Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Jimpy mouse is an x-linked recessive mutation of the house mouse resulting a myelin deficiency in the central nervous system. It is of interest as an animal model of human leukodystrophy. Clinical symptoms include ataxia and tremor as initial signs, followed by tonic-clonic convulsions prefinally. The myelin deficiency is probably caused by a developmental disturbance of the oligodendrogial cell line. Clinical and pathological findings in the mouse mutant Jimpy show some remarkable similarities to Pelizaeus-Merzbacher disease.
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PMID:[The mouse mutant "Jimpy". Animal model of leukodystrophy]. 91 20

A group of inherited neurological disorders are the X-chromosome linked dysmyelinoses, in which myelin membranes of the CNS are missing or perturbed due to a strongly reduced number of differentiated oligodendrocytes. In animal dysmyelinoses (jimpy mouse, msd-mouse, md rat, shaking pup) mutations of the main integral myelin membrane protein, proteolipid protein, have been identified. Pelizaeus-Merzbacher disease (PMD) or sudanophilic leucodystrophy is an X-linked dysmyelinosis in humans. We report here on the molecular basis of the defect of affected males of a PMD kindred. Rearrangements of the PLP gene were excluded by Southern blot hybridisation analysis and PCR amplification of overlapping domains of the PLP gene. Sequence analysis revealed one single C----T transition in exon IV, which leads to a threonine----isoleucine substitution within a hydrophobic intramembrane domain. The impact of this amino-acid exchange on the structure of PLP in the affected cis membrane domain is discussed. A space filling model of this domain suggests a tight packing of the alpha-helices of the loop which is perturbed by the amino-acid substitution in this PMD exon IV mutant. The C----T transition in exon IV abolishes a Hph I restriction site. This mutation at the recognition site for Hph I (RFLP) and allele-specific primers have been used for mutation screening the PMD kindred.
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PMID:A point mutation at the X-chromosomal proteolipid protein locus in Pelizaeus-Merzbacher disease leads to disruption of myelinogenesis. 170 72

Proteolipid protein (PLP) is a major myelin protein of the central nervous system. Mutations of the Plp gene are responsible for a number of sex-linked disorders in humans (Pelizaeus-Merzbacher disease) and in animals. We have identified a novel mutation of the Plp gene which gives rise to the paralytic tremor (pt) phenotype in rabbit. Pt rabbits are hypomyelinated and present very low levels of PLP protein and its mRNA. Sequence analysis revealed a single nucleotide change in exon 2 which results in the substitution of a histidine by a glutamine at position 36. Histidine36 is positioned at the boundary of the first transmembrane domain. Therefore, its position can be crucial for the efficient interaction of PLP with other proteins and lipids, and for correct incorporation into the membrane.
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PMID:Myelin proteolipid protein mutation in the rabbit: a new model of Pelizaeus-Merzbacher disease. 753 32

Mutations of the proteolipid protein (Plp) gene cause a generalized central nervous system (CNS) myelin deficit in Pelizaeus-Merzbacher disease of man and various tremor syndromes in animal models. X-linked spastic paraplegia is also due to Plp gene mutations but has a different clinical profile and more restricted pathology involving specific tracts and regions. We have shown previously that PLP overexpression in mice homozygous for a Plp transgene results in premature arrest of CNS myelination and premature death. Here, we demonstrate that a low-level increase in Plp gene expression in transgenic mice causes significant axonal degeneration and demyelination with predilection for specific tracts. Following normal motor development, aged mice develop progressive myelin loss, axonal swellings with resultant Wallerian degeneration, and marked vacuolation of the neuropil associated with ataxia, tremor, and seizures. The age of onset and severity of the phenotype is a function of Plp gene dosage. The corticospinal tracts, optic nerve, fasciculus gracilis cerebellum, and brainstem are particularly involved. Although oligodendrocyte cell bodies show little abnormality, their inner adaxonal tongue is often abnormal, suggesting a perturbation of the axon/glial interface that may underlie the axonal changes. We conclude that abnormal expression of an oligodendrocyte-specific gene can cause axonal damage, a finding that is relevant to the pathogenesis of PLP-associated disorders and probably to other myelin-related diseases.
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PMID:Late-onset neurodegeneration in mice with increased dosage of the proteolipid protein gene. 959 May 58

The shaking (sh) pup, an animal model of Pelizaeus-Merzbacher disease, is characterized by severe central nervous system dysmyelination in affected males, and myelin mosaicism in some female heterozygotes as a result of X-linked inactivation. Heterozygous females develop a tremor of varying severity that usually disappears at 4 to 6 weeks, whereas male hemizygotes have severe, generalized tremor that persists throughout life. We have used these two myelin-deficient models to study the potential for recovery with time as reflected by brainstem auditory evoked responses (BAERs). At set time points, the state of myelination in the trapezoid body was studied microscopically. Sequential BAERs demonstrated consistently prolonged interpeak latencies during the period of gross tremor in heterozygotes, with the trend continuing to a lesser extent after tremor cessation. The random nature of X-linked inactivation resulted in variable myelin mosaicism that was reflected in variations in BAER changes within animals in the same litter. In most heterozygotes, the tremor resolved with time, the BAERs returned to near normal, and myelin mosaicism was lost. In contrast, in the affected males, the severity of tremor and lack of recovery was demonstrated by consistent abnormalities in BAER waves at all times studied, and severe and persistent myelin deficiency in the trapezoid body. These findings show that despite the normal tightly programmed temporal development of myelin in the brain in the heterozygous mosaic state, sufficient plasticity persists during the neonatal period for late-stage myelination to occur.
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PMID:Myelin mosaicism and brain plasticity in heterozygous females of a canine X-linked trait. 981 33

We report the autopsy cases of two brothers which are pathologically compatible with Pelizaeus-Merzbacher disease (PMD). Both patients had a late onset (at the ages of 29 and 42 years) and chronic neurological symptoms including tremor, ataxia and dementia. The T2-weighted magnetic resonance imaging of the younger brother demonstrated increased signal areas with sparing of small areas in the cerebral white matter. The postmortem examinations, obtained at the ages of 45 and 61 years, showed similar neuropathological findings. Histologically, a cardinal finding was a lack of myelin in large parts of white matter with the preservation of islands of intact myelin, resulting in a "tigroid" appearance. Only small amounts of sudanophilic material were present. The axons were relatively well preserved, but oligodendrocytes were numerically reduced. Ultrastructurally, myelin sheaths in the white matter were markedly thin. Immunohistochemistry showed that proteolipid protein (PLP) was reduced in the affected white matter. However, genetic studies did not reveal exonic mutations or duplications of the PLP gene. We conclude that the two cases are a rare type of dysmyelinating disorder with PMD phenotype of adult onset and could be caused by previously unrecognized abnormalities of the PLP gene or other genes.
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PMID:Two autopsy cases with Pelizaeus-Merzbacher disease phenotype of adult onset, without mutation of proteolipid protein gene. 1065 Oct 21

The paralytic tremor (pt) disease in rabbits results from a point mutation in a plp gene and manifests itself by a broad range of neurological signs. Biochemical studies have shown that myelinogenesis is retarded and deficient in mutant rabbits. Myelin sheaths are usually thin and malformed. The number of oligodendrocytes is normal, however their differentiation and maturation is prolonged. The effects of the pt mutation were investigated in morphological, biochemical and molecular studies, resulting in the well-documented characteristics of the disease. The pt phenotype and its detailed characteristics make the mutated rabbit a good model of Pelizaeus-Merzbacher disease.
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PMID:Rabbit paralytic tremor phenotype--a plp1 gene mutation as a model of human Pelizaeus-Merzbacher disease. 1596 Mar 10

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder with a prototype of a dysmyelinating leukodystrophy that is caused by a mutation in the proteolipid protein 1 (PLP1) gene on the long arm of the X chromosome in band Xq22. This mutation results in abnormal expression or production of PLP. We here present a Korean boy with spastic quadriplegia, horizontal nystagmus, saccadic gaze, intentional tremor, head titubation, ataxia, and developmental delay. The brain magnetic resonance imaging (MRI) showed abnormally high signal intensities in the white matter tract, including a subcortical U fiber on the T2-weighted and fluid attenuated inversion recovery (FLAIR) image. The chromosomal analysis was normal; however, duplication of the PLP1 gene in chromosome Xq22 was detected when the multiplex ligation-dependent probe amplification (MLPA) method was used. We also investigated the pedigree for a genetic study related to PMD. This case suggests that the duplication mutation of the PLP1 gene in patients with PMD results in a mild clinical form of the disorder that mimics the spastic quadriplegia of cerebral palsy.
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PMID:Identification of proteolipid protein 1 gene duplication by multiplex ligation-dependent probe amplification: first report of genetically confirmed family of Pelizaeus-Merzbacher disease in Korea. 1843 21

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder affecting myelination of the central nervous system, and is caused by mutations of the proteolipid protein 1 (PLP1) gene. Clinical manifestations of PMD are variable and major features include progressive nystagmus, spasticity, tremor, ataxia, and psychomotor delay. We describe a classical PMD patient who had been misdiagnosed as cerebral palsy. He had nystagmus and psychomotor delay since infancy and tremor with ataxia developing gradually. Brain MRI revealed demyelination over white matter of the cerebral hemispheres and posterior limbs of the internal capsules. Positive family history led to subsequent mutation analysis, which identified a novel mutation (c.88G>C) in PLP1 in the proband, as well as his affected brother and maternal uncle, and asymptomatic maternal grandmother, mother and two sisters. Therefore, PMD should be considered in a cerebral palsy-like patient with or without positive family history. Mutation analysis is crucial for early diagnosis and further genetic counseling.
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PMID:Pelizaeus-Merzbacher disease, easily misdiagnosed as cerebral palsy: a report of a three-generation family. 2359 42

Major gaps in our understanding of the leukodystrophies result from their rarity and the lack of tissue for the interdisciplinary studies required to extend our knowledge of the pathophysiology of the diseases. This study details the natural evolution of changes in the CNS of the shaking pup (shp), a model of the classical form of the X-linked disorder Pelizaeus-Merzbacher disease, in particular in glia, myelin, and axons, which is likely representative of what occurs over time in the human disease. The mutation in the proteolipid protein gene, PLP1, leads to a delay in differentiation, increased cell death, and a marked distension of the rough endoplasmic reticulum in oligodendrocytes. However, over time, more oligodendrocytes differentiate and survive in the spinal cord leading to an almost total recovery of myelination, In contrast, the brain remains persistently hypomyelinated. These data suggest that shp oligodendrocytes may be more functional than previously realized and that their early recruitment could have therapeutic value.
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PMID:Modeling the natural history of Pelizaeus-Merzbacher disease. 2556 56


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