Niemann-Pick disease type C
TL;DR: The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin, and genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis.
Abstract: 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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TL;DR: The complement of efflux systems of 63 sequenced prokaryotes was compared with that of the heavy metal resistant bacterium Ralstonia metallidurans and showed that heavy metal resistance is the result of multiple layers of resistance systems with overlapping substrate specificities, but unique functions.
Abstract: What makes a heavy metal resistant bacterium heavy metal resistant? The mechanisms of action, physiological functions, and distribution of metal-exporting proteins are outlined, namely: CBA efflux pumps driven by proteins of the resistance–nodulation–cell division superfamily, P-type ATPases, cation diffusion facilitator and chromate proteins, NreB- and CnrT-like resistance factors. The complement of efflux systems of 63 sequenced prokaryotes was compared with that of the heavy metal resistant bacterium Ralstonia metallidurans. This comparison shows that heavy metal resistance is the result of multiple layers of resistance systems with overlapping substrate specificities, but unique functions. Some of these systems are widespread and serve in the basic defense of the cell against superfluous heavy metals, but some are highly specialized and occur only in a few bacteria. Possession of the latter systems makes a bacterium heavy metal resistant.
1,333 citations
TL;DR: This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death.
Abstract: Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented.
645 citations
Icahn School of Medicine at Mount Sinai1, International Longevity Center2, Albert Einstein College of Medicine3, University of California, Los Angeles4, Veterans Health Administration5, University of California, San Diego6, University of Pittsburgh7, University of Connecticut8, University of Kentucky9, Montefiore Medical Center10, University of Washington11, Northwestern University12
TL;DR: The goals of this article are to help guide clinicians in their general understanding of sleep problems in older persons, examine specific sleep disorders that occur in older Persons, and suggest evidence‐ and expert‐based recommendations for the assessment and treatment of sleep disorders in older people.
Abstract: Sleep-related disorders are most prevalent in the older adult population. A high prevalence of medical and psychosocial comorbidities and the frequent use of multiple medications, rather than aging per se, are major reasons for this. A major concern, often underappreciated and underaddressed by clinicians, is the strong bidirectional relationship between sleep disorders and serious medical problems in older adults. Hypertension, depression, cardiovascular disease, and cerebrovascular disease are examples of diseases that are more likely to develop in individuals with sleep disorders. Conversely, individuals with any of these diseases are at a higher risk of developing sleep disorders. The goals of this article are to help guide clinicians in their general understanding of sleep problems in older persons, examine specific sleep disorders that occur in older persons, and suggest evidence- and expert-based recommendations for the assessment and treatment of sleep disorders in older persons. No such recommendations are available to help clinicians in their daily patient care practices. The four sections in the beginning of the article are titled, Background and Significance, General Review of Sleep, Recommendations Development, and General Approach to Detecting Sleep Disorders in an Ambulatory Setting. These are followed by overviews of specific sleep disorders: Insomnia, Sleep Apnea, Restless Legs Syndrome, Circadian Rhythm Sleep Disorders, Parasomnias, Hypersomnias, and Sleep Disorders in Long-Term Care Settings. Evidence- and expert-based recommendations, developed by a group of sleep and clinical experts, are presented after each sleep disorder.
401 citations
TL;DR: Points of consensus among experts in the diagnosis and treatment of NP-C are reported based on a follow-up meeting in Paris, France in September 2011, providing further information on detection/diagnostic methods, potential new methods of monitoring disease progression, and therapy.
395 citations
TL;DR: An understanding of cholesterol metabolism in the brain and its role in disease requires a close look at individual cell types, including neurons and astrocytes, which are identified as net producers and consumers of cholesterol.
364 citations
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TL;DR: There was no significant increase in the rate of either clinical diagnoses or prenatal diagnoses of lysosomal storage disorders during the study period, and as a group, they are relatively common and represent an important health problem in Australia.
Abstract: ContextLysosomal storage disorders represent a group of at
least 41 genetically distinct, biochemically related, inherited
diseases. Individually, these disorders are considered rare, although
high prevalence values have been reported in some populations. These
disorders are devastating for individuals and their families and result
in considerable use of resources from health care systems; however, the
magnitude of the problem is not well defined. To date, no comprehensive
study has been performed on the prevalence of these disorders as a
group.ObjectiveTo determine the prevalence of lysosomal storage
disorders individually and as a group in the Australian population.DesignRetrospective case studies.SettingAustralia, from January 1, 1980, through December 31,
1996.Main Outcome MeasureEnzymatic diagnosis of a lysosomal storage
disorder.ResultsTwenty-seven different lysosomal storage disorders were
diagnosed in 545 individuals. The prevalence ranged from 1 per
57,000 live births for Gaucher disease to 1 per 4.2 million live
births for sialidosis. Eighteen of 27 disorders had more than 10
diagnosed cases. As a group of disorders, the combined prevalence was 1
per 7700 live births. There was no significant increase in the rate of
either clinical diagnoses or prenatal diagnoses of lysosomal storage
disorders during the study period.ConclusionsIndividually, lysosomal storage disorders are rare
genetic diseases. However, as a group, they are relatively common and
represent an important health problem in Australia.
1,963 citations
"Niemann-Pick disease type C" refers background in this paper
...20 per 100,000, respectively, were reported in studies from Australia (20 cases between 1980-1996), The Netherlands (25 cases between 1970-1996) and Northern Portugal (9 cases 1985-2003) [21-23]....
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TL;DR: Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking.
Abstract: Niemann-Pick type C (NP-C) disease, a fatal neurovisceral disorder, is characterized by lysosomal accumulation of low density lipoprotein (LDL)-derived cholesterol. By positional cloning methods, a gene (NPC1) with insertion, deletion, and missense mutations has been identified in NP-C patients. Transfection of NP-C fibroblasts with wild-type NPC1 cDNA resulted in correction of their excessive lysosomal storage of LDL cholesterol, thereby defining the critical role of NPC1 in regulation of intracellular cholesterol trafficking. The 1278-amino acid NPC1 protein has sequence similarity to the morphogen receptor PATCHED and the putative sterol-sensing regions of SREBP cleavage-activating protein (SCAP) and 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase.
1,403 citations
"Niemann-Pick disease type C" refers background in this paper
...Etiology Mutations in either of the two genes, NPC1 or NPC2, may cause the disease [13-16]....
[...]
...Major advances have been the description of two genetic complementation groups [13,14] and the subsequent isolation of the two underlying genes [15,16]....
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TL;DR: Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.
Abstract: Niemann-Pick type C2 disease (NP-C2) is a fatal hereditary disorder of unknown etiology characterized by defective egress of cholesterol from lysosomes. Here we show that the disease is caused by a deficiency in HE1, a ubiquitously expressed lysosomal protein identified previously as a cholesterol-binding protein. HE1 was undetectable in fibroblasts from NP-C2 patients but present in fibroblasts from unaffected controls and NP-C1 patients. Mutations in the HE1 gene, which maps to chromosome 14q24.3, were found in NP-C2 patients but not in controls. Treatment of NP-C2 fibroblasts with exogenous recombinant HE1 protein ameliorated lysosomal accumulation of low density lipoprotein-derived cholesterol.
817 citations
"Niemann-Pick disease type C" refers background in this paper
...Etiology Mutations in either of the two genes, NPC1 or NPC2, may cause the disease [13-16]....
[...]
...Major advances have been the description of two genetic complementation groups [13,14] and the subsequent isolation of the two underlying genes [15,16]....
[...]
...The remainder have mutations in the NPC2 gene, which encodes a small soluble lysosomal protein that binds cholesterol with high affinity [16,55,56]....
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TL;DR: It is found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells, which represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.
Abstract: Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the acidic compartment (which we define as the late endosome and the lysosome) protein, NPC1. The function of NPC1 is unknown, but when it is dysfunctional, sphingosine, glycosphingolipids, sphingomyelin and cholesterol accumulate. We have found that NPC1-mutant cells have a large reduction in the acidic compartment calcium store compared to wild-type cells. Chelating luminal endocytic calcium in normal cells with high-affinity Rhod-dextran induced an NPC disease cellular phenotype. In a drug-induced NPC disease cellular model, sphingosine storage in the acidic compartment led to calcium depletion in these organelles, which then resulted in cholesterol, sphingomyelin and glycosphingolipid storage in these compartments. Sphingosine storage is therefore an initiating factor in NPC1 disease pathogenesis that causes altered calcium homeostasis, leading to the secondary storage of sphingolipids and cholesterol. This unique calcium phenotype represents a new target for therapeutic intervention, as elevation of cytosolic calcium with curcumin normalized NPC1 disease cellular phenotypes and prolonged survival of the NPC1 mouse.
762 citations
"Niemann-Pick disease type C" refers background or methods in this paper
...It has also been postulated that sphingosine storage could be the primary trigger of a pathogenic cascade in NP-C since this lipid can disrupt calcium homeostasis in NPC1 lysosomes [85,86]....
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...Data have been published in the mouse using imatinib [137], curcumin [85], non-steroid anti-inflammatory drugs [138], neurosteroids (allopregnanolone) in combination with 2-HP-ß-cyclodextrin [139], and with 2HP-ß-cyclodextrin alone [64,140]....
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TL;DR: The relative frequency and the birth prevalence of lysosomal storage diseases in The Netherlands based on all 963 enzymatically confirmed cases diagnosed during the period 1970–1996 is calculated.
Abstract: We have calculated the relative frequency and the birth prevalence of lysosomal storage diseases (LSDs) in The Netherlands based on all 963 enzymatically confirmed cases diagnosed during the period 1970-1996. The combined birth prevalence for all LSDs is 14 per 100,000 live births. Glycogenosis type II is the most frequent LSD with a birth prevalence of 2.0 per 100,000 live births, representing 17% of all diagnosed cases. Within the group of lipidoses, metachromatic leukodystrophy (MLD) is the most frequent LSD. MLD was diagnosed in 24% of lipidoses and the calculated birth prevalence was 1.42 per 100,000 for all types combined. Krabbe disease, diagnosed in 17% of cases, also belongs to the more frequent lipid storage diseases in The Netherlands with a birth prevalence of 1.35 per 100,000. The birth prevalence of Gaucher disease, commonly regarded as the most frequent lipid storage disease is 1.16 per 100,000 for all types combined. The combined birth prevalence for all lipid storage diseases is 6.2 per 100,000 live births. Within the group of mucopolysaccharidoses (MPSs), MPS I has the highest calculated birth prevalence of 1.19 per 100,000 (25% of all cases of MPS diagnosed), which is slightly more frequent than MPS IIIA with an estimated birth prevalence of 1.16 per 100,000. As a group, MPS III comprises 47% of all MPS cases diagnosed and the combined birth prevalence is 1.89 per 100,000 live births. The birth prevalence of MPS II is 0.67 per 100,000 (1.30 per 100,000 male live births). All other MPSs are rare. The combined birth prevalence for all MPSs is 4.5 per 100,000 live births. Mucolipidoses and oligosaccharidoses are very rare with birth prevalences between 0.04 and 0.20 for individual diseases. Only 49 cases were diagnosed between 1970 and 1996. Their combined birth prevalence is 1.0 per 100,000 live births.
652 citations