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)

X-linked hereditary spastic paraplegias (HSPs) present with two distinct phenotypes: pure and complicated. The pure form is characterized by slowly progressive weakness and spasticity of the lower limbs, whereas the complicated forms have additional features (optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, epilepsy, ataxia, ichthyosis, mental retardation, and deafness). Three X-linked loci have been identified for the complicated HSP, while mutations in the proteolipid gene (PLP) (locus SPG2) were implicated in both pure and complicated forms. The absence of identified mutations in the PLP gene in families with both complicated and pure HSP, linked to the SPG2 locus, suggests the existence of another gene in close proximity. We had previously reported a large pedigree with an X-linked form of pure HSP affecting 24 males [Zatz et al., 1976: J Med Genet 13:217-222]. Here, we present the results of linkage analysis in 19 members of this Brazilian family with markers in or near the PLP locus. Positive LOD scores were obtained with markers at the PLP locus (Zmax = 2.41 at Theta = 0); however, no mutation was found in the coding region of PLP, the intron-exon boundaries, or part of the promoter region. The possibility of a duplication of the PLP gene was also excluded. These results suggest either that there is another X-linked gene in close proximity to the PLP gene or that a novel mutation in the noncoding regions of the PLP gene may cause the disease in this family.
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PMID:Further evidence for a fourth gene causing X-linked pure spastic paraplegia. 1221 Mar 42

The introduction of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy into clinical practice has permitted advances in the definition and categorization of unknown leukodystrophies in children. We report a new type of leukodystrophy, defined by particular MRI and clinical findings, in a child with uneventful pre- and perinatal histories, spasticity, severe mental impairment with absence of language, and deafness. Brain MRI showed lobar white-matter signal abnormalities with extensive cysts in the anterior temporal lobe. The results of all metabolic screening tests, including the specific investigations for leukodystrophy, have been negative. Six years of clinical and MRI-magnetic resonance spectroscopy patient follow-up indicate a nonprogressive clinical and magnetic resonance picture. Owing to the striking similarities with the previous eight patients reported, this additional case supports the identification of a new leukodystrophy.
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PMID:Leukoencephalopathy with bilateral anterior temporal lobe cysts: a further case of this new entity. 1254 34

The Mohr-Tranebjaerg syndrome (MTS) is a rare neurodegenerative disorder characterized by early-onset deafness, dystonia and further neurological abnormalities such as cortical blindness, spasticity, dementia and mental retardation. Causative mutations were identified within the deafness-dystonia peptide (DDP1/TIMM8a) gene on the X-chromosome. The DDP1 protein is located in the intermembrane space of human mitochondria. Here, it acts in a complex together with its partner protein Tim13 in a chaperone-like manner to facilitate the import of nuclear-encoded precursor proteins into the mitochondrial inner membrane. Thus, MTS is a novel type of mitochondrial disorder. To obtain more insight into the pathophysiology of this neurodegenerative disorder, we performed for the first time a comprehensive clinical and functional characterization of a patient suffering from MTS. This patient exhibited a typical combination of deafness, dystonia and visual loss. Sequence analysis of the patient's DDP1 gene revealed a G to C transversion at nucleotide position 38 of the first exon. The mutation affects the ATG start codon, thereby changing methionine to isoleucine (M1I), and leads to a complete absence of the DDP1 protein. In addition, the partner protein Tim13 was found to be significantly reduced, suggesting that Tim13 requires the presence of DDP1 for its stabilization. The assessment of mitochondrial functions showed the enzyme activities of the mitochondrial energy-generating systems to be normal in the muscle biopsy. Structural abnormalities or aggregations of mitochondria were absent. Electron microscopy revealed only a mild neurogenic atrophy. Neurophysiological investigations showed cochlear dysfunction and disturbance of visual pathways. PET and MRI studies revealed a multifocal pattern of neurodegeneration with hypometabolic areas predominantly located over the right striatum and parietal cortex and marked atrophy of the occipital lobes. Although the visual loss is caused predominantly by neurodegeneration of the visual cortex, degeneration of the retina and the optic nerve contributes to the visual impairment. The pathological changes in basal ganglia and sensory cortex demonstrate the disintegration of subcortico-cortical circuits and correlate well with the clinical presentation of multifocal dystonia. The data presented here showed that, in contrast to most of the known mitochondrial disorders, MTS appears not to be associated with a functional defect of the energy generation system of the mitochondria. Whereas the specific mitochondrial dysfunction leading to neuronal loss in MTS remains to be clarified, the electrophysiological and neuroimaging findings allowed the multifocal manifestation of neurodegenerative lesions in MTS to be characterized specifically.
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PMID:Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene. 1280 99

A newly described disease is characterized by anterior bilateral temporal lobe cysts associated with multilobar leukoencephalopathy and a non-progressive clinical course. We report a patient with bilateral anterior temporal lobe cystic changes associated with a non-progressive neurological disorder, microcephaly, spasticity, mental retardation, and sensorineural deafness. From the literature, 12 other patients have shown a similar phenotype. The common neuroradiological findings in these patients have been bilateral anterior temporal lobe cystic changes and non-progressive leukoencephalopathy. By contrast, variability in the clinical phenotype has been observed, ranging from severe neuromotor handicap with mental retardation and microcephaly to spasticity in the lower limbs associated with normal cognitive function. The pathological basis of the defect remains to be defined.
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PMID:Non-progressive leukoencephalopathy with bilateral anterior temporal cysts: a case report and review of the literature. 1562 47

We report on a female patient with severe mental retardation, dysmorphic features, deafness, spasticity, and behavioural problems in whom a 2.3 Mb duplication of 12q24.21q24.23 was detected by genome-wide tiling-path resolution array-based comparative genomic hybridization. Mental retardation, microcephaly, short stature, recurrent infections, hypotonia and facial features, such as hypertelorism, epicanthal folds, and a broad nasal bridge, were also described in patients with larger duplications overlapping the 12q24.21q24.23 region. The duplicated region contains 16 genes, of which several genes, such as thyroid hormone receptor associated protein 2, replication factor C5 and nitric oxide synthase 1, are expressed in the brain and/or are involved in embryogenesis. The current case shows that microduplications might be a more frequent cause of mental retardation and human malformation than previously appreciated.
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PMID:A novel 2.3 Mb microduplication of 12q24.21q24.23 detected by genome-wide tiling-path resolution array comparative genomic hybridization in a girl with syndromic mental retardation. 1676 Jul 30

Mohr-Tranebjaerg syndrome (MTS) is an X-linked disorder characterized by childhood-onset progressive deafness, dystonia, spasticity, mental deterioration, and blindness. It is due to mutations in the deafness/dystonia peptide (DDP1) gene. We describe a sporadic 42-year-old man with MTS presenting with postlingual deafness, adult-onset progressive dystonia with marked arm tremor, mild spasticity of the legs, and visual disturbance due to a novel mutation (g to a transition at the invariant gt of the 5' splice donor site of exon 1) in the DDP1 gene. This case, and a review of previously reported cases, highlights a variety of potential diagnostic pitfalls in this condition.
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PMID:Blepharospasm and limb dystonia caused by Mohr-Tranebjaerg syndrome with a novel splice-site mutation in the deafness/dystonia peptide gene. 1753 80

We examined the clinical, molecular and genetic features of a 16-year-old boy (XP2GO) with xeroderma pigmentosum (XP) and progressive neurological symptoms. The parents are not consanguineous. Increased sun sensitivity led to the diagnosis of XP at 2 years of age and a strict UV protection scheme was implemented. Besides recurrent conjunctivitis and bilateral pterygium, only mild freckling was present on his lips. He shows absent deep tendon reflexes, progressive sensorineural deafness and progressive mental retardation. MRI shows diffuse frontal cerebral atrophy and dilated ventricles. Symptoms of trichothiodystrophy (brittle hair with a tiger-tail banding pattern on polarized microscopy) or Cockayne syndrome (cachectic dwarfism, cataracts, pigmentary retinopathy and spasticity) were absent. XP2GO fibroblasts showed reduced post-UV cell survival (D(37) = 3.8 J/m(2)), reduced nucleotide excision repair, reduced expression of XPD mRNA and an undetectable level of XPD protein. Mutational analysis of the XPD gene in XP2GO revealed two different mutations: a common p.Arg683Trp amino acid change (c.2047C>T) known to be associated with XP and a novel frameshift mutation c.2009delG (p.Gly670Alafs*39). The latter mutation potentially behaves as a null allele. While not preventing neurological degeneration, early diagnosis and rigorous sun protection can result in minimal skin disease without cancer in XP patients.
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PMID:Strict sun protection results in minimal skin changes in a patient with xeroderma pigmentosum and a novel c.2009delG mutation in XPD (ERCC2). 1863 29

Hereditary spastic paraplegias (HSP) constitute a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. Only a few different mutations in the SPG10 gene, KIF5A, have been described in pure dominant forms of the disease. We sequenced the motor domain of KIF5A in a large panel of 205 European HSP patients with either pure or complicated forms of the disease. We identified eight different heterozygous missense mutations, seven novels, in eight different families of French origin. Residue R280 was a mutational hot spot. Interestingly, the patients in 7/8 families had a complex phenotype, with peripheral neuropathy, severe upper limb amyotrophy (Silver syndrome-like), mental impairment, parkinsonism, deafness and/or retinitis pigmentosa as variably associated features. We report the largest series of SPG10 families described so far, which extends both the mutational spectrum of the disease and its phenotype, which now includes complicated forms of HSP. SPG10 mutations were found in 10% of our complicated forms of HSP, suggesting that mutations in KIF5A represent the major cause of complicated AD-HSP in France.
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PMID:Complicated forms of autosomal dominant hereditary spastic paraplegia are frequent in SPG10. 1885 58

The combination of neurologic disease and ichthyosis defines a heterogeneous group of rare inherited disorders that present in infancy through early adulthood. Although affected patients share the cutaneous feature of ichthyosis, there is variability in the nature and severity of neurologic disease. Impaired cognition, spasticity, sensorineural deafness, visual impairment, and/or seizures are the primary neurologic findings. Most of these disorders are caused by genetic defects in lipid metabolism, glycoprotein synthesis, or intracellular vesicle trafficking. The clinical features of some of the neuro-ichthyoses are distinct enough to allow their clinical recognition, but confirmatory biochemical or genetic tests are necessary for accurate diagnosis. Treatment of the ichthyosis is largely symptomatic, and except for Refsum's disease, there are no effective pathogenesis-based therapies for the neurologic disease.
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PMID:Recognition and diagnosis of neuro-ichthyotic syndromes. 2242 10

Hereditary spastic paraplegia (SPG) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterised by progressive spasticity and weakness of the lower-limbs (pure SPG) and, majoritorian, additional more extensive neurological or non-neurological manifestations (complex or complicated SPG). Pure SPG is characterised by progressive spasticity and weakness of the lower-limbs, and occasionally sensory disturbances or bladder dysfunction. Complex SPGs additionally include cognitive impairment, dementia, epilepsy, extrapyramidal disturbances, cerebellar involvement, retinopathy, optic atrophy, deafness, polyneuropathy, or skin lesions in the absence of coexisting disorders. Nineteen SPGs follow an autosomal-dominant (AD-SPG), 27 an autosomal-recessive (AR-SPG), 5 X-linked (XL-SPG), and one a maternal trait of inheritance. SPGs are due to mutations in genes encoding for proteins involved in the maintenance of corticospinal tract neurons. Among the AD-SPGs, 40-45% of patients carry mutations in the SPAST-gene (SPG4) and 10% in the ATL1-gene (SPG3), while the other 9 genes are more rarely involved (NIPA1 (SPG6), KIAA0196 (SPG8), KIF5A (SPG10), RNT2 (SPG12), SPGD1 (SPG13), BSCL2 (SPG17), REEP1 (SPG31), ZFYVE27 (SPG33, debated), and SLC33A1 (SPG42, debated)). Among the AR-SPGs, ~20% of the patients carry mutations in the KIAA1840 (SPG11) gene whereas the 15 other genes are rarely mutated and account for SPGs in single families yet (CYP7B1 (SPG5), SPG7 (SPG7), ZFYVE26 (SPG15), ERLIN2 (SPG18), SPG20 (SPG20), ACP33 (SPG21), KIF1A (SPG30), FA2H (SPG35), NTE (SPG39), GJA12/GJC2 (SPG44), KIAA0415 (SPG48) and 4 genes encoding for the AP4-complex (SPG47)). Among the XL-SPGs, 3 causative genes have been identified (L1CAM (SPG1), PLP1 (SPG2), and SLC16A2 (SPG22)). The diagnosis of SPGs is based on clinical, instrumental and genetic investigations. Treatment is exclusively symptomatic.
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PMID:Hereditary spastic paraplegias with autosomal dominant, recessive, X-linked, or maternal trait of inheritance. 2255 90


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