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 paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterized by progressive spasticity and weakness of the lower limbs. HSP genetic loci are designated SPG1-72 in order of their discovery. In 206 Japanese families with autosomal dominant HSP, SPG4 was the most common form, accounting for 38%, followed by SPG3A (5%), SPG31 (5%), SPG10 (2%), and SPG8 (1%). We have identified novel mutations in the C12orf65 gene and the LYST gene in several Japanese families with autosomal recessive HSP. JASPAC will facilitate gene discovery and mechanistic understanding of HSP. The future challenge will be the establishment of treatment of HSP.
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PMID:[Hereditary spastic paraplegia: up to date]. 2551 60

Hereditary spastic paraplegias (HSPs) were characterized by progressive leg spasticity with various additional symptoms as follows: peripheral neuropathy, cerebellar ataxia, extrapyramidal symptoms, mental impairment, optic atrophy, pigmental retinopathy, and so on. Many genetic loci (SPG1-72) and more than 50 genes were identified so far. Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55). We also identified the mutation of the LYST gene, that is causative gene for Chediak-Higashi syndrome, for the autosomal recessive complicated spastic paraplegia with cerebellar ataxia and neuropathy. In this review, we introduced clinical symptoms about our cases suffered from SPG4, SPG11, SPG55 and complicated spastic paraplegia due to adult Chediak-Higashi syndrome. SPG4, that is usually exhibits pure spastic paraplegia, but our case shows mental impairment and variable age of onset. HSPs are clinically and genetically heterogeneous syndromes, i. e., same gene mutations with different clinical manifestations or same clinical presentations with different gene mutations. We should perform board range differential diagnosis and analysis of numerous causative genes to the patients with spastic paraplegia, especially autosomal recessive trait.
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PMID:[Clinical aspects of hereditary spastic paraplegias]. 2551 61

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder which is characterized by spasticity of the leg. HSP is a clinically and genetically heterogeneous disorder. Mutations were detected in about 60% of autosomal dominant HSP patients. SPG4 is the most common form of autosomal dominant HSP worldwide. In autosomal recessive HSP patients, we detected mutations in about 40% using exome sequencing. Causes of autosomal recessive HSP are more heterogeneous than those of autosomal dominant HSP. We have to consider leukodystrophies/leukoencephalopathies, motor neuron diseases, spinocerebellar degenerations, or various metabolic diseases as differential diagnosis of complicated HSP. X-linked HSP or HSP with mitochondorial inheritance are rare. Further work on familial patients would lead to identify novel causative genes, which helps to understand pathophysiology of HSP and the nature of corticospinal tract and establish disease modifying therapy. Mutation detection rate for sporadic HSP is low at the moment, and molecular delineation of sporadic HSP is expected in the future.
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PMID:[Molecular genetics and gene analysis of hereditary spastic paraplegia]. 2567 95

Mutations in SPAST, encoding spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). HSP is characterized by weakness and spasticity of the lower limbs, owing to progressive retrograde degeneration of the long corticospinal axons. Spastin is a conserved microtubule (MT)-severing protein, involved in processes requiring rearrangement of the cytoskeleton in concert to membrane remodeling, such as neurite branching, axonal growth, midbody abscission, and endosome tubulation. Two isoforms of spastin are synthesized from alternative initiation codons (M1 and M87). We now show that spastin-M1 can sort from the endoplasmic reticulum (ER) to pre- and mature lipid droplets (LDs). A hydrophobic motif comprised of amino acids 57 through 86 of spastin was sufficient to direct a reporter protein to LDs, while mutation of arginine 65 to glycine abolished LD targeting. Increased levels of spastin-M1 expression reduced the number but increased the size of LDs. Expression of a mutant unable to bind and sever MTs caused clustering of LDs. Consistent with these findings, ubiquitous overexpression of Dspastin in Drosophila led to bigger and less numerous LDs in the fat bodies and increased triacylglycerol levels. In contrast, Dspastin overexpression increased LD number when expressed specifically in skeletal muscles or nerves. Downregulation of Dspastin and expression of a dominant-negative variant decreased LD number in Drosophila nerves, skeletal muscle and fat bodies, and reduced triacylglycerol levels in the larvae. Moreover, we found reduced amount of fat stores in intestinal cells of worms in which the spas-1 homologue was either depleted by RNA interference or deleted. Taken together, our data uncovers an evolutionarily conserved role of spastin as a positive regulator of LD metabolism and open up the possibility that dysfunction of LDs in axons may contribute to the pathogenesis of HSP.
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PMID:Spastin binds to lipid droplets and affects lipid metabolism. 2587 45

Mutations in more than 70 distinct loci and more than 50 mutated gene products have been identified in patients with hereditary spastic paraplegias, a diverse group of neurological disorders characterized predominantly, but not exclusively, by progressive lower limb spasticity and weakness resulting from distal degeneration of corticospinal tract axons. Mutations in the SPAST (previously known as SPG4) gene that encodes the microtubule-severing protein called spastin, are the most common cause of the disease. The aetiology of the disease is poorly understood, but partial loss of microtubule-severing activity resulting from inactivating mutations in one SPAST allele is the most postulated explanation. Microtubule severing is important for regulating various aspects of the microtubule array, including microtubule number, length, and mobility. In addition, higher numbers of dynamic plus-ends of microtubules, resulting from microtubule-severing events, may play a role in endosomal tubulation and fission. Even so, there is growing evidence that decreased severing of microtubules does not fully explain HSP-SPG4. The presence of two translation initiation codons in SPAST allows synthesis of two spastin isoforms: a full-length isoform called M1 and a slightly shorter isoform called M87. M87 is more abundant in both neuronal and non-neuronal tissues. Studies on rodents suggest that M1 is only readily detected in adult spinal cord, which is where nerve degeneration mainly occurs in humans with HSP-SPG4. M1, due to its hydrophobic N-terminal domain not shared by M87, may insert into endoplasmic reticulum membrane, and together with reticulons, atlastin and REEP1, may play a role in the morphogenesis of this organelle. Some mutated spastins may act in dominant-negative fashion to lower microtubule-severing activity, but others have detrimental effects on neurons without further lowering microtubule severing. The observed adverse effects on microtubule dynamics, axonal transport, endoplasmic reticulum, and endosomal trafficking are likely caused not only by diminished severing of microtubules, but also by neurotoxicity of mutant spastin proteins, chiefly M1. Some large deletions in SPAST might also affect the function of adjacent genes, further complicating the aetiology of the disease.
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PMID:Hereditary spastic paraplegia SPG4: what is known and not known about the disease. 2609 31

Hereditary spastic paraplegias (HSPs) consist of a heterogeneous group of genetically determined neurodegenerative disorders. Progressive lower extremity weakness and spasticity are the prominent features of HSPs resulting from retrograde axonal degeneration of the corticospinal tracts. Three genetic types, SPG3 (ATL1), SPG4 (SPAST) and SPG31 (REEP1), appear predominantly and may account for up to 50% of autosomal dominant hereditary spastic paraplegias (AD-HSPs). Here, we present the results of genetic testing of the three mentioned SPG genetic types in a group of 216 unrelated Polish patients affected with spastic paraplegia. Molecular evaluation was performed by multiplex ligation-dependent probe amplification (MLPA) and DNA sequencing. Nineteen novel mutations: 13 in SPAST, 4 in ATL1 and 2 in REEP1, were identified among overall 50 different mutations detected in 57 families. Genetic analysis resulted in the identification of molecular defects in 54% of familial and 8.4% of isolated cases. Our research expanded the causative mutations spectrum of the three most common genetic forms of HSPs found in a large cohort of probands originating from the Central Europe.
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PMID:Molecular spectrum of the SPAST, ATL1 and REEP1 gene mutations associated with the most common hereditary spastic paraplegias in a group of Polish patients. 2667 Oct 83

Hereditary spastic paraplegia (HSP) is an inherited neurological condition that leads to progressive spasticity and gait abnormalities. Adult-onset HSP is most commonly caused by mutations in SPAST, which encodes spastin a microtubule severing protein. In olfactory stem cell lines derived from patients carrying different SPAST mutations, we investigated microtubule-dependent peroxisome movement with time-lapse imaging and automated image analysis. The average speed of peroxisomes in patient-cells was slower, with fewer fast moving peroxisomes than in cells from healthy controls. This was not because of impairment of peroxisome-microtubule interactions because the time-dependent saltatory dynamics of movement of individual peroxisomes was unaffected in patient-cells. Our observations indicate that average peroxisome speeds are less in patient-cells because of the lower probability of individual peroxisome interactions with the reduced numbers of stable microtubules: peroxisome speeds in patient cells are restored by epothilone D, a tubulin-binding drug that increases the number of stable microtubules to control levels. Patient-cells were under increased oxidative stress and were more sensitive than control-cells to hydrogen peroxide, which is primarily metabolised by peroxisomal catalase. Epothilone D also ameliorated patient-cell sensitivity to hydrogen-peroxide. Our findings suggest a mechanism for neurodegeneration whereby SPAST mutations indirectly lead to impaired peroxisome transport and oxidative stress.
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PMID:Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia. 2722 99

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders mainly characterized by progressive spasticity of the lower limbs. Adult case series dominate the literature, and there have been only a few studies in children. The purpose of this study is to describe our experience with pediatric HSP in Greece. We report the clinical and genetic findings in our patients and aim to offer insights into the diagnostic difficulties of childhood-onset disease. A series of 15 Greek children affected by pure HSP underwent extensive diagnostic investigations. Molecular analysis included whole exome sequencing (WES) or consecutive screening of candidate genes ATL1, SPAST, REEP1, and CYP7B1. WES performed in three cases yielded previously reported mutations in ATL1 and CYP7B1, and a variant c.397C>T of unknown significance in SPG7. Candidate gene screening performed in the remaining patients identified previously reported mutations in ATL1 (2), SPAST (2), and REEP1 (1), and two novel mutations, c.1636G>A and c.1413+3_6delAAGT, in SPAST. In six cases, the mutations were inherited from their parents, while in three cases, the mutations were apparently de novo. Our data confirm the genetic heterogeneity of childhood-onset pure HSP, with SPG4/SPAST and SPG3A/ATL1 being the most frequent forms. De novo occurrence of HSP does not seem to be uncommon. Candidate gene studies guided by diagnostic algorithms and WES seem both to be reasonable genetic testing strategies.
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PMID:A series of Greek children with pure hereditary spastic paraplegia: clinical features and genetic findings. 2726 Feb 92

Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized in vivo loss of function models of two very rare forms of HSP caused by loss of the ER-shaping proteins ARL6IP1 (SPG61) and RTN2 (SPG12). These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.
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PMID:Rare disease models provide insight into inherited forms of neurodegeneration. 2860 88

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*5. Measurement of SPAST transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation.
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PMID:Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability. 2887 May 97


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