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)

Two sisters who manifested downbeat nystagmus at the early stage of leukodystrophy are reported. The younger sister whose onset was at the age of 20, deteriorated rapidly to the vegetative state, and died of acute pneumonia 7 years after. Her downbeat nystagmus was observed only during the early 2 years of the course of her disease. The histopathological study on her brain enabled a diagnosis of sudanophilic leukodystrophy which demonstrated overall gliosis of white matter in the cerebrum and severe depopulation of Purkinje cells in the cerebellum, particularly in the vermis. The elder sister's onset was at the age of 29 and deteriorated rapidly to akinetic mutism. Her downbeat nystagmus was observed only during the first year of the course of her disease. For over 10 years she has been at the vegetative state. CT-scan of her brain demonstrates low density areas in the white matter of the cerebrum and in the vermis of the cerebellum. These two cases showed similar clinical signs and courses of their diseases, which were spontaneous nystagmus, early changes of personality and intelligence, and extra-pyramidal sign and later rapid deterioration of the stage of akinetic mutism. Histopathologically these cases are suspected as having an identical hereditary etiology of sudanophilic leukodystrophy. In these cases it is noted that downbeat nystagmus was the early sign of the disease.
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PMID:Spontaneous downbeat nystagmus in two sisters with sudanophilic leukodystrophy. 382 50

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

A 50-year-old woman, who had consanguineous parents, developed gait disturbance at age 3, and revealed nystagmus, cerebellar ataxia, peripheral neuropathy, and spastic tetraparesis. She admitted to our hospital at age 14, and the symptoms progressed very slowly. MRI of this case at age 45 showed a remarkable, diffuse hypomyelination of the cerebrum. Her older sister who already deceased at age 16 showed neurological symptoms similar to this case. The patient was found to have no proteolipid protein-1 gene duplications and deletions and base substitution. Her symptoms were considered to be different from those of typical HLD2, 3, 4 and 5. She carried no GJA12 mutations. These facts suggested that this disease is a novel, autosomal recessive hypomyelinating leukodystrophy.
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PMID:[A case of autosomal recessive hypomyelinating leukodystrophy without GJA12 mutation presenting a novel phenotype]. 2012 Mar 47

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher-like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue.
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PMID:Pathologic and phenotypic alterations in a mouse expressing a connexin47 missense mutation that causes Pelizaeus-Merzbacher-like disease in humans. 2175 Jun 83

Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked leukodystrophy presenting with motor developmental delay associated with spasticity and nystagmus. PMD is mainly caused by abnormalities in the proteolipid protein 1 gene (PLP1), most frequently due to duplications of chromosomal segments including PLP1. In this study, a 9-year-old male patient manifesting severe developmental delay and spasticity was analyzed for PLP1 alteration, and triplication of PLP1 was identified. Further examination revealed an underlying genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which a triplicated segment was nested between 2 junctions. One of the 2 junctions was caused by inverted homologous regions, and the other was caused by non-homologous end-joining. PMD patients with PLP1 duplications usually show milder-classical forms of the disease compared with patients with PLP1 missense mutations manifesting severe connatal forms. The present patient showed severe phenotypic features that represent an intermediate form of PMD between classical and connatal forms. This is the first report of a patient with PLP1 triplication caused by a DUP-TRP/INV-DUP structure. This study adds additional evidence about the consequences of PLP1 triplication.
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PMID:Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region. 2249 Apr 26

We report the case of a 49-year old woman affected by hypomyelinating leukodystrophy. She presented with typical pendular nystagmus that was analyzed with video-oculography which is provided in the supplementary material of the report. The pendular nystagmus was accompanied by upper limb ataxia on the index-to-nose test. The video was partly recorded with a slow-motion technique in order to better demonstrate the ataxia and the pendular nystagmus. The brain MRI demonstrated a characteristic pattern of hypomyelination. Pendular nystagmus is a key clinical sign that contributes to the diagnosis of CNS hypomyelination when a leukodystrophic pattern is observed on brain MRI.
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PMID:Pendular nystagmus in hypomyelinating leukodystrophy. 2384 62

A 3-year-old boy was admitted with psychomotor delay, spasticity, progressive visual loss, nystagmus, macrocephaly, and epileptic seizures for diagnostics. Cranial magnetic resonance imaging (MRI) revealed leukodystrophy and multicystic changes. Urine excretion of N-acetylaspartic acid was grossly increased, suggesting Canavan disease. Mutation screening of the ASPA gene confirmed this diagnosis. The underlying enzymatic defect causes accumulation of N-acetylaspartic acid and subsequent progressive myelin degeneration with characteristic spongy degeneration of the subcortical white matter, normally only seen histologically. We describe this case to show that spongy degeneration in Canavan disease may also be present macroscopically in the form of multiple beaded periventricular cysts on cranial MRI.
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PMID:Leukodystrophy with multiple beaded periventricular cysts: unusual cranial MRI results in Canavan disease. 2564 44

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by mutations or rearrangements in PLP1. It presents in infancy with nystagmus, jerky head movements, hypotonia and developmental delay evolving into spastic tetraplegia with optic atrophy and variable movement disorders. A clinically similar phenotype caused by recessive mutations in GJC2 is known as Pelizaeus-Merzbacher-like disease. Both genes encode proteins associated with myelin. We describe three siblings of a consanguineous family manifesting the typical infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy and peripheral neuropathy in adulthood. Magnetic resonance imaging and spectroscopy were consistent with a demyelinating leukodystrophy. Using genetic linkage and exome sequencing, we identified a homozygous missense c.399C>G; p.S133R mutation in MAG. This gene, previously associated with hereditary spastic paraplegia, encodes myelin-associated glycoprotein, which is involved in myelin maintenance and glia-axon interaction. This mutation is predicted to destabilize the protein and affect its tertiary structure. Examination of the sural nerve biopsy sample obtained in childhood in the oldest sibling revealed complete absence of myelin-associated glycoprotein accompanied by ill-formed onion-bulb structures and a relatively thin myelin sheath of the affected axons. Immunofluorescence, cell surface labelling, biochemical analysis and mass spectrometry-based proteomics studies in a variety of cell types demonstrated a devastating effect of the mutation on post-translational processing, steady state expression and subcellular localization of myelin-associated glycoprotein. In contrast to the wild-type protein, the p.S133R mutant was retained in the endoplasmic reticulum and was subjected to endoplasmic reticulum-associated protein degradation by the proteasome. Our findings identify involvement of myelin-associated glycoprotein in this family with a disorder affecting the central and peripheral nervous system, and suggest that loss of the protein function is responsible for the unique clinical phenotype.
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PMID:Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder. 2617 19

The MAG gene encodes myelin-associated glycoprotein (MAG), an abundant protein involved in axon-glial interactions and myelination during nerve regeneration. Several members of a consanguineous family with a clinical syndrome reminiscent of Pelizaeus-Merzbacher disease and demyelinating leukodystrophy on brain MRI were recently found to harbor a homozygous missense p.Ser133Arg MAG mutation. Here, we report two brothers from a nonconsanguineous family afflicted with progressive cognitive impairment, neuropathy, ataxia, nystagmus, and gait disorder. Exome sequencing revealed the homozygous missense mutation p.Arg118His in MAG. This Arg118 residue in immunoglobulin domain 1 is critical for sialic acid binding, providing a compelling mechanistic basis for disease pathogenesis.
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PMID:Neurologic syndrome associated with homozygous mutation at MAG sialic acid binding site. 2760 46

AARS2 gene (NM_020745.3) mutations result in two different phenotypic diseases: infantile mitochondrial cardiomyopathy and late-onset leukoencephalopathy. The patient's first symptoms appeared at the age of 18 years with behavioral changes and psychiatric problems. Some years later, extrapyramidal symptoms, cognitive impairment, nystagmus, dysarthria and pyramidal symptoms also developed. The brain magnetic resonance imaging (MRI) indicated extensive white matter abnormalities. The diagnosis of AARS2 gene mutations causing leukodystrophy was confirmed by genetic testing. Segregation analysis confirmed the compound heterozygous state of the patient. Histological examination of the biopsy did not prove specific pathological alterations. The clinical phenotype of our patient was compared with seven previously described patients suffering from leukoencephalopathy caused by AARS2 mutations. We have documented a new, nonsense AARS2 gene mutation (c.578T>G, p.Leu193*) and a known missense mutation (c.595C>T, p.Arg199Cys) associated with leukoencephalopathy in a male patient. Clinical features, imaging characteristics and genetic testing are presented, and histological data from an AARS2-related leukodystrophy patient are described for the first time.
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PMID:Novel AARS2 gene mutation producing leukodystrophy: a case report. 2773 37


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