Neurofibrillary tangles in Niemann-Pick disease type C

Suzuki, K.; Parker, Clarissa C.; Pentchev, Peter G.; Katz, David; Ghetti, Bernardino; D'Agostino, A; Carstea, Eugene D.

doi:10.1007/s004010050241

Cited by 20 publications

(29 citation statements)

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“…However, no plaques were found in NPC disease, despite the presence of PHFs-rich NFTs. 24,28 The distribution of neurons bearing NFTs was generally similar to that of the swollen storage neurons and the storage neurons often contained NFTs in their perikarya and ⁄ or in the meganeurites. Neurofibrillary tangles, ectopic dendritogenesis and meganeurite formation in the cortex are known to provide an anatomical substrate for dementia and seizures.…”

Section: Human Brainmentioning

confidence: 85%

“…23 Similar inclusions are found in glial cells. 24 The use of the Golgi staining method to investigate cortical neurons in a human brain has revealed abnormal dendritic spines projecting from the swelling at the axon hillock. 25 The formation of the spines was described as 'ectopic dendritogenesis' due to their peculiar and inappropriate location on cells.…”

Section: Human Brainmentioning

confidence: 99%

“…Granular spheroids are composed of apparently degenerated organelles, pleiomorphic bodies and amorphous dense substances. 24 Antibodies to ubiquitin and phosphorylated neurofilaments bind spheroids in brains from NPC patients. 22 There is also evidence of fragmentation of the Golgi ⁄ trans-Golgi network (TGN) in cerebellar Purkinje cells and cerebral cortical neurons.…”

Section: Human Brainmentioning

confidence: 99%

“…11 The distribution and number of NFT-expressing neurons varies from case to case. 24 Neurofibrillary tangles are conspicuous feature of NPC patients who are homozygous for the ApoEe4 allele, in whom the deposition of b-amyloid is also detectable. 27 Neurofibrillary tangles are most common in the hippocampus, medial temporal lobes, orbital gyrus, cingulate gyrus and entorhinal region, but are also frequently found in the basal ganglia, thalamus and hypothalamus.…”

Section: Human Brainmentioning

confidence: 99%

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Niemann–Pick disease Type C: From molecule to clinic

Tang

Liu

2009

Clin Exp Pharma Physio

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1. Niemann-Pick Type C disease (NPC) is an incurable cholesterol-storage disorder that stems from inherited deficiencies of lysosomal proteins involved in intracellular lipid-trafficking proteins. The condition manifests as progressive neurological impairment and leads to death at an early age. 2. To improve clinical recognization and investigate therapeutic strategies, recent studies using molecular and genetic approaches have led to significant advances in the creation of animal models of NPC, as well as in the understanding of the cellular and molecular mechanisms underlying the pathogenesis of NPC. 3. Patients with NPC are divided into four groups based on age at presentation, whereas the clinical features of NPC can be divided into five categories based on the severity of the disease. Progressive neuronal loss, especially of cerebellar Purkinje cells, is a hallmark of NPC. Ballooned neurons, axonal abnormalities and astroglyosis are among the pathological changes seen. Severe demyelination is also present in the mouse model of NPC. 4. Mutations in the NPC1 gene cause approximately 95% of cases of NPC, whereas mutations in the NPC2 gene account for the remainder of cases. NPC1 is a transmembrane protein and NPC2 is a soluble protein involved in lipid trafficking in lysosomes. Loss-of-function mutations in the NPC1 gene lead to a failure of the calcium-mediated fusion of endosomes with lysosomes, resulting in the accumulation of cholesterol and other lipids in late endosomes and lysosomes. 5. The present review updates the disorders of NPC from clinical features to animal models and molecular mechanisms.

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Section: Human Brainmentioning

confidence: 85%

Section: Human Brainmentioning

confidence: 99%

Section: Human Brainmentioning

confidence: 99%

Section: Human Brainmentioning

confidence: 99%

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Niemann–Pick disease Type C: From molecule to clinic

Tang

Liu

2009

Clin Exp Pharma Physio

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“…Among other features (6), neuropathology of NPC shows similarities to Alzheimer disease, with the presence of neurofibrillary tangles with paired helical filaments of tau protein (52) and the accumulation of amyloid-b-protein (53). A relationship with abnormalities of cholesterol metabolism is under discussion, as the latter finding may be related to elevated cholesterol levels in late endosomes.…”

Section: Lipid Storage Profilesmentioning

confidence: 99%

Niemann-Pick disease type C

Vanier

2010

Orphanet J Rare Dis

998

1,069

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Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

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Niemann–Pick type C disease: Accelerated neurofibrillary tangle formation and amyloid β deposition associated with apolipoprotein E ε4 homozygosity

Saito

Suzuki

Nanba

et al. 2002

Annals of Neurology

104

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Niemann-Pick type C disease is a neurovisceral storage disorder. Neurofibrillary tangles similar to those in Alzheimer's disease have been reported in most juvenile/adult patients without amyloid beta protein (Abeta) deposits. Recently, we found deposits of Abeta in the form of diffuse plaques in three (31- and 32-year-old sisters and a 37-year-old man) of nine Niemann-Pick type C disease patients, who presented with most severe tauopathy and with numerous neurofibrillary tangles. Abeta deposits were not detected in any of the control brains of patients younger than age 42 years. These three patients with Abeta deposit all were homozygotes of apolipoprotein E epsilon 4. Our study suggested that NPC1 gene mutations combined with homozygosity of apolipoprotein E epsilon 4 alleles could manifest neuropathology similar to that of Alzheimer's disease. Investigation of these patients may provide an important clue for understanding the pathogenesis of Alzheimer's disease.

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Neurofibrillary tangles in Niemann-Pick disease type C

Cited by 20 publications

References 0 publications

Niemann–Pick disease Type C: From molecule to clinic

Niemann–Pick disease Type C: From molecule to clinic

Niemann-Pick disease type C

Niemann–Pick type C disease: Accelerated neurofibrillary tangle formation and amyloid β deposition associated with apolipoprotein E ε4 homozygosity

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