99. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann–Pick C1 disease

Ory, Daniel S.; Porter, Forbes D.; Scherrer, David E.; Lanier, M; Langmade, S. Joshua; Molugu, Vasumathi; Gale, Sarah E.; Olzeski, Dana; Sidhu, Rohini; Wassif, Christopher A.; Yanjanin, Nicole M.; Schaffer, Jean E.

doi:10.1016/j.ymgme.2009.10.116

Cited by 9 publications

(2 citation statements)

References 37 publications

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“…Having to start from a skin biopsy excludes NP-C from all "metabolic screens" and significantly contributes to the delay in diagnosis. Importantly, a recent pilot study indicates that plasma of patients with NP-C show a specific oxysterol profile that could be used as a biomarker [ 143 ]. This observation may impact the future diagnostic strategy.…”

Section: Unresolved Questionsmentioning

confidence: 99%

Niemann-Pick disease type C

Vanier

2010

Orphanet J Rare Dis

955

1,019

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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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Section: Unresolved Questionsmentioning

confidence: 99%

Niemann-Pick disease type C

Vanier

2010

Orphanet J Rare Dis

955

1,019

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“…Very recent data has been presented indicating that the plasma concentration of certain oxysterols, in particular the auto-oxidation products 7-oxocholesterol and cholestane 3,5,6-triol, is elevated in NPC disease, indicating a possible role for measurement of these sterols in the diagnosis and/or monitoring of NPC disease ( 103,108 ). These data are consistent with the previous demonstration by Alvelius et al ( 109 ) that the urine of an NPC patient contains unusual knowledge, although it is possible that it may infl uence cholesterol supply to the ER, where 24S-OHC is synthesized.…”

Section: Niemann-pick Diseasementioning

confidence: 99%

Genetic connections between neurological disorders and cholesterol metabolism

Björkhem

Leoni²,

Meaney³

2010

Journal of Lipid Research

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and store such a large amount of cholesterol indicates that there is a close link between the evolution of the nervous system and a specifi c role for cholesterol. Within the brain, some 70% of cholesterol is present in myelin, where it fulfi lls a critical insulating role. It is likely that the requirement for effi cient signaling despite a small transverse diameter of axons was a key selective pressure driving the accretion of cholesterol in the mammalian brain ( 1, 2 ). The requirement for large amounts of cholesterol is further underscored by the long half-life of brain cholesterol; overall brain cholesterol turns over some 250-300 times slower than that in the circulation ( 3 ).At a cellular level, the myelin sheath consists of sections of plasma membrane repeatedly wrapped around an axon, with the extrusion of virtually all of the cytoplasm. Myelin is formed by 2 very specialized cells: the oligodendrocyte in the central nervous system (CNS) and the Schwann cell in the peripheral nervous system (PNS). Because an individual axon may be ensheathed by myelin from several oligodendrocytes, periodic gaps are present in the sheath. These are called the "nodes of Ranvier" and are the site of propagation of the action potential. Myelin can thus be regarded as a discontinuous insulation that enables the saltatory conduction of the action potential ( 1, 2 ). In addition Abstract Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defi ned defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington's disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer's disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders. -Björkhem, I., V. Leoni, and S. Meaney. The mammalian nervous system contains a disproportionate amount of cholesterol. In the brain, the cholesterol content is about 10-fold greater than in any other organ ( 1 ). The development of the capacity to synthesize

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