Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

Alobaidy, Hanna

doi:10.1155/2015/816593

Cited by 37 publications

(31 citation statements)

References 35 publications

(100 reference statements)

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“…or NPC2 which regulate the intracellular trafficking and processing of cholesterol and other lipids resulting in lysosomal accumulation of cholesterol, glycosphingolipids, and sphingomyelin (Alobaidy, 2015). The infantile and late infantile forms are most severe and are characterized by cerebellar ataxia, dementia, cognitive decline, seizures, and premature death (Vanier, 2010).…”

Section: Niemann-pick Type C (Npc) Is Caused By Inherited Defects In mentioning

confidence: 99%

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Groh

Martini

2017

Glia

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Genetically caused neurological disorders of the central nervous system (CNS) are usually orphan diseases with poor or even fatal clinical outcome and few or no treatments that will improve longevity or at least quality of life. Neuroinflammation is common to many of these disorders, despite the fact that a plethora of distinct mutations and molecular changes underlie the disorders. In this article, data from corresponding animal models are analyzed to define the roles of innate and adaptive inflammation as modifiers and amplifiers of disease. We describe both common and distinct patterns of neuroinflammation in genetically mediated CNS disorders and discuss the contrasting mechanisms that lead to adverse versus neuroprotective effects. Moreover, we identify the juxtaparanode as a neuroanatomical compartment commonly associated with inflammatory cells and ongoing axonopathic changes, in models of diverse diseases. The identification of key immunological effector pathways that amplify neuropathic features should lead to realistic possibilities for translatable therapeutic interventions using existing immunomodulators. Moreover, evidence emerges that neuroinflammation is not only able to modify primary neural damage-related symptoms but also may lead to unexpected clinical outcomes such as neuropsychiatric syndromes.

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Section: Niemann-pick Type C (Npc) Is Caused By Inherited Defects In mentioning

confidence: 99%

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Groh

Martini

2017

Glia

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“…Combination of drug regimens have been shown to lower hepatic and plasma cholesterol but there is no evidence that these results affect the progression of the disease in humans or murine models. Behavioral and speech problems or schooling difficulties should be referred to as psychiatric team and special schooling [8,9].…”

Section: Previous Treatments Employedmentioning

confidence: 99%

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Megías‐Vericat¹,

Company-Albir²,

García-Robles³

et al. 2018

Cyclodextrin - A Versatile Ingredient

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Niemann-Pick disease type C (NPD-C) is a rare neurodegenerative disorder characterized by a lysosomal storage disorder. Treatment has been supportive and symptomatic. In animal studies, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) showed a significant decrease in cerebellar damage, neurological progression, and higher lifespan. Based on these results, HP-β-CD has been tested in NPD-C patients for last 8 years. The first compassionate uses of intravenous HP-β-CD obtained a limited improvement in neurological symptoms, probably associated to the non-permeation of the blood-brain barrier. The change or combination with intrathecal administrations of HP-β-CD achieved higher benefits, especially improvement or stabilization of NPD-C progression. Biomarkers of neurological cholesterol homeostasis are being investigated in order to quantify the response of HP-β-CD treatment. The results of a clinical trial recently published have reproduced the slowing of NPD-C progression in 14 patients treated with a dose-escalation protocol of HP-β-CD intrathecal monthly infusions, with respect to a historical comparison cohort. The safety profile of this therapy is acceptable, being the loss of hearing as the most frequent adverse event. However, some severe toxicities have been reported in relation with HP-β-CD, including chemical meningitis and fever. The short experience with HP-β-CD suggested that it could be effective in the management of NPD-C.

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“…Glycolipids are among the lipids that accumulate in LSOs as a consequence of the elevated cholesterol levels, and reducing their abundance might reduce the effects of lipid storage. Zavesca treatment has been shown to slow the disease progression (Alobaidy 2015;Di Rocco et al 2012;Skorpen et al 2012).…”

Section: Therapies For Npc Diseasementioning

confidence: 99%

Role of STARD4 and NPC1 in intracellular sterol transport

Maxfield

Iaea

Pipalia

2016

Biochem. Cell Biol.

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Cholesterol plays an important role in determining the biophysical properties of membranes in mammalian cells, and the concentration of cholesterol in membranes is tightly regulated. Cholesterol moves among membrane organelles by a combination of vesicular and nonvesicular transport pathways, but the details of these transport pathways are not well understood. In this review, we discuss the mechanisms for nonvesicular sterol transport with an emphasis on the role of STARD4, a small, soluble, cytoplasmic sterol transport protein. STARD4 can rapidly equilibrate sterol between membranes, especially membranes with anionic lipid headgroups. We also discuss the sterol transport in late endosomes and lysosomes, which is mediated by a soluble protein, NPC2, and a membrane protein, NPC1. Homozygous mutations in these proteins lead to a lysosomal lipid storage disorder, Niemann-Pick disease type C. Many of the disease-causing mutations in NPC1 are associated with degradation of the mutant NPC1 proteins in the endoplasmic reticulum. Several histone deacetylase inhibitors have been found to rescue the premature degradation of the mutant NPC1 proteins, and one of these is now in a small clinical trial.

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Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

Cited by 37 publications

References 35 publications

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Neuroinflammation as modifier of genetically caused neurological disorders of the central nervous system: Understanding pathogenesis and chances for treatment

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

Role of STARD4 and NPC1 in intracellular sterol transport

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