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)

Intraocular kainic acid injection in Long-Evans rats induces loss of retinal afferents to subcortical visual centers as assessed by the axoplasmic transport of [14C]valine. The optical terminal fields of the pretectal nucleus of the optic tract (NOT), superior colliculus and accessory optic system (AOS) nuclei appear particularly affected. Since NOT and the AOS dorsal terminal nucleus (DTN) represent the first relay station of the visuomotor pathway mediating horizontal optokinetic nystagmus (HOKR), we have studied the characteristics of HOKR after various degrees of retinal deafferentation of these nuclei induced by intraocular KA injection. Taking advantage of the arrangement of the primary optic projections to NOT-DTN, that in rats are almost entirely crossed, in each animal, monocular HOKR induced by stimulation of the injected eye was compared to monocular HOKR elicited by stimulation of the intact, ipsilateral eye. Following NOT-DTN optic denervation, HOKR gain always worsened, and in a way, that the greater the deficits of retinal afferents, the greater the HOKR inability to compensate for visual motion. Furthermore, for any given retinal denervation the higher the stimulus velocity, the greater the HOKR deficit. While the correlation between HOKR gain and the amount of retinal afferents to NOT-DTN would seem to indicate a functional homogeneity of the retinal ganglion cells sending axons to these nuclei, the finding that the extent of HOKR impairment also varied with velocity might not support the above view.
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PMID:Correlation between amount of retinal afferents to the pretectal nucleus of the optic tract and dorsal terminal accessory optic nucleus and performance of horizontal optokinetic reflex in rat. 176 8

Pelizaeus Merzbacher disease (PMD) is an X-linked recessive disorder of the central nervous system myelination caused by mutations involving the proteolipid protein gene (PLP). Early nystagmus and developmental delay, progressive pyramidal, cerebellar and dystonic signs as well as white matter changes in brain MRI are typical for PMD. The PLP gene can be affected by two major types of mutations. A duplication of the whole PLP gene is the most common mutation and results usually in the milder classical phenotype, whereas point mutations in PLP gene often result in the rarer and more severe connatal form of PMD. The PLP protein is a higly conserved across species and is identical in human, mouse and rat. We describe a 13-year-old Czech boy with an early and severe developmental delay. His maternal uncle died at the age of one year and was also early and severely psychomotoricly retarded. The patient was the first child of healthy unrelated parents born after an uneventful pregnancy and delivery in 1988. Hyperbilirubinemia and bronchopneumonia and early stridor complicated his neonatal period. Diffuse hypotonia, nystagmus, psychomotor retardation, visual and hearing impairment have been observed in the patient since the age of 6 weeks. White matter abnormalities, cortical and periventricular atrophy were detected by MRI at the age of 6 and 11 years, respectively. Despite these signs and results an accurate clinical diagnosis was unclear until the age of 11 years. Last neurological examination in 1999 showed no nystagmus anymore, but extremely dystrophic limbs, truncal deformation, due to severe scoliosis, tetraplegia with hyperreflexia in C5C7 and areflexia L2S2 and positive pyramidal signs. The boy had no visual or speech contact. DNA tests followed the clinical suspicion for PMD. At first, duplication of PLP gene was excluded by quantitative comparative PCR. Direct sequencing of PLP gene detected a novel mutation in exon 6, a missense mutation 725C-->A (Ala242Glu) in the patient and in his mother and later also in his maternal grandmother. The same codon, but to valine (Ala242Val) is mutated in jimpy(msd) mouse, which is the frequently used animal model for PMD. Prenatal diagnosis for the next pregnancy has been offered to the family. The patient died recently at the age of 13 years due to respiratory failure. Our results support the data on the importance of this conserved amino acid alanine at codon 242.
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PMID:A severe connatal form of Pelizaeus Merzbacher disease in a Czech boy caused by a novel mutation (725C>A, Ala242Glu) at the 'jimpy(msd) codon' in the PLP gene. 1178 21

We describe a novel mutation in the gene coding for protein kinase C gamma (PRKCG) in patients of a German family affected with slowly progressive gait ataxia, dysarthria, and nystagmus. The G/T missense mutation occurred in exon 2 of PRKCG and results in a substitution of glycine by valine (G63V) in the evolutionarily highly conserved cysteine-rich region 1/C1 domain of PRKCG. Among the 20 mutations described to date, this is the first mutation located in exon 2 of PRKCG.
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PMID:Spinocerebellar ataxia 14: novel mutation in exon 2 of PRKCG in a German family. 1714 11

Idiopathic congenital nystagmus (ICN) is the most common form of oculomotor disorder characterized by involuntary bilateral ocular oscillations. Primarily the disease is an ocular anomaly but the pathophysiology is associated with neuronal cytoskeletal dynamics in the brain. In the current study, a three generation North Indian family affected with X-linked idiopathic congenital nystagmus (XLICN) was recruited. Our aim was to identify the causal mutation for ICN in the family by screening the candidate gene, FERM domain containing-7 (FRMD7). This gene has been implicated in XLICN as it regulates neuronal cytoskeletal proteins and neurite outgrowth in the developing brain. Therefore, the entire protein coding region, including splice junctions, 5' UTR and 3' UTR of FRMD7 was screened by PCR-Sanger sequencing. Targeted sequencing revealed a novel A to G transition in the exon seven (c.556A>G), resulting in a conservative substitution of methionine by valine at codon 186 (p.M186V). A cohort of healthy individuals was also checked for presence of the putative causal variant by allele specific PCR. All the affected males and carriers in the family shared this variant; however, this was absent in the unaffected males as well as 100 unrelated healthy individuals. Further, protein homology modeling revealed that the change p.M186V might destabilize the interaction between the FERM-M and FERM-C domains. The in silico prediction supports pathogenicity of the mutation; nevertheless it needs in vivo validation in the future. This is the first genetic investigation of XLICN in a North Indian family where we report a novel causal mutation c.556A>G (p.M186V) in the gene FRMD7.
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PMID:A novel mutation in FRMD7 causes X-linked idiopathic congenital nystagmus in a North Indian family. 2591 82

Leigh syndrome (LS) is a rare heterogeneous progressive neurodegenerative disorder usually presenting in infancy or early childhood. Clinical presentation is variable and includes psychomotor delay or regression, acute neurological or acidotic episodes, hypotonia, ataxia, spasticity, movement disorders, and corresponding anomalies of the basal ganglia and brain stem on magnetic resonance imaging. To date, 35 genes have been associated with LS, mostly involved in mitochondrial respiratory chain function and encoded in either nuclear or mitochondrial DNA. We used whole-exome sequencing to identify disease-causing variants in four patients with basal ganglia abnormalities and clinical presentations consistent with LS. Compound heterozygote variants in ECHS1, encoding the enzyme enoyl-CoA hydratase were identified. One missense variant (p.Thr180Ala) was common to all four patients and the haplotype surrounding this variant was also shared, suggesting a common ancestor of French-Canadian origin. Rare mutations in ECHS1 as well as in HIBCH, the enzyme downstream in the valine degradation pathway, have been associated with LS or LS-like disorders. A clear clinical overlap is observed between our patients and the reported cases with ECHS1 or HIBCH deficiency. The main clinical features observed in our cohort are T2-hyperintense signal in the globus pallidus and putamen, failure to thrive, developmental delay or regression, and nystagmus. Respiratory chain studies are not strikingly abnormal in our patients: one patient had a mild reduction of complex I and III and another of complex IV. The identification of four additional patients with mutations in ECHS1 highlights the emerging importance of this pathway in LS.
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PMID:Whole-exome sequencing identifies novel ECHS1 mutations in Leigh syndrome. 2609 13

Idiopathic infantile nystagmus (IIN) is the involuntary oscillation of the eyes with onset in the first few months of life. The most common form of inheritance is X-linked, and mutations in FRMD7 gene are a major cause. To identify the FRMD7 gene mutations associated with X-linked IIN, we performed PCR-based DNA direct sequencing in 4 affected subjects from 2 Korean families. We also assessed structural abnormalities of retina and optic nerve head using optical coherence tomography (OCT). Genetic analysis revealed a A>G transversion at nucleotide c.1, the first base of the start codon. This mutation leads to the loss of the primary start codon ATG for methionine, which is replaced by a triplet GTG for valine. The alternative in-frame start codon is not present around a mutation. OCT revealed the morphological changes within the optic nerve head, including shallow cup depth and small cup-to-disc ratio. In summary, we identified a novel start codon mutation within the FRMD7 gene of 2 Korean families. Our data expands the mutation spectrum of FRMD7 causing IIN. We also demonstrated abnormal developments of afferent system in patients with FRMD7 mutations using OCT, which may help to understand the etiological factor in development of nystagmus.
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PMID:A start codon mutation of the FRMD7 gene in two Korean families with idiopathic infantile nystagmus. 2626 55

Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.
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PMID:Late-onset episodic ataxia associated with SLC1A3 mutation. 2782 85

3-Hydroxyisobutyryl-CoA dehydrogenase (HIBCH) deficiency is a rare error in valine catabolism associated with a Leigh syndrome-like phenotype, mitochondrial dysfunction, and increased C4-OH. We report the most severe case to date in a full-term female who presented with poor feeding and nystagmus on day of life (DOL) 1. Although initial neuroimaging findings were concerning for metabolic disease, further metabolic testing was nondiagnostic and she was discharged on DOL 18. She was readmitted on DOL 22 after severe apneic episodes requiring intubation, with EEG demonstrating multifocal seizures and MRI/MRS demonstrating worsening findings. Care was withdrawn DOL 27 and she expired. Rapid whole exome sequencing (WES) demonstrated compound heterozygous variants in HIBCH with a paternal pathogenic variant (c.852delA, p.L284FfsX10) and a maternal likely pathogenic variant (c.488G>T, p.C163F). Fibroblast enzymatic testing demonstrated marked reduction in HIBCH levels. This case demonstrates the importance of rapid WES and follow-up functional testing in establishing a diagnosis when metabolic disease is suspected but lacks an expected biochemical signature.
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PMID:A phenotypically severe, biochemically "silent" case of HIBCH deficiency in a newborn diagnosed by rapid whole exome sequencing and enzymatic testing. 3202 91

Biallelic mutations in ECHS1, encoding the mitochondrial enoyl-CoA hydratase, have been associated with mitochondrial encephalopathies with basal ganglia involvement. Here, we describe a novel clinical presentation consisting of dystonia-ataxia syndrome with hearing loss and a peculiar torsional nystagmus observed in two adult siblings. The presence of a 0.9-ppm peak at MR spectroscopy analysis suggested the accumulation of branched-chain amino acids. Exome sequencing in index probands identified two ECHS1 mutations, one of which was novel (p.V82L). ECHS1 protein levels and residual activities were reduced in patients' fibroblasts. This paper expands the phenotypic spectrum observed in patients with impaired valine catabolism.
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PMID:Dystonia-ataxia syndrome with permanent torsional nystagmus caused by ECHS1 deficiency. 3232 85