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

SPG8 is a rare autosomal dominant hereditary spastic paraplegia (AD-HSP), with only six SPG8 families described so far. Our purpose was to screen for KIAA0196 (SPG8) mutations in AD-HSP patients and to investigate their phenotype. Extensive family investigation was performed after positive KIAA0196 mutation analysis, which was part of an on-going mutation screening effort in AD-HSP patients. A novel pathogenic KIAA0196 mutation p.(Gly696Ala) was identified in two AD-HSP patients, who subsequently were shown to belong to a single large Dutch pedigree with more than 10 affected family members. The phenotype consisted of a pure HSP with ages at onset between 20 and 60 years, distally reduced vibration sense in the legs in all, and urinary urgency in seven out of 10 patients. Frequent features were exercise- or emotion-induced increase of spasticity and gait problems and chronic nonspecific lower back and joint pains. We have identified a fourth pathogenic KIAA0196 mutation in a Dutch HSP-family, the seventh family worldwide, with a less severe clinical course than described before.
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PMID:Pure adult-onset spastic paraplegia caused by a novel mutation in the KIAA0196 (SPG8) gene. 2345 31

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is due to mutations in the "spastin" gene (SPAST gene) encoding the AAA protein. The main clinical features of "pure" HSP are progressive lower-limb spasticity with corticospinal tracts and dorsal column degeneration without peripheral neuropathy. Here we report the case of HSP with novel SPAST gene mutation that misdiagnosed with subacute combined degeneration initially. A 58-year-old man with gait disturbance came to our hospital. He was unable to regulate his steps by himself. The impaired gait began 3 years after he had undergone subtotal gastrectomy and chemotherapy for 6 months. Thereafter, he started feeling tingling sensations in the hands and feet and acquired gait difficulties. He denied having a family history of abnormal gait or developmental problem. We diagnosed him with subacute combined degeneration on the evidence of history of gastrectomy, lower normal limit of vitamin B12 (363 pg/ml), apparent absence of vibration sensations and paresthesia in the feet. He was intramuscularly administered cyanocobalamin regularly. However, there was no improvement in his condition. We reconsidered his symptoms and signs, decided to examine the SPAST gene, which is the most common mutation in HSP. The SPAST gene, c.870+1delG, heterozygote, splicing mutation is detected from the gene sample. There was no previous information of this polymorphism or mutation at this locus. We examined his two children, and the same mutation was founded in his son. We report a patient of novel SPAST gene mutation with AD-HSP which is misdiagnosed with SCD.
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PMID:Hereditary Spastic Paraplegia with a Novel SPAST Mutation Misdiagnosed with Subacute Combined Degeneration. 2383 62

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

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

Autosomal recessive hereditary spastic paraparesis is rare.We present 4 patients with slowly progressive predominantly lower limb spasticity and ataxia. Only one patient had family history of ataxia but without any underlying diagnosis. All of them proved negative for the mutation of Spinocerebelalr ataxia genes SCA 1,2,3 and 6. All had mutation in the SPG 7 gene suggestive of autosomal recessive hereditary spastic paraparesis. One of the heterozygous mutatnts showed a novel c1617delC ,p(Val540fs) frameshift mutation in exon 12 of the SPG 7 gene. SPG7 mutation accounts for 1.5-7% of all the HSP but it is the cause of undiagnosed ataxia in 18.6% in a recent case series. SPG7 mutation should be remembered as an important cause of undiagnosed ataxia especially where next generation sequencing is not widely avaialbale or affordable.
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PMID:Case series of autosomal recessive hereditary spastic paraparesis with novel mutation in SPG 7 gene. 2905 57

Kinesins are a family of proteins for anterograde transport of the molecules from the neuronal cell body and their impairment has been widely associated with neurodegeneration of the motor neurons. KIF5A gene causes autosomal dominant spastic paraplegia 10, a neurological disorder characterized by spasticity and weakness of the lower limbs (SPG10). We carried out a screening of KIF5A gene in 50 subjects affected by HSP negative to diagnostic test for SPG4, ATL1 and REEP1. We identified a novel variation p.Ile255Met in a 58-year-old man who developed progressive gait disturbance due to spastic paraparesis complicated by axonal neuropathy.
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PMID:Kinesins in neurological inherited diseases: a novel motor-domain mutation in KIF5A gene in a patient from Southern Italy affected by hereditary spastic paraplegia. 3041 Dec 8

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
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PMID:FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. 3113 52

BACKGROUND Hereditary spastic paraplegia (HSP or SPG) consists of a heterogeneous group of disorders, clinically divided into pure and complex forms. The former is characterized by neurological impairment limited to lower-extremity spasticity. The latter presents additional symptoms such as seizures, psychomotor impairment, cataract, deafness, and peripheral neuropathy. The genetic structure of HSP is diverse, with more than 72 loci and 55 genes identified so far. The most common type is SPG4, accounting for 40% of cases. This case report describes 2 siblings presenting SPG4, one presumptive and one confirmed with a homozygous SPAST variant. CASE REPORT Two siblings born to third-degree consanguineous and healthy parents presented a SPG4 complex phenotype characterized by progressive psychomotor deterioration, mixed seizure patterns, corneal opacity, dysostotic bones, limb spasticity with extensor plantar responses, and axial hypotonia. After ruling out most inborn errors of metabolism in one of the patients, the complexity of the case derived from exome sequencing. The identification of a homozygous variant in the SPAST gene established a diagnosis for SPG4. The phenotype-genotype did not correlate to classical manifestations, most likely due to the variant's zygosity. Moreover, 34 patient's relatives were identified with SPG4 clinical manifestations or asymptomatic with the same genetic variant in heterozygous state. CONCLUSIONS We described visual loss and seizures for SPG4 complex phenotype associated with a homozygous variant in the SPAST gene. This diagnosis will lead clinicians to consider it as a differential diagnosis providing adequate genetic counseling.
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PMID:Clinical Characterization of 2 Siblings with a Homozygous SPAST Variant. 3238 98

Variants in the PNPLA6 gene are known to cause 4 distinct phenotypes. One known phenotype is Hereditary Spastic Paraplegia type 39 (HSP 39), a rare neurodegenerative condition characterized by variable onset of lower limb spasticity, weakness and ataxia. Little is known about complications of HSP 39 in adulthood. Here, we report a family of three siblings who presented with bilateral lower limb spasticity in childhood, consistent with HSP, with confirmed bi-allellic PNPLA6 mutations. Two siblings developed parkinsonian features in middle age, a novel finding in this sibship. The proband had a positive dopamine transporter scan, indicating degeneration in dopaminergic neurons, and dopa-responsive extrapyramidal symptoms. Testing for known genetic causes of Parkinsonism was negative. The PNPLA6 gene encodes neuropathy target esterase, an enzyme involved in lipid metabolism that is critical to the stability of cell membranes. We hypothesize that the development of Parkinsonism in these patients may be related to the PNPLA6 mutations, as lipid dysregulation has been implicated in the pathogenesis of Parkinson disease.
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PMID:Bi-allelic variants in PNPLA6 possibly associated with Parkinsonian features in addition to spastic paraplegia phenotype. 3262 94


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