterogeneity. More than 20 HSP loci and 10 spastic paraplegia genes (SPG) have been identified to date, including the genes responsible for the two most frequent forms of autosomal dominant spastic paraplegia (AD-HSP), encoding spastin (SPG4) and atlastin (SPG3A), respectively. To date, only eight mutations have been described in the atlastin gene, which was reported to account for about 10% of all AD-HSP families. We investigated 15 German and French AD-HSP families, including the 3 large pedigrees that allowed the mapping and subsequent refinement of the SPG3A locus. Three novel mutations were found in exons 4, 9, and 12 of the atlastin gene and the common R239C mutation located in exon 7 was confirmed in a 7th family of European origin. Overall, the comparison of the clinical data for all SPG3A-HSP families reported to date failed to reveal any genotype/phenotype correlation as demonstrated for other forms of AD-HSP. However, it confirmed the early onset of this form of HSP, which was observed in almost all affected individuals with a mutation in the atlastin gene.
 ...
PMID:Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A. 1551 45

Hereditary spastic paraplegia (HSP) comprises a group of inherited neurodegenerative disorders with the shared characteristics of progressive weakness and spasticity predominantly affecting the lower limbs. Limited pathological accounts have described a 'dying back' axonal degeneration in this disease. However, the distribution and extent of axonal loss has not been elucidated in a quantitative way. We have studied post-mortem material from six HSP patients and 32 controls in detail. The population of axons was examined quantitatively in the corticospinal tracts from the medulla to the lumbar spinal cord and the sensory tracts from the lumbar to upper cervical spinal cord. Myelin and axon-stained sections were employed to estimate the notional area and axonal density, respectively, of both tracts. Our results indicate that in the corticospinal tracts there is a significant reduction in area and axonal density at all levels investigated in HSP compared to controls. In the corticospinal tracts, the ratio of medulla and lumbar total axonal number was significantly greater in HSP cases compared to controls suggesting more pronounced axonal loss in the distal neuraxis in HSP than in controls. The sensory tracts in HSP, in contrast, showed a significant reduction in area and axonal density only in the upper regions of the spinal cord. Similar to the corticospinal tracts, the ratio of lumbar and upper cervical cord total axonal number in the sensory tracts was increased in HSP cases compared to controls. These findings are consistent with a length-dependent 'dying back' axonopathy. Nerve fibre loss was not size-selective with both small and large diameter fibres affected. In HSP, axonal loss is widespread and symmetrical and its extent tract-specific. The characterization of the nature of axonal loss in HSP, where this is a primary phenomenon, may help the interpretation of axonal loss in conditions such as multiple sclerosis where the sequence of events is less clear.
 ...
PMID:The extent of axonal loss in the long tracts in hereditary spastic paraplegia. 1554 Sep 98


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>