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Objectives. We aim to report the clinical repercussions of a nutritional approach in a patient diagnosed with Niemann Pick disease type C (NPC) using miglustat as pharmacological therapy. Case report. A 33-year-old woman diagnosed with NPC using miglustat was instructed to look for a dietary management at our nutrition service. Patient's symptoms were weight loss and important gastrointestinal alterations. Our nutritional prescription was a high-calorie and high-protein, lactose- and sucrose-free diet, as well as a daily supplementation of L-glutamine, probiotics, omega 3, and coenzyme Q10. After two months, the patient had weight gain and improvement in the intestinal health. Conclusions. We found that nutritional prescription aided in the treatment of NPC and revealed that nutritional care represents an important strategy in the management of rare genetic diseases.

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Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1-/- mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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Niemann-Pick type C (NPC), a lysosomal storage disorder, is mainly caused by mutations in the NPC1 gene. Niemann-Pick type C patients and mice show intracellular cholesterol accumulation leading to hepatic failure with increased inflammatory response. The complement cascade, which belongs to the innate immunity response, recognizes danger signals from injured tissues. We aimed to determine whether there is activation of the complement system in the liver of the NPC mouse and to assess the relationship between C3 activation, a final component of the pathway, and NPC liver pathology. Niemann-Pick type C mice showed high levels of C3 staining in the liver which unexpectedly decreased with aging. Using an inducible NPC1 hepatocyte rescue mouse model, we restored NPC1 expression for a short time in young mice. We found C3 positive cells only in non-rescued cells, suggesting that C3 activation in NPC cells is reversible. Then, we studied the effect of C3 ablation on NPC liver damage at two postnatal time points, P56 and P72. Deletion of C3 reduced the presence of hepatic CD68-positive cells at postnatal day 56 and prevented the increase of transaminase levels in the blood of NPC mice. These positive effects were abrogated at P72, indicating that the complement cascade participates only during the early stages of liver damage in NPC mice, and that its inhibition may serve as a new potential therapeutic strategy for the disease.

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Introducción: La enfermedad de Niemann-Pick tipo C es una enfermedad poco frecuente, autosómica recesiva, caracterizada por el depósito de lípidos a nivel lisosomal, que, a pesar de ser tratable, es mortal en todos los casos y representa una importante carga para los pacientes y sus familias. Objetivo: Contribuir al conocimiento de esta rara enfermedad neurovisceral progresiva de curso fatal. Presentación del caso: Se trata de una niña de 7 años de edad, que a los 2 años asistió a consulta por trastornos de la marcha, con deterioro progresivo de esta, así como del lenguaje y el comienzo de crisis epilépticas. Evolutivamente presentó cataplejías gelásticas, paresia de la mirada vertical y esplenomegalia. Estos elementos clínicos evolutivos fueron lo suficientemente distintivos para orientar la sospecha clínica y las investigaciones necesarias para llegar al diagnóstico definitivo de la enfermedad. Con la confirmación de que se trataba de la enfermedad de Niemann-Pick tipo C, se comenzó tratamiento con miglustad a dosis de 100 mg dos veces al día. Conclusiones: El deterioro neurológico progresivo, la cataplejía gelástica, la paresia de la mirada vertical y la esplenomegalia, unido a los resultados del medulograma y el estudio genético permitieron el diagnóstico de esta entidad(AU)

Introduction: Niemann-Pick type C disease is a non-frequent, recessive autosomal one, which is characterized by lipids deposit in the lysosomal level. Although this disease is treatable, it is fatal in all the cases and it represents a important burden to patients and their families. Objective: To contribute to the knowledge on this rare, progressive neurovisceral disease with fatal evolution. Case presentation: Seven- years- old girl, whom at two years old attended to a consultation for walk disorders presenting a progressive worsening of it, as well of the speech, and also presented an onset of epileptic crisis. In the evolution she presented gelastic cataplexy, vertical look´s paresia and splenomegaly. These clinical evolutive elements were sufficiently distinctive to indicate the clinical suspicion and the necessary research to reach its definitive diagnostic. With the confirmation of Niemann-Pick type C disease, miglustad was used as treatment with a dose of 100 mg twice in the day. Conclusions: Progressive neurological worsening, gelastic cataplexy, vertical look´s paresia and splenomegaly joined with the results of a medulogram and the genetic study permitted this disease to be identified(AU)

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Cataplexy is a transient loss of muscle tone that can be triggered by emotions such as laughter, excitement or fear. Other causes of cataplexy include Niemann-Pick type C Disease, Angelman Syndrome, Norrie Disease, Prader-Willi Syndrome. In addition, cataplexy can be a side effect of several drugs (eg, lamotrigine, clozapine, and gamma-hydroxybutyrate). Yet, the most prevalent causes of cataplexy without narcolepsy are rare genetic diseases; which explains why cataplexy is classically linked to narcolepsy. Therefore, it is essential disconnecting cataplexy from narcolepsy especially in pediatric population and after use of a few medications. In this review, we described few conditions of cataplexy not related to narcolepsy. We performed a review of literature (MEDLINE and EMBASE database), without limited date or publication restrictions.

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Niemann-Pick type C (NP-C) is a rare autosomal recessive disorder characterized by storage of unesterified glycolipids and cholesterol in lysosome and/or late endosome due to mutations in either NPC1 or NPC2 gene. This study aims to identify the spectrum of sequence alterations associated to NP-C in individuals with clinical suspicion of this disease. The entire coding region and flanking sequences of both genes associated to NP-C were evaluated in a total of 265 individuals that were referred to our laboratory. Clinical and/or biochemical suspicion of NP-C was confirmed by molecular analysis in 54 subjects. In this cohort, 33 different sequence alterations were identified in NPC1 and one in NPC2. Among those, 5 novel alterations in NPC1 gene were identified as follows: one deletion (p.Lys38_Tyr40del), one frameshift (p.Asn195Lysfs*2), and three missense mutations (p.Cys238Arg, p.Ser365Pro and, p.Val694Met) that are likely to be pathogenic through different approaches, including in silico tools as well as multiple sequence alignment throughout different species. We have also reported main clinical symptoms of patients with novel alterations and distribution of frequent symptoms in the cohort. Findings reported here contribute to the knowledge of mutation spectrum of NP-C, defining frequent mutations as well as novel sequence alterations associated to the disease.

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Niemann⁻Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68-A marker of Kupffer cells in the liver-and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated.

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BACKGROUND: Niemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of free cholesterol in lysosomes. There are currently no effective FDA-approved treatments for NPC, although in the last years the inhibition of histone deacetylases (HDACs) has emerged as a potential treatment for this disease. However, the molecular mechanisms that deregulate HDAC activity in NPC disease are unknown. Previously our group had shown that the proapoptotic tyrosine kinase c-Abl signaling is activated in NPC neurons. Here, we demonstrate that c-Abl activity increases HDAC2 levels inducing neuronal gene repression of key synaptic genes in NPC models. RESULTS: Our data show that: i) HDAC2 levels and activity are increased in NPC neuronal models and in Npc1(-/-) mice; ii) inhibition of c-Abl or c-Abl deficiency prevents the increase of HDAC2 protein levels and activity in NPC neuronal models; iii) c-Abl inhibition decreases the levels of HDAC2 tyrosine phosphorylation; iv) treatment with methyl-ß-cyclodextrin and vitamin E decreases the activation of the c-Abl/HDAC2 pathway in NPC neurons; v) in vivo treatment with two c-Abl inhibitors prevents the increase of HDAC2 protein levels in the brain of Npc1(-/-) mice; and vi) c-Abl inhibition prevents HDAC2 recruitment to the promoter of neuronal genes, triggering an increase in their expression. CONCLUSION: Our data show the involvement of the c-Abl/HDAC2 signaling pathway in the regulation of neuronal gene expression in NPC neuronal models. Thus, inhibition of c-Abl could be a pharmacological target for preventing the deleterious effects of increased HDAC2 levels in NPC disease.

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The objective of this study was to determine the effect of U18666A, an inhibitor of cholesterol synthesis and its intracellular transport, on oxidative stress parameters in cortical astrocytes cultured from Wistar rats (0-3 days old). The cultures were incubated with U18666A (0.25 µg/mL) for 48 h, conditions that are considered ideal to mimic Niemann-Pick type C disease. A variety of indicators of oxidative stress were measured. U18666A treatment increased cholesterol 2-fold in treated compared to control astrocytes. Oxidative stress was significantly elevated in treated cells as demonstrated by a 1.7-fold increase in thiobarbituric acid reactive substances, a 60% decrease is sulfhydral groups, and a 3.7-fold increase in carbonyl groups, indicative of increased lipid and protein oxidation following U18666A treatment. Consistent with these changes, both catalase and superoxide dismutase activities were significantly reduced nearly 50% in treated compared to control astrocytes. Collectively, these change resulted in a 50% reduction in Na(+), K(+)-ATPase specific activity following U18666A treatment, suggesting a significant alteration in its plasma membrane environment. Overall, these changes indicate that U18666A treatment results in increased cholesterol levels and an increased level of oxidative stress in cortical astrocytes, consistent with what is observed in Niemann-Pick type C disease.

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