Niemann-Pick Research Articles

Eponyms that honor Jewish dermatologists: A celebration and a remembrance, Part three: Jewish physicians who practiced during the Holocaust and in its aftermath

Part III of this contribution continues to celebrate the many contributions that Jewish physicians have made to advance the specialty of dermatology, as reflected by eponyms that honor their names. Part I covered the years before 1933, a highly productive period of creativity by Jewish dermatologists, especially in Germany and Austria. The lives of 17 Jewish physicians and their eponyms were described in Part I. Part II focused on the years of 1933 to 1945, when the Nazis rose to power in Europe, and how their anti-Semitic genocidal policies affected leading Jewish dermatologists caught within the Third Reich. Fourteen Jewish physicians and their eponyms are discussed in Part II. Part III continues the remembrance of the Holocaust era by looking at the careers and eponyms of an additional 13 Jewish physicians who contributed to dermatology during the period of 1933 to 1945. Two of these 13 physicians, pathologist Ludwig Pick (1868-1944) and neurologist Arthur Simons (1877-1942), perished in the Holocaust. They are remembered by the following eponyms of interest to dermatologists: Lubarsch-Pick syndrome, Niemann-Pick disease, and Barraquer-Simons syndrome. Four of the 13 Jewish physicians escaped the Nazis: Felix Pinkus (1868-1947), Herman Pinkus (1905-1985), Arnault Tzanck (1886-1954), and Erich Urbach (1893-1946). Eponyms that honor their names include nitidus Pinkus, fibroepithelioma of Pinkus, Tzanck test, Urbach-Wiethe disease, Urbach-Koningstein technique, Oppenheim-Urbach disease, and extracellular cholesterinosis of Karl-Urbach. The other seven Jewish physicians lived outside the reach of the Nazis, in either Canada, the United States, or Israel. Their eponyms are discussed in this contribution. Part III also discusses eponyms that honor seven contemporary Jewish dermatologists who practiced dermatology after 1945 and who continue the nearly 200 years of Jewish contribution to the development of the specialty. They are A. Bernard Ackerman (1936-2008), Irwin M. Braverman, Sarah Brenner, Israel Chanarin, Maurice L. Dorfman, Dan Lipsker, and Ronni Wolf. Their eponyms are Ackerman syndrome, Braverman sign, Brenner sign, Chanarin-Dorfman syndrome, Lipsker criteria of the Schnitzler syndrome, and Wolf's isotopic response.

Trial of N-Acetyl-l-Leucine in Niemann–Pick Disease Type C

BackgroundNiemann–Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann–Pick disease type C.MethodsIn this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann–Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo.ResultsA total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was −1.97±2.43 points after 12 weeks of receiving NALL and −0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, −1.28 points; 95% confidence interval, −1.91 to −0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred.ConclusionsAmong patients with Niemann–Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann–Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.)

Transport®NPC: open phase 3 global trial of intravenous hydroxy-propyl-beta-cyclodextrin in patients with Niemann-Pick disease type C1 (NPC1)

Transport®NPC: open phase 3 global trial of intravenous hydroxy-propyl-beta-cyclodextrin in patients with Niemann-Pick disease type C1 (NPC1)

Results of a phase III, randomized, placebo-controlled crossover trial with N-acetyl-L-leucine for Niemann-Pick disease type C

Results of a phase III, randomized, placebo-controlled crossover trial with N-acetyl-L-leucine for Niemann-Pick disease type C

What lies beneath: Next generation sequencing unraveling Niemann-Pick disease type C in adults

What lies beneath: Next generation sequencing unraveling Niemann-Pick disease type C in adults

PPCS, the biomarker with the best clinical utility for Niemann-Pick disease type B?

PPCS, the biomarker with the best clinical utility for Niemann-Pick disease type B?

Real-world data collection in Niemann-Pick disease type C: Data from expanded access program with arimoclomol

Real-world data collection in Niemann-Pick disease type C: Data from expanded access program with arimoclomol

Severe form of Niemann-Pick disease type B in Iranian population: A review of the spectrum of disease in acid sphingomyelinase deficiency

Severe form of Niemann-Pick disease type B in Iranian population: A review of the spectrum of disease in acid sphingomyelinase deficiency

Niemann-Pick Type C2 Proteins in Aedes aegypti: Molecular Modelling and Prediction of Their Structure-Function Relationships.

Aedes aegypti is a major vector that transmits arboviruses through the saliva injected into the host. Salivary proteins help in uninterrupted blood intake and enhance the transmission of pathogens. We studied Niemann-Pick Type C2 (NPC2) proteins, a superfamily of saliva proteins that play an important role in arbovirus infections. In vertebrates, a single conserved gene encodes for the NPC2 protein that functions in cholesterol trafficking. Arthropods, in contrast, have several genes that encode divergent NPC2 proteins. We compared the sequences of 20 A. aegypti NPC2 proteins to the cholesterol-binding residues of human and bovine, and fatty-acid-binding residues of ant NPC2 protein. We identified four mosquito NPC2 proteins as potential sterol-binding proteins. Two of these proteins (AAEL006854 and/or AAEL020314) may play a key role in ecdysteroid biosynthesis and moulting. We also identified one mosquito NPC2 protein as a potential fatty-acid-binding protein. Through molecular modelling, we predicted the structures of the potential sterol- and fatty-acid-binding proteins and compared them to the reference proteins.

Novel compound heterozygous mutations of the NPC1 gene associated with Niemann-pick disease type C: a case report and review of the literature

BackgroundNiemann-Pick Disease type C is a fatal autosomal recessive lipid storage disorder caused by NPC1 or NPC2 gene mutations and characterized by progressive, disabling neurological deterioration and hepatosplenomegaly. Herein, we identified a novel compound heterozygous mutations of the NPC1 gene in a Chinese pedigree.Case presentationThis paper describes an 11-year-old boy with aggravated walking instability and slurring of speech who presented as Niemann-Pick Disease type C. He had the maternally inherited c.3452 C > T (p. Ala1151Val) mutation and the paternally inherited c.3557G > A (p. Arg1186His) mutation using next-generation sequencing. The c.3452 C > T (p. Ala1151Val) mutation has not previously been reported.ConclusionsThis study predicted that the c.3452 C > T (p. Ala1151Val) mutation is pathogenic. This data enriches the NPC1 gene variation spectrum and provides a basis for familial genetic counseling and prenatal diagnosis.

Niemann-pick Disease: A Diagnostic Approach, Evolution Clinic and Review

Introduction: Niemann-Pick disease is a rare autosomal recessive enzymopathy, which causes a deficiency in the activity of the acid sphingomyelinase enzyme found in liposomal cells, resulting in a defect in the degradation of sphingomyelin into ceramide - the product that makes up the lipid bilayer of the cells. In this way, it generates accumulation and deposition of sphingomyelin mainly in the liver, spleen, brain, bone marrow and lungs, which can cause hepatosplenomegaly, pulmonary/neurological diseases and cytopenia. Case presentation: Male patient, 16 years old, seeks care at a health center, accompanied by his mother, due to the drop in school performance in the last year. According to school assessment, the patient presents gradual cognitive impairment, in addition to dysarthria. Discussion: The disease in this report is rare and can occur in both sexes, with incidence and clinical presentation varying according to each subtype of the pathology. Due to its multisystem involvement, its clinical presentation can be nonspecific and make its diagnosis difficult. Conclusion: It should be noted that this work aims to spread knowledge about this rare pathology, showing the importance of recognizing it in childhood so that the diagnosis can be made as early as possible, bringing better survival for those affected.

Innate immune sensing of lysosomal dysfunction drives multiple lysosomal storage disorders.

Lysosomal storage disorders (LSDs), which are characterized by genetic and metabolic lysosomal dysfunctions, constitute over 60 degenerative diseases with considerable health and economic burdens. However, the mechanisms driving the progressive death of functional cells due to lysosomal defects remain incompletely understood, and broad-spectrum therapeutics against LSDs are lacking. Here, we found that various gene abnormalities that cause LSDs, including Hexb, Gla, Npc1, Ctsd and Gba, all shared mutual properties to robustly autoactivate neuron-intrinsic cGAS-STING signalling, driving neuronal death and disease progression. This signalling was triggered by excessive cytoplasmic congregation of the dsDNA and DNA sensor cGAS in neurons. Genetic ablation of cGAS or STING, digestion of neuronal cytosolic dsDNA by DNase, and repair of neuronal lysosomal dysfunction alleviated symptoms of Sandhoff disease, Fabry disease and Niemann-Pick disease, with substantially reduced neuronal loss. We therefore identify a ubiquitous mechanism mediating the pathogenesis of a variety of LSDs, unveil an inherent connection between lysosomal defects and innate immunity, and suggest a uniform strategy for curing LSDs.

Filipin complex-reactive brain lesions: a cautionary tale.

Filipin complex is an autooxidation-prone fluorescent histochemical stain used in the diagnosis of Niemann-Pick Disease Type C (NP-C), a neurodegenerative lysosomal storage disorder. It is also widely used by researchers examining the distribution and accumulation of unesterified cholesterol in cell and animal models of neurodegenerative diseases including NP-C and Sanfilippo syndrome (mucopolysaccharidosis IIIA; MPS IIIA). Recently, it has been suggested to be useful in studying Alzheimer's and Huntington's disease. Given filipin's susceptibility to photobleaching, we sought to establish a quantitative biochemical method for free cholesterol measurement. Brain tissue from mice with MPS IIIA was stained with filipin. Total and free cholesterol in brain homogenates was measured using a commercially available kit and a quantitative LC-MS/MS assay was developed. Gangliosides GM1, GM2 and GM3 were also quantified using LC-MS/MS. As anticipated, the MPS IIIA mouse brain displayed large numbers of filipin-positive intra-cytoplasmic inclusions, presumptively endo-lysosomes. Challenging the prevailing dogma, however, we found no difference in the amount of free cholesterol in MPS IIIA mouse brain homogenates cf. control tissue, using either the fluorometric kit or LC-MS/MS assay. Filipin has previously been reported to bind to GM1 ganglioside, however, this lipid does not accumulate in MPS IIIA cells/tissues. Using a fluorometric assay, we demonstrate for the first time that filipin cross-reacts with both GM2 and GM3 gangliosides, explaining the filipin-reactive inclusions observed in MPS IIIA brain cells. Filipin is not specific for free cholesterol, and positive staining in any setting should be interpreted with caution.

Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann-Pick Disease Type C.

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the NPC1 or NPC2 genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic Npc1-/- mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic Npc1-/- mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease.

Niemann-Pick Disease: Seven Questions about it

Acid sphingomyelinase deficiency is a rare hereditary disease caused by enzyme deficiency due to mutations in the SMPD1 gene. Decreased enzyme activity leads to accumulation of sphingomyelin in lysosomes. This disease is characterized by wide diversity of clinical manifestations: from infantile neurovisceral form (Niemann-Pick disease type A) with severe rapidly progressive neurodegeneration to chronic visceral form (Niemann-Pick disease type B) with almost no central nervous system involvement. There is also intermediate phenotype: chronic neurovisceral form (Niemann-Pick disease type A/B) that includes manifestations two other forms, both visceral and neurological. The disease course is most commonly progressive and multi-system due to sphingomyelin accumulation in cells of the monocyte-macrophage system, as well as in other cells such as hepatocytes.

Uncovering the Challenges of Rare Diseases: Insights From a Retrospective Cross-Sectional Study in Albania (2005-2022).

Diagnosing and treating rare diseases pose significant challenges within global healthcare systems due to their low prevalence and varying criteria for defining them. In Albania, the absence of a dedicated registry for rare diseases exacerbates these challenges. Recognising this gap, a retrospective cross-sectional study was conducted from January 2005 to December 2022 to analyse the incidence and prevalence of rare haematologic diseases in the country, diagnosed in the Hematology Service at the University Hospital Centre "Mother Teresa," which is the sole diagnostic center for blood diseases in Albania. This study aims to provide insights into the frequency of these diseases within the adult Albanian population and seeks to underscore the critical need for improved data collection and research in this field of healthcare. The primary objective of this study is to assess the incidence and prevalence of rare hematologic diseases diagnosed at the Hematology Service of the University Hospital Centre "Mother Teresa" in Albania from January 2005 to December 2022. This retrospective cross-sectional study employed a descriptive study design, focusing on the analysis of rare hematologicdisease incidence and prevalence. The study was conducted exclusively at the University Hospital Centre "Mother Teresa" in Albania, the primary diagnostic center for blood-related disorders in the country. Data collection spanned a period of 18 years, from January 2005 to December 2022, encompassing patient records. Inclusion criteria encompassed adult patients aged 15 years and older who had received diagnoses of rare hematologic diseases during the specified timeframe, without specific operational definitions applied. Non-probability convenience sampling was used, including all eligible cases identified within the study's timeframe, obviating the need for formal sample size calculation. Data were extracted from the records of the Hematology Service at the University Hospital Centre "Mother Teresa," primarily using medical records containing essential patientinformation. Data analysis utilised software such as EXCEL 16.0 and SPSS (v. 25.0), applying descriptive statistical methods, including frequencies and percentages, to assess the incidence and prevalence of rare hematologic diseases. The study's findings were summarised and presented in a tabular format to provide a clear and concise overview of the results. Our study identified 64 cases of rare hematologic diseases among adults. Notably, primary myelofibrosis (MF) exhibited the highest incidence andprevalence rate, followed byWaldenström macroglobulinemia (WM) and Gaucher disease (GD) emerging as the most prevalent diagnoses after MF, with 16 and 10 cases, respectively. Several ultra-rare diseases, such as Fanconi anemia and chronic eosinophilic leukemia, were also detected, indicating a significant disease burden, while diseases such as Factor X deficiency and Niemann-Pick disease type C were exceptionally rare. Diagnosing and treating rare diseases remain formidable challenges in healthcare systems worldwide. This study underscores the need for enhanced awareness, research, and thepressing need for dedicated registries, collaborative research initiatives, and heightened attention to these conditions to enhance our understanding and management of rare hematological diseases, particularly within the Albanian healthcare context.

Cyclodextrins as therapeutic drugs for treating lipid metabolism disorders.

This study sought to systematically compare the efficacy and mechanism of cyclodextrins as drug interventions in lipid metabolism diseases, potentially providing ideas for subsequent research directions and clinical applications. We used the bibliometric method for feature mining, applied VOSviewer software for clustering analysis, and applied content analysis for objective descriptions and accurate analysis. (1) We collected more than 50 studies, which is the basic database of this study. (2) The academic bubble map showed that this research area was popular in the United States. (3) Cluster analysis showed that the intensively studied diseases in this field were Niemann-Pick type C (NPC), atherosclerosis (AS), and obesity. The hot-spot cyclodextrin types were HP-β-CD. (4) Literature measurement revealed the involvement of 15 types of lipid metabolism diseases. Among them, NPC, diabetes, and obesity were studied in clinical trials. Dyslipidemia and AS have been reported relatively more frequently in animal experiments. The studies of cellular experiments provide insight into the molecular mechanisms that intervene in lipid metabolism diseases from multiple perspectives. The exploration of the molecular mechanisms by which cyclodextrins exert their pharmacological effects mainly revolves around lipid metabolism. It is worthwhile to investigate the role and mechanism of cyclodextrins in other lipid metabolism diseases. The potential efficacy evaluation of cyclodextrins as pharmaceutical drugs for oral or injectable formulations is less studied and may become a new focus in the future.

Lysosomal storage disorders identified in adult population from India: Experience of a tertiary genetic centre and review of literature.

Lysosomal storage disorders (LSDs) in adults have milder phenotype and variable age at presentation. Several studies have described the phenotype, genotype and treatment outcomes for adult-onset LSDs like Gaucher, Fabry, Pompe disease and others. We describe the first systematic study on the occurrence of LSDs in an adult population from India. It describes, the key clinical signs seen in these patients and those from literature review that can aid in early detection. Of 2102 biochemically diagnosed LSDs cases, 32 adult patients were identified with LSDs. Based on the clinical suspicion, screening test and enzyme study was carried out. Twenty-two patients were subjected to a genetic study to identify the causative variant in a respective gene. Of the 32 adult patients, we observed a maximum percentage of 37.5% (n = 12) cases with Gaucher disease, followed by 13% (n = 4) with Fabry disease. We found 10% of cases with MPS IVA and MPS I, and 9% cases with Pompe. Single case of adult mucolipidosis III and two cases each of Type 1 Sialidosis, Niemann-Pick disease B and metachromatic leukodystrophy were identified. We observed two common variants p.Leu483Pro and p.Ala487Thr in the GBA1 gene in 23% of Indian patients with adult Gaucher disease. No common variants were observed in other aforementioned LSDs. Study identified 50% of Fabry patients and 4% of Gaucher patients diagnosed at our centre to be adults. The prevalence of adult Pompe patients was low (3.4%) as compared to 80% reported in the Caucasian population. Adult LSDs such as, MPS III, GM1/GM2 gangliosidosis and Krabbe disease were not identified in our cohort.

Genetic and clinical characterization of Niemann-Pick disease type C with homozygous NPC1 gene mutation: insights from whole exome sequencing and advanced neuroimaging of two familial cases

Background: Niemann-Pick disease Type C (NPC) is a rare genetic lipid storage disorder characterized by heterogeneous clinical presentations primarily affecting the neurological and visceral systems. This study aims to elucidate the clinical manifestations, radiological findings, and genetic characteristics of NPC, emphasizing the implications of familial aggregation and consanguinity. Case Presentation: We present two cases from a single family, detailing the clinical progression, radiological findings, and genetic mutations. Case 1 involves a 39-year-old male exhibiting symptoms such as dysarthria, cerebellar ataxia, and progressive neurological decline over eight years. Case 2, a relative aged five, displays similar early-onset neurological symptoms. Both cases demonstrate significant cerebellar atrophy on MRI and share a familial NPC1 gene mutation, suggesting a hereditary pattern influenced by consanguineous relationships. Whole Exome Sequencing identified a pathogenic homozygous mutation in the NPC1 gene, confirming the diagnosis of NPC. This finding underscores the genetic basis of the disease and highlights the role of familial genetics in its pathogenesis. Conclusion: These cases underscore the critical role of genetic testing, particularly whole exome sequencing, in diagnosing NPC, which can often present with diverse clinical symptoms. The familial clustering observed also draws attention to the genetic counseling needs in populations with high rates of consanguinity, emphasizing the importance of community genetic studies to understand and manage such rare disorders.

Unraveling the Connection: Cholesterol, Calcium Signaling, and Neurodegeneration.

Cholesterol and calcium play crucial roles as integral structural components and functional signaling entities within the central nervous system. Disruption in cholesterol homeostasis has been linked to Alzheimer's, Parkinson's, and Huntington's Disease while alterations in calcium signaling is hypothesized to be a key substrate for neurodegeneration across many disorders. Despite the importance of regulated cholesterol and calcium homeostasis for brain health there has been an absence of research investigating the interdependence of these signaling molecules and how they can tune each other's abundance at membranes to influence membrane identity. Here, we discuss the role of cholesterol in shaping calcium dynamics in a neurodegenerative disorder that arises due to mutations in the lysosomal cholesterol transporter, Niemann Pick Type C1 (NPC1). We discuss the molecular mechanisms through which altered lysosomal cholesterol transport influences calcium signaling pathways through remodeling of ion channel distribution at organelle-organelle membrane contacts leading to neurodegeneration. This scientific inquiry not only sheds light on NPC disease but also holds implications for comprehending other cholesterol-associated neurodegenerative disorders.