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)

The arguments over the nomenclature of the syndrome are reviewed. Ethical considerations favour replacing the present eponyms with the title of panthothenate kinase-associated neurodegeneration (PKAN), now that more is known about the cause of the condition. The symptoms and signs of the syndrome are described, and these can present from infancy to adult life. Dystonia, involuntary movements and spasticity are prominent causes of disability. If the onset is delayed the presentation can be unusual. Tests that can help in diagnosis are reviewed, especially the "eye of the tiger" revealed by magnetic resonance imaging scanning. Death usually occurs about 10 years after the onset, but the course may be more prolonged. The findings on autopsy are also considered, with the typical findings of iron pigment deposits and axonal spheroids. Then the causes are discussed. Once the responsible gene PANK2 had been discovered on chromosome 20 it was found that this encoded for pantothenate kinase which is essential for the synthesis of coenzyme A from pantothenate; and this is integral to fatty acid synthesis and energy metabolism. Also this can lead to a concentration of cysteine in the basal ganglia, and then to an accumulation of iron in these areas. The cysteine-iron complex will result in tissue damage by promoting oxidative stress, as in some other neurodegenerative diseases. The syndrome of PKAN can therefore be identified as a disorder of pantothanate, vitamin B5, metabolism. Infantile neuroaxonal dystrophy is briefly described as there have been suggestions that it is a variety of PKAN, but the evidence is in favour of the two diseases being separate entities. There may as yet be no specific treatment for this syndrome, but much can be done to help these children. Drugs may be needed to control epilepsy, and when dystonia is severe it may be possible to alleviate this by medical or surgical means. Also there will be other problems needing expert management, such as the provision of alternative means of communication if dysarthria is marked. The hope for the future is that now the cause has been found it will be possible to use methods such as antioxidative therapy and gene induction procedures.
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PMID:Pantothenate kinase-associated neurodegeneration (Hallervorden-Spatz syndrome). 1237 76

A 37-year-old macrocephalic woman was investigated for increasing gait disturbance due to longstanding spasticity and ataxia. MRI showed widespread bilateral increase in signal from cerebral white matter on T2-weighted images. Numerous subcortical cysts were visible in anterior-temporal and parietal regions. These clinical and neuroradiological features are those of megalencephalic leukoencephalopathy with subcortical cysts (MLC), a recently delineated white-matter disease with onset in childhood. Quantitative localised proton MR spectroscopy of white matter revealed marked reduction of N-acetylaspartate, creatine, and choline with normal values for myo-inositol, consistent with axonal loss and astrocytic proliferation. Diffusion tensor imaging showed an increased apparent diffusion coefficient and reduced anisotropy in affected white matter pointing to reduced cell density with an increased extracellular space. These findings are in line with histological changes alterations known to occur in MLC.
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PMID:Megalencephalic leukoencephalopathy with subcortical cysts in an adult: quantitative proton MR spectroscopy and diffusion tensor MRI. 1268 14

A 48-year-old women was admitted to our hospital because of gradually developed spastic gait. She showed spasticity of the lower extremities with mild weakness. Laboratory tests disclosed decreased WBC and platelet counts and mild increases of transaminase and total bilirubin. Blood manganese level was markedly increased (6.0 micrograms/dl). Abdominal ultrasound showed splenomegaly, and abdominal angiography showed a dilatation of the portal and paraumbilical veins. T1-weighted MR images showed high signal intensities at the bilateral globus pallidus and cerebral peducles, and T2-weighted images showed high signal intensities at the bilateral deep white matter, posterior limbs of the internal capsule and right upper cervical spinal cord. Following the diagnosis of IPH, splenectomy was performed. The blood level of manganese decreased thereafter and her neurological deficits gradually improved. Hepatic diseases often show high signal intensities at the basal ganglia on T1-weighted images, and this seemed to be due to accumulation of manganese in our case. Because demyelination or axonal injury of the spinal cord are found in hepatic disease, we speculate that the high signal intensities at the spinal cord on T2-weighted images of our case reflect hepatic myelopathy, which may also be caused by high blood levels of manganese.
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PMID:[A case of idiopathic portal hypertension (IPH) with hypermanganemia presenting as spastic gait]. 1271 91

Retrospective clinical analysis with a special focus on pyramidal syndrome expression in the disease course as well as morphological study of brain and spinal structures in all levels of cortical-spinal projection (from brain motor cortex to spinal lumbar segments) have been conducted for 11 section cases of lateral amyotrophic sclerosis (LAS), sporadic type. Two groups of patients were studied: with pronounced pyramidal syndrome (spasticity, hyperreflexia, etc)--7 cases and with some signs of pyramidal deficiency (anisoreflexia, stability of peritoneal reflexes)--4 cases. Pyramidal syndrome in LAS is considered as an emergence of current neurodegenerative process, embracing a significant part of upper motor neurons of both precentral convolution and its axons along the whole length of cerebrospinal axis in the form of cytoplasmic inclusions and axonal spheroids. A presence of pathomorphological changes in other upper segmental structures of motor control reveals their role in pyramidal deficiency. Comparative analysis showed that expression of pyramidal syndrome signs and its correlation to atrophic paresis appearances is specifically determined by the severity of upper and lower motor neurons lesions. With regard to morphological changes in CNS structures, the peculiarities of some pyramidal syndrome appearances in LAS are analyzed.
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PMID:[Pyramidal syndrome in lateral amyotrophic sclerosis: clinico-morphological analysis]. 1278 20

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.
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PMID:Hereditary spastic paraplegia: clues from a rare disorder for a common problem? 1293 37

Neuromuscular blockade via injection of alcohol, phenol, or botulinum toxin reduces the tone of overactive muscles in order to restore the appropriate balance between agonists and antagonists. Such a restoration allows improved stretch and increased resting length and can reduce the likelihood of contracture. Alcohol or phenol, injected onto the motor nerve, denatures proteins and promotes axonal degeneration. The onset of action is within hours, whereas the duration of action is variable, ranging from 2 weeks to 6 months and beyond. The advantages of alcohol or phenol chemodenervation lie in their low cost and lack of antigenicity. The disadvantages include the technical difficulty of the injections and significant risk for pain as a result of treatment. Botulinum toxins, purified forms of Clostridium botulinum exotoxins, are injected directly into muscle, where they cleave one or more vesicle fusion proteins, thus blocking release of acetylcholine at the neuromuscular junction. Three commercial products--two of serotype A and one of B--are available. Each differs in its unit potency, side effects, and duration of action. On average, botulinum toxin has a clinical onset of action approximately 12 to 72 hours after injection, with a peak effect at 1 to 3 weeks. Effects then plateau for 1 to 2 months, with patients often requiring reinjection approximately every 3 months. Side effects may include local discomfort at the site of the injection and excessive weakness of the injected or nearby muscles, although more distant effects may occur. Antibody formation is a significant clinical concern and eventually obviates treatment benefit in approximately 5% of patients. Switching serotypes may be effective, at least temporarily. Consensus dosing guidelines have been developed and are presented within. Numerous studies have suggested that botulinum toxin has a role in the care of children with spasticity or dystonia related to cerebral palsy, and may improve equinus, gait, upper extremity use, comfort, and care. Evidence of functional improvement remains equivocal in the severely impaired child; however, there is evidence for improvement in less impaired children. The optimal candidate for injectable neuromuscular blockade is one who has a limited number of muscles that need treatment, who does not have fixed contracture, and who retains selective motor control. The ultimate goal of treatment for the hypertonic child is to maximize function, comfort, and independence. Hypertonia is only one aspect of the upper motoneuron syndrome, which includes both positive and negative symptoms. The treatment program, in which chemodenervation is only one tool, requires a multidisciplinary evaluation and individualized plan to address the whole patient.
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PMID:Injectable neuromuscular blockade in the treatment of spasticity and movement disorders. 1367 71

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.
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PMID:Cellular localization, oligomerization, and membrane association of the hereditary spastic paraplegia 3A (SPG3A) protein atlastin. 1450 57

The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders characterized by progressive lower-extremity weakness and spasticity. The molecular pathogenesis is poorly understood. We report discovery of a dominant negative mutation in the NIPA1 gene in a kindred with autosomal dominant HSP (ADHSP), linked to chromosome 15q11-q13 (SPG6 locus); and precisely the same mutation in an unrelated kindred with ADHSP that was too small for meaningful linkage analysis. NIPA1 is highly expressed in neuronal tissues and encodes a putative membrane transporter or receptor. Identification of the NIPA1 function and ligand will aid an understanding of axonal neurodegeneration in HSP and may have important therapeutic implications.
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PMID:NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). 1450 10

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.
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PMID:Evidence of kinesin heavy chain (KIF5A) involvement in pure hereditary spastic paraplegia. 1545 12

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.
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PMID:The extent of axonal loss in the long tracts in hereditary spastic paraplegia. 1554 Sep 98


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