Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This is the first description of slowly progressive Niemann-Pick disease type C (NPC) without the typical lysosomal storage in bone marrow and viscera in two descendants of a group of 17th century French-Canadians. The index patient was a married 43-year-old woman with onset of dementia in her thirties, later followed by the development of ataxia and athetoid movements. Her autopsy disclosed frontal lobe atrophy, neurolysosomal storage with oligolamellar inclusion and tau-positive neurofibrillary tangles. Of the 119 family members screened, only a married 42-year-old sister displayed symptoms of a dementia. Both women displayed vertical supranuclear ophthalmoplegia; expressive aphasia; concrete, stimulus-bound, perseverative behavior; and impaired conceptualization and planning. Cultured fibroblasts showed decreased cholesterol esterification and positive filipin staining, but no mutation was detected in coding or promoter regions of the NPC1 gene using conformation sensitive gel electrophoresis and sequencing. Sequencing showed a homozygous gene mutation that is predicted to result in an amino acid substitution, V39M, in the cholesterol binding protein HE1 (NPC2). Adult-onset NPC2 with lysosomal storage virtually restricted to neurons represents a novel phenotypic and genotypic variant with diffuse cognitive impairment and focal frontal involvement described for the first time.
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PMID:Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. 1244 27

Niemann-Pick type C disease is an autosomal-recessive, inherited neurovisceral lipid storage disorder. This disease results from either protein NPC1 or HE1 deficiency, which leads to cholesterol metabolism disturbance and is characterized by early hepatosplenomegaly and progressive ataxia, dystonia, cataplexy, dysarthria, and dementia. We describe a 3 1/2-year-old patient with Niemann-Pick type C disease, who presented with regression in both cognitive and motor domains. Almost 10 months before admission to the hospital, the child developed progressive speech and behavioral changes, as well as gait disturbances with frequent falls. The examination demonstrated hepatosplenomegaly, ataxia, and vertical gaze palsy. Nerve conduction velocities demonstrated mild demyelinating peripheral neuropathy. Bone marrow examination revealed foam cells, and cholesterol esterification studies found massive accumulation of unesterified cholesterol and very low intracellular esterification of exogenous lipoprotein-derived cholesterol. These results indicate Niemann-Pick type C disease. Peripheral neuropathy is a rare complication in patients with Niemann-Pick type C disease, which certainly contributes to their neurologic deterioration.
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PMID:Niemann-Pick type C disease associated with peripheral neuropathy. 1462 10

Niemann Pick type C (NPC) disease is an autosomal recessive disorder characterized by abnormal cholesterol metabolism and accumulation in lysosomal and endosomal compartments. Although peripheral organs are affected, the progressive neurodegeneration in the brain is typically most deleterious, leading to dystonia, ataxia, seizures, and premature death. Although the two genes underlying this disorder in humans and mouse models of the disease have been identified (NPC1 in 95% and NPC2/HE1 in 5% of human cases), their cellular roles have not Been fully defined, and there is currently no effective treatment for this disorder. To help address these issues, we constructed a recombinant adenovirus, Ad(NPC1-GFP), which contains a cDNA encoding a mouse NPC1 protein with a green fluorescent protein (GFP) fused to its C-terminus. Fluorescence microscopy and cholesterol trafficking assays demonstrate that the GFP-tagged NPC1 protein is functional and detectable in cells from different species (hamster, mouse, human) and of different types (ovary-derived cells, fibroblasts, astrocytes, neurons from peripheral and central nervous systems) in vitro. Combined with results from time-lapse microscopy and in vivo brain injections, our findings suggest that this adenovirus offers advantages for expressing NPC1 and analyzing its cellular localization, movement, functional properties, and beneficial effects in vitro and in vivo.
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PMID:Adenovirus expressing an NPC1-GFP fusion gene corrects neuronal and nonneuronal defects associated with Niemann pick type C disease. 1601 97