Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028738 (nystagmus)
 7,431 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

X-linked hereditary spastic paraplegias (HSP) present with two distinct phenotypes, pure and complicated. The pure form is characterized by spasticity and gait difficulties but lacks the additional features (nystagmus, dysarthria, mental retardation) present in the complicated form. The complicated form is heterogeneous, caused by mutations of the L1CAM gene at Xq28 (SPG1) or the PLP gene at Xq22 (SPG2) that is allelic to Pelizaeus-Merzbacher disease (PMD). Since in one kindred (K313) the pure form of HSP was also mapped to Xq22, this raises the issue as to whether a pure form of HSP exists that is allelic to X-linked complicated HSP (SPG2) and PMD. To answer this question, we carried out linkage analysis in a new pedigree with pure HSP (K101) and refined linkage in pedigree K313. The PLP gene was also screened for mutation by direct sequencing and reverse-transcriptase polymerase chain reaction (RT-PCR). In both families, the disease locus mapped to Xq22 with Lod scores at zero recombination of 5.3 for COL4A5 2B6 in K313 and 2.4 for DXS101 in K101. A T to C transition in exon 5 of the PLP gene was identified from affected individuals of K313. This transition causes a Ser to Pro mutation in the major extracellular loop of PLP/DM20. This finding demonstrates that a form of X-linked pure spastic paraplegia, X-linked complicated HSP (SPG2) and PMD are allelic disorders. There was no evidence of mutations in either coding sequences or the intron/exon junctions of PLP in pedigree K101, suggesting that the disease-producing mutation may be in the noncoding portions of PLP or in a nearby gene.
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PMID:Refined genetic mapping and proteolipid protein mutation analysis in X-linked pure hereditary spastic paraplegia. 878 Jan 1

A 3.5-year-old boy had intact cognition, delayed walking, progressive spastic paraparesis and congenital nystagmus. The mother denied family history of any neurological disorders, so an extensive work-up was begun. Lysinuria, increased signal on cerebral T2-weighted MRI imaging and the rumpshaker mutation (Ile186Thr) in his proteolipid protein gene. PLP, were found. When faced with these facts, the mother admitted that she was related to the family reported by Johnston and McKusick in 1962 and Kobayashi in 1994, in whom this mutation has been reported. This is the first report of an abnormal MRI scan in this family.
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PMID:A male child with the rumpshaker mutation, X-linked spastic paraplegia/Pelizaeus-Merzbacher disease and lysinuria. 942 51

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 a rare dysmyelinating disorder caused by mutations in the proteolipid protein 1 (PLP1) gene. PMD is generally classified according to its clinical or pathological features into classical or connatal forms. We describe here a 19-year-old male with classical form PMD who presented with stridor and nystagmus in early infancy and whose psychomotor development has been severely delayed. Brain magnetic resonance imaging revealed white matter abnormalities typical of PMD. Direct sequencing of the PLP1 gene identified two nucleotide substitutions. One was a C-to-T transition at -31 in the 5'-flanking region of exon 1; the other was a novel point mutation, T-to-C transition in exon 4, which led to substitution of cysteine for arginine at residue 184. Because Cys184 forms a disulphide bridge with Cys228, the Cys184Arg mutation probably removes the bridge and changes the tertiary structure of PLP protein. A defective disulfide bond in PLP protein could be important in the pathogenesis of PMD.
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PMID:A novel proteolipid protein 1 gene mutation causing classical type Pelizaeus-Merzbacher disease. 2117 54

Pelizaeus-Merzbacher disease (PMD) is a fatal hypomyelinating disorder characterized by early impairment of motor development, nystagmus, choreoathetotic movements, ataxia and progressive spasticity. PMD is caused by variations in the proteolipid protein gene PLP1, which encodes the two major myelin proteins of the central nervous system, PLP and its spliced isoform DM20, in oligodendrocytes. Large duplications including the entire PLP1 gene are the most frequent causative mutation leading to the classical form of PMD. The Plp1 overexpressing mouse model (PLP-tg66/66 ) develops a phenotype very similar to human PMD, with early and severe motor dysfunction and a dramatic decrease in lifespan. The sequence of cellular events that cause neurodegeneration and ultimately death is poorly understood. In this work, we analyzed patient-derived fibroblasts and spinal cords of the PLP-tg66/66 mouse model, and identified redox imbalance, with altered antioxidant defense and oxidative damage to several enzymes involved in ATP production, such as glycolytic enzymes, creatine kinase and mitochondrial proteins from the Krebs cycle and oxidative phosphorylation. We also evidenced malfunction of the mitochondria compartment with increased ROS production and depolarization in PMD patient's fibroblasts, which was prevented by the antioxidant N-acetyl-cysteine. Finally, we uncovered an impairment of mitochondrial dynamics in patient's fibroblasts which may help explain the ultrastructural abnormalities of mitochondria morphology detected in spinal cords from PLP-tg66/66 mice. Altogether, these results underscore the link between redox and metabolic homeostasis in myelin diseases, provide insight into the pathophysiology of PMD, and may bear implications for tailored pharmacological intervention.
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PMID:Oxidative stress and mitochondrial dynamics malfunction are linked in Pelizaeus-Merzbacher disease. 2902 61