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)

Metabotropic gamma-aminobutyric acid(B) (GABAB) receptors for the major inhibitory transmitter GABA, together with metabotropic glutamate (mGLuRs) receptors, the extracellular calcium-sensing receptors (CaSRs), some V2R pheromone receptors and T1R taste receptors, belong to the family of 3 G-protein-coupled receptors (GPCRs). GABAB receptors are known to control neuronal excitability and modulate synaptic neurotransmission, playing a very important role in many physiological activities. These receptors are widely expressed and distributed in the nervous system and have been implicated in a variety of neurodegenerative and pathophysiological disorders including epilepsy, spasticity, chronic pain, depression, schizophrenia and drug addiction. To form a functional receptor entity, GABAB receptors must exist as a heterodimer consisting of GABAB1 and GABAB2 receptor subtypes with two 7-transmembrane proteins, and these subunits arise from distinct genes. The GABAB1 subunit binds the endogenous ligand within its extracellular N-terminus, whilst the GABAB2 subunit is not only essential for the correct trafficking of the GABAB1 subunit to the cell surface, but is also responsible for the interaction of the receptor with its cognate G-protein. Allosteric modulation has recently been recognized as an alternative pharmacological approach to gain selectivity in drug action. It is now generally accepted that modulators acting at the allosteric sites provide a novel perspective for the development of subtype-selective agents acting at GPCRs. These agents interact with allosteric binding sites quite separate from the highly conserved agonist binding region. In this review, we present a new class of phenylalkylamines, based on the lead compound fendiline, that are potent positive potentiators of GABAB receptor-mediated function and discuss their putative clinical applications. It is proposed that these new modulators may have therapeutic value in GABAB receptor pharmacology and are capable of selectively modifying GABAB receptor function. The allosteric modulators are offering an attractive and novel means to identify new leads, that are devoid of side effects associated with GABAB receptor agonists, and may, therefore, represent a major advance in the drug discovery process.
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PMID:Clinical potential of GABAB receptor modulators. 1638 96

gamma-Aminobutyric acid (GABA) emerged as a potentially important brain chemical just over 50 years ago, but its significance as a neurotransmitter was not fully realized until over 16 years later. We now know that at least 40% of inhibitory synaptic processing in the mammalian brain uses GABA. Establishing its role as a transmitter was a lengthy process and it seems hard to believe with our current knowledge that there was ever any dispute about its role in the mammalian brain. The detailed information that we now have about the receptors for GABA together with the wealth of agents which facilitate or reduce GABA receptor mechanisms make the prospects for further research very exciting. The emergence of glycine as a transmitter seems relatively painless by comparison to GABA. Perhaps this is appropriate for the simplest of transmitter structures! Its discovery within the spinal cord and brainstem approximately 40 years ago was followed only 2 years later by the proposal that it be conferred with 'neurotransmitter' status. It was another 16 years before the receptor was biochemically isolated. Now it is readily accepted as a vital spinal and supraspinal inhibitory transmitter and we know many details regarding its molecular structure and trafficking around neurones. The pharmacology of these receptors has lagged behind that of GABA. There is not the rich variety of allosteric modulators that we have come to readily associate with GABA receptors and which has provided us with a virtual treasure trove of important drugs used in anxiety, insomnia, epilepsy, anaesthesia, and spasticity, all stemming from the actions of the simple neutral amino acid GABA. Nevertheless, the realization that glycine receptors are involved in motor reflexes and nociceptive pathways together with the more recent advent of drugs that exhibit some subtype selectivity make the goal of designing selective therapeutic ligands for the glycine receptor that much closer.
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PMID:GABA and glycine as neurotransmitters: a brief history. 1640 94

The role of CNS neuromodulators in cognitive neurorehabilitation can be related to two main issues: 1) the negative impact on cognition of drug categories prescribed for different neurologic symptoms, such as spasticity, extrapyramidal symptoms, or epileptic seizures; 2) their possible role in neuroprotection and amelioration of the cognitive status of the patient, especially attention and memory. This paper reviews different pharmacological aspects of cognitive neurorehabilitation in epilepsy.
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PMID:Neuropharmacological aspects of cognitive neurorehabilitation in epilepsy. 1672 Sep 61

Cerebral palsy (CP) is a common pediatric disorder occurring in about 2 to 2.5 per 1000 live births. It is a chronic motor disorder resulting from a non-progressive (static) insult to the developing brain. CP is the clinical presentation of a wide variety of cerebral cortical or sub-cortical insults occurring during the first year of life. The commonest cause of CP remains unknown in 50% of the cases; prematurity remains the commonest risk factor. Children with CP suffer from multiple problems and potential disabilities such as mental retardation, epilepsy, feeding difficulties, and ophthalmologic and hearing impairments. Screening for these conditions should be part of the initial assessment. The child with CP is best cared for with an individualized treatment plan that provides a combination of interventions. This requires the provision of a number of family-centered services that make a difference in the lives of these children and their families. Management of spasticity can be challenging with a wide variety of possible therapeutic interventions. The treatment must be goal oriented, such as to assist with mobility, reduce or prevent contractures, improve positioning and hygiene, and provide comfort. Each member of the child's multidisciplinary team, including the child and both parents, should participate in the serial evaluations and treatment planning.
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PMID:Cerebral palsy: comprehensive review and update. 1676 50

The central nervous system (CNS) is, after the peripheral nervous system, the second most frequently affected organ in mitochondrial disorders (MCDs). CNS involvement in MCDs is clinically heterogeneous, manifesting as epilepsy, stroke-like episodes, migraine, ataxia, spasticity, extrapyramidal abnormalities, bulbar dysfunction, psychiatric abnormalities, neuropsychological deficits, or hypophysial abnormalities. CNS involvement is found in syndromic and non-syndromic MCDs. Syndromic MCDs with CNS involvement include mitochondrial encephalomyopathy, lactacidosis, stroke-like episodes syndrome, myoclonic epilepsy and ragged red fibers syndrome, mitochondrial neuro-gastrointestinal encephalomyopathy syndrome, neurogenic muscle weakness, ataxia, and retinitis pigmentosa syndrome, mitochondrial depletion syndrome, Kearns-Sayre syndrome, and Leigh syndrome, Leber's hereditary optic neuropathy, Friedreich's ataxia, and multiple systemic lipomatosis. As CNS involvement is often subclinical, the CNS including the spinal cord should be investigated even in the absence of overt clinical CNS manifestations. CNS investigations comprise the history, clinical neurological examination, neuropsychological tests, electroencephalogram, cerebral computed tomography scan, and magnetic resonance imaging. A spinal tap is indicated if there is episodic or permanent impaired consciousness or in case of cognitive decline. More sophisticated methods are required if the CNS is solely affected. Treatment of CNS manifestations in MCDs is symptomatic and focused on epilepsy, headache, lactacidosis, impaired consciousness, confusion, spasticity, extrapyramidal abnormalities, or depression. Valproate, carbamazepine, corticosteroids, acetyl salicylic acid, local and volatile anesthetics should be applied with caution. Avoiding certain drugs is often more beneficial than application of established, apparently indicated drugs.
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PMID:Central nervous system manifestations of mitochondrial disorders. 1694 41

Hereditary spastic paraparesis (HSP) includes a heterogeneous group of neurodegenerative diseases characterised by progressive spasticity and hyper-reflexia of the lower limbs. Autosomal dominant HSP type 4 is the most common clinical form, accounting for about 40-50% of autosomal dominant HSP families. This form is due to mutation of the gene encoding spastin (SPG4), an ATP-ase associated with a variety of cellular function (AAA). Here we describe a novel missense mutation (1297T>C; 391L>P) in exon 8 of SPG4 gene, identified in 2 members (mother and son) of an Italian family with autosomal dominant HSP, clinically pure in the mother and complicated in the son. The mutation lies in a highly conserved AAA box domain between amino acids 342 and 599 in spastin sequence. In both patients, this novel mutation was associated with the absence of relatively common clinical characteristics, such as vibratory sensory deficit and loss of sphincter control, and partial temporal epilepsy, particularly in the son, with infantile onset, secondarily generalised and moderately severe neuropsychiatric symptoms.
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PMID:Identification of a novel mutation in the spastin gene (SPG4) in an Italian family with hereditary spastic paresis. 1712 56

Two female patients with clinical features resembling spinal muscular atrophy were presented. Patient 1 presented with hypotonia and proximal weakness of extremities at age 4 months. Electromyography revealed motor neuronopathy suggestive of spinal muscular atrophy. Patient 2 presented with severe hypotonia, motor weakness, and joint contractures since birth. Muscle biopsy findings were consistent with spinal muscular atrophy. However, deletions in the survival motor neuron gene and the neuronal apoptosis inhibitor protein gene were not found in both patients. They finally manifested clinical features unlike spinal muscular atrophy: epileptic seizure, cardiomyopathy, and spasticity. The clinical course of each patient was not like that of spinal muscular atrophy type I. Mitochondrial respiratory chain complex enzyme activities in cultured skin fibroblasts were measured. Respiratory complex I enzyme activity was decreased, suggestive of isolated complex I deficiency in both patients. In conclusion, in patients who have clinical features resembling spinal muscular atrophy but no deletions in the spinal muscular atrophy gene, the possibility of the mitochondrial respiratory chain complex I deficiency should be considered.
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PMID:Mitochondrial respiratory complex I deficiency simulating spinal muscular atrophy. 1716 96

We herein report a Japanese patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC) who developed late-onset neuropsychological symptoms. He demonstrated characteristic clinical features of MLC during childhood, such as slowly progressive megalencepaly, motor impairment with ataxia and spasticity, mild mental retardation, and well-controlled epilepsy. Thereafter, he showed specific neuropsychological symptoms, such as motor and vocal tics, compulsive behavior, perseveration, acquired stuttering, and dystonia since the age of 12. His performance abilities had been unchanged but his verbal abilities had degraded during the past 14 years. Higher cortical dysfunction tests revealed a frontal lobe dysfunction. On repeated brain MRI, a leukoencephalopathy with subcortical cysts remained stationary from infancy. On single photon emission computed tomography (SPECT), a hypoperfusion in the frontal lobe was detected at the age of 3.5 and 17, but the severity of hypoperfusion was also unchanged, respectively. Our results indicate that the frontal lobe dysfunction may be relevant to the late-onset neuropsychological symptoms with MLC.
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PMID:Late-onset neuropsychological symptoms in a Japanese patient with megalencephalic leukoencephalopathy with subcortical cysts. 1723 7

The aim of this study was to examine whether severity of epilepsy, motor functioning, and epilepsy-related restrictions change in children with medically intractable epilepsy who are ineligible for epilepsy surgery. The study was a prospective, longitudinal, 2-year follow-up of 28 children (14 females, 14 males). Their median age was 6 years 1 month (range 7mo-15y 4mo). Seizure types were: complex partial seizures (n=16), secondary generalized seizures (n=7), simple partial seizures (n=2), and mixed seizures (n=3). Severity of seizures, motor impairments, motor development, activities of daily life, and epilepsy-related restrictions were rated at baseline and 6, 12, and 24 months thereafter. Seizure severity did not change significantly, nor did muscle strength, range of motion, or muscle tone. Motor retardation was ubiquitous but did not increase in 20 children without spasticity. Motor function of eight children with spasticity improved (Gross Motor Function Measure: baseline 70.5 [SD 35.5]; 24 months later 81.6 [SD 29.6], p < 0.05) but remained below reference values in four children. In the entire group, functional skills increased and caregiver assistance lessened. Restrictions did not change significantly. We conclude that during a 2-year follow-up period, in children with medically intractable epilepsy who do not have surgical intervention, seizure severity does not deteriorate, motor impairments do not increase, motor development does not deflect negatively, and activities of daily living and restrictions do not worsen.
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PMID:No deterioration in epilepsy and motor function in children with medically intractable epilepsy ineligible for surgery. 1735 79

The aim of this study was to describe the epidemiology, aetiology, and clinical findings in dyskinetic cerebral palsy (CP)in a population-based follow-up study of children born between 1991 and 1998. Age range at ascertainment was 4 to 8 years and prevalence was 0.27 per 1000 live-births. Forty-eight children were examined (27 males, 21 females; mean age 9y, range 5-13y). Thirty-nine had dystonic CP and nine a choreo-athetotic subtype. Primitive reflexes were present in 43 children and spasticity in 33. Gross Motor Function Classification System levels were: Level IV, n= 10 and Level V, n= 28. The rate of learning disability (n= 35) and epilepsy (n= 30) increased with the severity of the motor disability. Thirty-eight children had anarthria. Peri- or neonatal adverse events had been present in 34 of 42 children born at >or=34 weeks' gestation. Motor impairment was most severe in this group. Placental abruption or uterine rupture had occurred in 8 participants and 19 of the 42 near-term/term children required assisted ventilation, compared with 1% and 12% respectively in other CP types. Neuroimaging in 39 children born at >or=34 weeks revealed isolated, late third trimester lesions in 24 and a combination of early and late third trimester lesions in seven. Dyskinetic CP is the dominant type of CP found in term-born, appropriate-for-gestational-age children with severe impairments who have frequently experienced adverse perinatal events.
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PMID:Dyskinetic cerebral palsy: a population-based study of children born between 1991 and 1998. 1737 31


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