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)

Hereditary spastic paraplegias (HSPs; SPG1-48) are inherited neurological disorders characterized by lower extremity spasticity and weakness. Loss-of-function mutations in the SPG20 gene encoding spartin cause autosomal recessive Troyer syndrome (SPG20), which has additional features of short stature, cognitive deficits and distal amyotrophy. To identify cellular impairments underlying Troyer syndrome, we generated Spg20-/- mice, which exhibit progressive gait defects. Although gross central nervous system pathology appeared largely normal, cerebral cortical neurons cultured from neonatal Spg20-/- mice exhibited increased axon branching, a phenotype suppressed by reintroducing spartin and which required its interaction with the endosomal sorting complex required for transport (ESCRT)-III protein IST1. Analysis of the bone morphogenetic protein (BMP) signaling pathway in Spg20-/- embryonic fibroblasts indicated that Smad1/5 phosphorylation is modestly elevated, possibly due to alterations in BMP receptor trafficking. Cytokinesis was impaired in embryonic fibroblasts cultured from Spg20-/- mice, and binucleated chondrocytes were prominent in epiphyseal growth plates of bones in Spg20-/- mice, perhaps explaining the short stature of patients. Finally, adipose tissue from Spg20-/- female mice exhibited increased lipid droplet (LD) numbers and alterations in perilipin levels, supporting a role for spartin in LD maintenance. Taken together, our results support multimodal functions for spartin that provide important insights into HSP pathogenesis.
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PMID:Spg20-/- mice reveal multimodal functions for Troyer syndrome protein spartin in lipid droplet maintenance, cytokinesis and BMP signaling. 2261 77

Amyotrophic lateral sclerosis (ALS) represents the most common motoneuron disorder in adulthood. It is characterized by selective degeneration of the motoneurons. About 10% of patients have a genetically determined ALS. Clinically, ALS is characterized by coexistence of signs of the first motoneuron, such as spasticity and hyperreflexia, as well as the second motoneuron, such as muscular atrophy and fasciculations. If such signs are present in at least three regions and if other possible causes have been excluded, a definite diagnosis of ALS can be made based on the revised El-Escorial criteria. Initial manifestations are often focalized and generalization develops during the course. The glutamate antagonist riluzole is worldwide the only approved ALS treatment. However, symptomatic treatments to ameliorate spasticity, drooling, speech and swallowing problems, and assisted ventilation to treat respiratory failure are essential.
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PMID:[Amyotrophic lateral sclerosis--diagnosis and treatment]. 2276 33

Inherited myelopathies are a small, but important subset of diseases that cause dysfunction of the spinal cord. Manifestations can include various combinations of signs and symptoms, including disturbance of gait, spasticity, paraplegia, amyotrophy, sensory loss, and urinary sphincter dysfunction. These diseases can be divided into classes that include (1) distal axonopathies-exemplified by hereditary spastic paraplegia, (2) motor neuron diseases including familial amyotrophic lateral sclerosis and spinal muscular atrophy, (3) inborn errors of metabolism such as adrenomyeloneuropathy, and (4) other inherited diseases with myelopathy as part of their spectrum of manifestations. Although the inherited myelopathies are relatively rare diseases, knowledge of them and their manifestations is important for the physician faced with a patient with myelopathy, particularly if there are similarly affected individuals in the patient's family. In addition, understanding the pathophysiologic underpinnings of these diseases provides insight into the molecular biology of the nervous system and provides a gateway toward developing treatments for these diseases.
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PMID:Inherited myelopathies. 2296 Nov 86

Premature declines in function among adults with cerebral palsy (CP) are generally attributed to weakness, spasticity and orthopaedic abnormalities, as well as chronic pain and fatigue. Very little research or clinical attention has been devoted to the confluence and consequences of early muscle wasting and obesity as mediators of secondary comorbidity in this population, and perhaps more importantly, to the role of lifestyle to potentiate these outcomes. At present, there are no national surveillance programmes that monitor chronic health in adults with CP; however, mortality records have demonstrated a greater prevalence of coronary heart disease as compared with the general population. Although by definition, CP is a 'non-progressive' condition, secondary factors such as habitual sedentary behaviour, obesity, and premature sarcoepenia may increase the severity of functional impairment throughout adulthood, and lead to cardiometabolic disease, fragility and/or early mortality. Herein we describe the heightened health risk represented in adults with CP, and discuss the hallmark phenotypic features that coincide with ageing, obesity and cardiometabolic disorders. Moreover, we provide discussion regarding the protective role of habitual physical activity to stimulate anti-inflammatory pathways and to ameliorate global risk. Although physical therapeutic modalities are already widely acknowledged as a vital component to improve movement quality in CP, the purpose of this review was to present a compelling case for the value of lifelong physical activity participation for both function and cardiometabolic health preservation.
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PMID:Chronic disease risk among adults with cerebral palsy: the role of premature sarcopoenia, obesity and sedentary behaviour. 2309 88

Hereditary spastic paraplegia(HSP or SPG) is a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by progressive spasticity, weakness of lower limbs, and pathologically by retrograde axonal degeneration of corticospinal tracts and posterior spinal tracts. Presence of additional features allows differentiation between simple and complex forms of the disease. Genetically, 16 loci for HSP accompanied by distal amyotrophy have been mapped, for which 13 genes have been identified. With the identification of causative genes, the molecular mechanism of this disease is gradually elucidated.
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PMID:[Molecular genetics study of hereditary spastic paraplegia accompanied by distal amyotrophy-an update]. 2392 10

Whole exome sequencing in two-generational kindred from Bangladesh with early onset spasticity, mild intellectual disability, distal amyotrophy, and cerebellar atrophy transmitted as an autosomal recessive trait identified the following two missense mutations in the EXOSC3 gene: a novel p.V80F mutation and a known p.D132A change previously associated with mild variants of pontocerebellar hypoplasia type 1. This study confirms the involvement of RNA processing proteins in disorders with motor neuron and cerebellar degeneration overlapping with spinocerebellar ataxia 36 and rare forms of hereditary spastic paraplegia with cerebellar features.
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PMID:Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3. 2397 61

Motor neuron diseases (MNDs) are an etiologically heterogeneous group of disorders of neurodegenerative origin, which result in degeneration of lower (LMNs) and/or upper motor neurons (UMNs). Neurodegenerative MNDs include pure hereditary spastic paraplegia (HSP), which involves specific degeneration of UMNs, leading to progressive spasticity of the lower limbs. In contrast, spinal muscular atrophy (SMA) involves the specific degeneration of LMNs, with symmetrical muscle weakness and atrophy. Amyotrophic lateral sclerosis (ALS), the most common adult-onset MND, is characterized by the degeneration of both UMNs and LMNs, leading to progressive muscle weakness, atrophy, and spasticity. A review of the comparative neuroanatomy of the human and zebrafish motor systems showed that, while the zebrafish was a homologous model for LMN disorders, such as SMA, it was only partially relevant in the case of UMN disorders, due to the absence of corticospinal and rubrospinal tracts in its central nervous system. Even considering the limitation of this model to fully reproduce the human UMN disorders, zebrafish offer an excellent alternative vertebrate model for the molecular and genetic dissection of MND mechanisms. Its advantages include the conservation of genome and physiological processes and applicable in vivo tools, including easy imaging, loss or gain of function methods, behavioral tests to examine changes in motor activity, and the ease of simultaneous chemical/drug testing on large numbers of animals. This facilitates the assessment of the environmental origin of MNDs, alone or in combination with genetic traits and putative modifier genes. Positive hits obtained by phenotype-based small-molecule screening using zebrafish may potentially be effective drugs for treatment of human MNDs.
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PMID:Zebrafish models of human motor neuron diseases: advantages and limitations. 2470 36

Silver syndrome/spastic paraplegia 17 is an autosomal dominant, complicated hereditary spastic paraparesis in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Heterozygous mutations of its causative gene, the Berardinelli-Seip congenital lipodystrophy gene, have a broader spectrum of phenotypes including Silver syndrome, distal hereditary motor neuropathy type V and Charcot-Marie-Tooth disease type 2. We report a Chinese family carrying the S90L mutation with Silver syndrome and discuss our literature review of the clinical phenotypes of S90L. Most reported patients (21 of 26) with this mutation showed a phenotype of Silver syndrome. The S90L mutation is predominantly associated with Silver syndrome.
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PMID:BSCL2 S90L mutation in a Chinese family with Silver syndrome with a review of the literature. 2548 75

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by muscular atrophy, spasticity, and bulbar signs caused by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. Here, we studied movement execution and inhibition in ALS patients using a stop-signal paradigm and functional magnetic resonance imaging. Seventeen ALS patients and 17 age-matched healthy controls performed a stop-signal task that required responding with a button press to a right- or left-pointing black arrow (go-stimuli). In stop-trials, a red arrow (stop-stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. Patients had by trend higher reaction times in go-trials but did not differ significantly in their inhibition performance. Patients showed stronger inhibition-related activity in inferior, superior, and middle frontal gyri as well as in putamen and pallidum. Error-related activity, conversely, was found to be stronger in healthy controls, particularly in the insula bilaterally. Patients also showed increased activity in the motor cortex during button presses. The results provide evidence for altered prefrontal and subcortical networks underlying motor execution, motor inhibition, and error monitoring in ALS.
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PMID:Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying motor inhibition and action monitoring. 2591 37

Troyer syndrome (MIM#275900) is an autosomal recessive form of complicated hereditary spastic paraplegia. It is characterized by progressive lower extremity spasticity and weakness, dysarthria, distal amyotrophy, developmental delay, short stature, and subtle skeletal abnormalities. It is caused by deleterious mutations in the SPG20 gene, encoding spartin, on Chromosome 13q13. Until now, six unrelated families with a genetically confirmed diagnosis have been reported. Here we report the clinical findings in three brothers of a consanguineous Moroccan family, aged 24, 17, and 7 yr old, with spastic paraplegia, short stature, motor and cognitive delay, and severe intellectual disability. Targeted exon capture and sequencing showed a homozygous nonsense mutation in the SPG20 gene, c.1369C>T (p.Arg457*), in the three affected boys.
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PMID:SPG20 mutation in three siblings with familial hereditary spastic paraplegia. 2867 90


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