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Genes (Basel) 2022 May 29;13(6). Epub 2022 May 29.

Pediatric Department, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan.

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral disease characterized by progressive neurodegeneration with variable involvement of multisystemic abnormalities. Crohn's disease (CD) is an inflammatory bowel disease (IBD) with a multifactorial etiology influenced by variants in . Here, we investigated a patient with plausible multisystemic overlapping manifestations of both NPC and CD. Read More

J Mol Neurosci 2022 Jun 21. Epub 2022 Jun 21.

Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.

Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of the aberrant lysosomal accumulation of SM on cell homeostasis, we loaded skin fibroblasts derived from a NPA patient with exogenous SM to mimic the levels of accumulation characteristic of the pathological neurons. Read More

Clin Neuropharmacol 2022 Jun 11. Epub 2022 Jun 11.

Department of Pediatric Metabolism, Ankara University Faculty of Medicine, Ankara, Turkey.

Background: Niemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal disease in which psychiatric symptoms, such as psychosis, can also be observed. Miglustat is indicated in cases with progressive neurological manifestations, and although there have been studies reporting that miglustat completely cures psychosis, it has been recently observed that miglustat may also trigger psychosis. We report on a rare case of probable miglustat-induced psychosis in a patient with NP-C. Read More

FASEB J 2022 07;36(7):e22411

Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, China.

NgBR is the Nogo-B receptor, encoded by NUS1 gene. As NgBR contains a C-terminal domain that is similar to cis-isoprenyltransferase (cis-IPTase), NgBR was speculated to stabilize nascent Niemann-Pick type C 2 (NPC2) to facilitate cholesterol transport out of lysosomes. Mutations in the NUS1 were known as risk factors for Parkinson's disease (PD). Read More

Wellcome Open Res 2022 11;7:11. Epub 2022 Jan 11.

Translational Gastroenterology Unit, University of Oxford, Oxford, UK.

 Blockade of tumour necrosis factor (anti-TNF) is effective in patients with Crohn's Disease but has been associated with infection risk and neurological complications such as demyelination. Niemann-Pick disease Type C1 (NPC1) is a lysosomal storage disorder presenting in childhood with neurological deterioration, liver damage and respiratory infections. Some NPC1 patients develop severe Crohn's disease. Read More

Hepatobiliary Surg Nutr 2022 Jun;11(3):498-501

Department of Transplantation, Xinhua Hospital Affifiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Mol Biol Cell 2022 Jun 2:mbcE21110595T. Epub 2022 Jun 2.

Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, New Mexico, 87131, USA.

Lysosomes receive extracellular and intracellular cholesterol and redistribute it throughout the cell. Cholesterol egress from lysosomes is critical for cholesterol homeostasis, and its failure underlies the pathogenesis of genetic disorders such as Niemann-Pick C disease. Here, we report that the BORC-ARL8-HOPS ensemble is required for egress of free cholesterol from lysosomes and for storage of esterified cholesterol in lipid droplets. Read More

Drugs 2022 Jun;82(8):941-947

Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.

Olipudase alfa (XENPOZYME) is a recombinant human acid sphingomyelinase that has been developed by Sanofi, for the treatment of acid sphingomyelinase deficiency (ASMD). Olipudase alfa catalyses the hydrolysis of sphingomyelin accumulated in hepatocytes and in mononuclear-macrophage cells, such as the lungs, liver, spleen, kidneys and bone marrow. Olipudase alfa was approved in Japan under the SAKIGAKE designation on 28 March 2022 for use in adult and paediatric patients with non-CNS manifestations of ASMD and has received a positive Committee for Medicinal Products for Human Use opinion in the EU. Read More

Biomolecules 2022 Apr 21;12(5). Epub 2022 Apr 21.

Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bld 35A, Room 1E623 35 Convent Drive, MSC 3708, Rockville, MD 20892, USA.

Lysosomes are ubiquitous membrane-bound organelles found in all eukaryotic cells. Outside of their well-known degradative function, lysosomes are integral in maintaining cellular homeostasis. Growing evidence has shown that lysosomal dysfunction plays an important role not only in the rare group of lysosomal storage diseases but also in a host of others, including common neurodegenerative disorders, such as Alzheimer disease and Parkinson disease. Read More

J Pediatr Endocrinol Metab 2022 May 27. Epub 2022 May 27.

Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

Background: Niemann-Pick disease type A (NPDA, MIM: 257200) is an autosomal recessive sphingolipidosis caused by lysosomal acid sphingomyelinase (ASM) deficiency. A cluster of genes located at chromosome 11p15 have been reported to be imprinted genes, such as TSSC5, TSSC3, and ZNF215 that flanking SMPD1 gene. It was reported by a few recent studies that SMPD1 gene was paternally imprinted and maternally preferentially expressed. Read More

Eur J Hum Genet 2022 May 25. Epub 2022 May 25.

CENTOGENE GmbH, 18055, Rostock, Germany.

To present our experience using a multiomic approach, which integrates genetic and biochemical testing as a first-line diagnostic tool for patients with inherited metabolic disorders (IMDs). A cohort of 3720 patients from 62 countries was tested using a panel including 206 genes with single nucleotide and copy number variant (SNV/CNV) detection, followed by semi-automatic variant filtering and reflex biochemical testing (25 assays). In 1389 patients (37%), a genetic diagnosis was achieved. Read More

Eur J Pharmacol 2022 Jul 19;926:175033. Epub 2022 May 19.

College of Pharmaceutical Science, Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Huzhou, 313200, Zhejiang, PR China. Electronic address:

Efficient antiviral drug discovery has been a pressing issue of global public health concern since the outbreak of coronavirus disease 2019. In recent years, numerous in vitro and in vivo studies have shown that 25-hydroxycholesterol (25HC), a reactive oxysterol catalyzed by cholesterol-25-hydroxylase, exerts broad-spectrum antiviral activity with high efficiency and low toxicity. 25HC restricts viral internalization and disturbs the maturity of viral proteins using multiple mechanisms. Read More

J Pharm Pharmacol 2022 May 21. Epub 2022 May 21.

The Engelke Group, Keymar, MD, USA.

Objectives: Cyclodextrins are increasingly used therapeutically. For example, 2-hydroxypropyl-ß-cyclodextrin (kleptose) is used for the treatment of Niemann-Pick disease. Kleptose crosses the blood-brain barrier poorly, in part because of a central nervous system (CNS)-to-blood (efflux) transporter, and so is administered by the intrathecal (IT) route in the treatment of Niemann-Pick disease. Read More

Mol Biotechnol 2022 May 19. Epub 2022 May 19.

School of Life Sciences and Technology, Xinxiang Medical University, Xinxiang, China.

NPC1 gene encodes a transmembrane glycoprotein on the late endosome/lysosomal membrane. Its mutation leads to a rare and aggravated autosomal recessive neurovisceral condition, termed Niemann-Pick disease type C1 (NPC1), which is characterized by progressive neurodegeneration, visceral symptoms, and premature death. To investigate the influence of NPC1 gene deletion on cell morphology, adhesion, proliferation, and apoptosis, CRISPR-Cas9 technology was used to knockout the NPC1 gene in HEK 293 T cells. Read More

Neurobiol Aging 2022 Aug 20;116:49-54. Epub 2022 Apr 20.

Department of Neurology, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China; Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha, China; Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha, China; Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China. Electronic address:

Despite the similar clinical and pathological features between Niemann-Pick type C (NPC) disease and Alzheimer's disease (AD), few studies have investigated the role of NPC genes in AD. To elucidate the role of NPC genes in AD, we sequenced NPC1 and NPC2 in 1192 AD patients and 2412 controls. Variants were divided into common variants and rare variants according to minor allele frequency (MAF). Read More

Int J Mol Sci 2022 May 3;23(9). Epub 2022 May 3.

Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.

Complex asparagine-linked glycosylation plays key roles in cellular functions, including cellular signaling, protein stability, and immune response. Previously, we characterized the appearance of a complex asparagine-linked glycosylated form of lysosome-associated membrane protein 1 (LAMP1) in the cerebellum of mice. This LAMP1 form was found on activated microglia, and its appearance correlated both spatially and temporally with cerebellar Purkinje neuron loss. Read More

J Neurochem 2022 May 12. Epub 2022 May 12.

Neurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.

Treating central nervous system (CNS) diseases is complicated by the incapability of numerous therapeutics to cross the blood-brain barrier (BBB), mainly composed of brain endothelial cells (BECs). Genetically modifying BECs into protein factories that supply the CNS with recombinant proteins is a promising approach to overcome this hindrance, especially in genetic diseases, like Niemann Pick disease type C2 (NPC2), where both CNS and peripheral cells are affected. Here, we investigated the potential of the BEC-specific adeno-associated viral vector (AAV-BR1) encoding NPC2 for expression and secretion from primary BECs cultured in an in vitro BBB model with mixed glial cells, and in healthy BALB/c mice. Read More

ACS Biomater Sci Eng 2022 Jun 10;8(6):2463-2476. Epub 2022 May 10.

Department of Organic Biomaterials, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda, Tokyo 101-0062, Japan.

β-Cyclodextrins (β-CDs) and β-CD-containing polymers have attracted considerable attention as potential candidates for the treatment of cholesterol-related metabolic and intractable diseases. We have advocated the use of β-CD-threaded acid-degradable polyrotaxanes (PRXs) as intracellular delivery carriers for β-CDs. As unmodified PRXs are insoluble in aqueous solutions, chemical modification of PRXs is an essential process to improve their solubility and impart novel functionalities. Read More

BMC Gastroenterol 2022 May 9;22(1):227. Epub 2022 May 9.

Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.

Background: Patients with acid sphingomyelinase deficiency (ASMD) may be referred to a hepatologist for liver manifestations. This study summarized the liver manifestations of patients with ASMD in the early disease course.

Methods: This study enrolled ASMD patients diagnosed by genetic tests between July 2016 and December 2020 in a national pediatric liver center. Read More

Case Rep Transplant 2022 27;2022:5428381. Epub 2022 Apr 27.

Hospital Universitario Marqués de Valdecilla, Respiratory Department, Avda. Valdecilla s/n., 39008 Santander, Spain.

Niemann-Pick disease is a rare autosomal recessive disease characterized by an abnormal intracellular lipid accumulation. Type B is later in onset and a less severe form of the disease, so affected people may survive in adulthood. Storage of sphingomyelin in pulmonary macrophages can lead to interstitial lung disease. Read More

J Nutr 2022 May 3. Epub 2022 May 3.

Department of Food Science and Technology.

Background: Dietary interventions for high cholesterol, a primary risk factor for cardiovascular disease, are generally considered before prescribing drugs.

Objective: This study investigated the effects of whole great northern beans (wGNB) and their hull (hGNB) incorporated into a high saturated fat (HSF) diet on cholesterol markers and hepatic/small intestinal genes involved in cholesterol regulation.

Methods: Each of the four groups of 11 male golden Syrian hamsters at 9 weeks old were fed a normal fat [NF, 5% (w/w) of soybean oil], HSF [5% (w/w) of soybean oil + 10% (w/w) of coconut oil], HSF+5% (w/w) wGNB or HSF+0. Read More

J Appl Genet 2022 May 5. Epub 2022 May 5.

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA.

Niemann-Pick C disease frequently presents as severe cholestatic disease in infants. However, it progressively becomes less of a problem as children age. We have found that, in an appropriate mouse model, liver cholesterol levels, which are initially very high, decrease while mitochondrial function, initially quite compromised, increases with age. Read More

Cell Rep 2022 05;39(5):110776

UK Dementia Research Institute at the University of Cambridge, Department of Clinical Neurosciences, Hills Road, Cambridge, CB2 0AH, UK. Electronic address:

Assemblies of tau can transit between neurons, seeding aggregation in a prion-like manner. To accomplish this, tau must cross cell-limiting membranes, a process that is poorly understood. Here, we establish assays for the study of tau entry into the cytosol as a phenomenon distinct from uptake, in real time, and at physiological concentrations. Read More

Proc Natl Acad Sci U S A 2022 05 4;119(18):e2201646119. Epub 2022 May 4.

Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755.

Multiple membrane organelles require cholesterol for proper function within cells. The Niemann-Pick type C (NPC) proteins export cholesterol from endosomes to other membrane compartments, including the endoplasmic reticulum (ER), plasma membrane (PM), trans-Golgi network (TGN), and mitochondria, to meet their cholesterol requirements. Defects in NPC cause malfunctions in multiple membrane organelles and lead to an incurable neurological disorder. Read More

ACS Appl Bio Mater 2022 05 4;5(5):2377-2388. Epub 2022 May 4.

Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan.

Niemann-Pick disease type C (NPC) is characterized by the accumulation of glycolipids such as free cholesterol, sphingomyelin, and gangliosides in late endosomes/lysosomes (endolysosomes) due to abnormalities in the membrane proteins NPC1 or NPC2. The main symptoms of NPC caused by free cholesterol accumulation in various tissues vary depending on the time of onset, but hepatosplenomegaly and neurological symptoms accompanied by decreased motor, cognitive, and mental functions are observed in all age groups. However, the efficacy of NPC treatment remains limited. Read More

Adv Exp Med Biol 2022 ;1372:189-213

Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Sphingolipidoses is a cluster of genetic rare disorders regarding glycosphingolipid metabolism, classified as lysosomal storage disorders (LSD). Here, we focus on eight inheritable diseases, including GM1 gangliosidosis, GM2 gangliosidosis, Fabry disease, Gaucher's disease, metachromatic leukodystrophy, Krabbe disease, Niemann-Pick disease A and B, and Farber disease. Mostly, pathogenic mutations in the key enzyme are loss-function, resulting in accumulation of substrates and deficiency of products. Read More

Exp Cell Res 2022 Jul 27;416(2):113175. Epub 2022 Apr 27.

Programa de Pós-Graduação Em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Serviço de Genética Médica, HCPA, Porto Alegre, Brazil. Electronic address:

Niemann Pick type C is an inborn error of metabolism (IEM), classified as a lysosomal storage disease (LSD) caused by a dysfunction in NPC transport protein, that leads to intracellular accumulation of non-esterified cholesterol and other lipids. Clinical manifestations are ample, with visceral and neurological symptoms. Miglustat, a molecule that reversibly inhibits glucosylceramide synthase is used as treatment for this disorder. Read More

Front Genet 2022 11;13:869859. Epub 2022 Apr 11.

Department of Forensic Medicine, Medical College of Soochow University, Suzhou, China.

Sudden cardiac death (SCD) was defined as an unexpected death from cardiac causes during a very short duration. It has been reported that Niemann-Pick type C1 () gene mutations might be related to cardiovascular diseases. The purpose of the study is to investigate whether common genetic variants of is involved in SCD susceptibility. Read More

Genet Med 2022 Apr 26. Epub 2022 Apr 26.

Clinical Development, Sanofi, Bridgewater, NJ.

Purpose: This trial aimed to assess the efficacy and safety of olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults.

Methods: A phase 2/3, 52 week, international, double-blind, placebo-controlled trial (ASCEND; NCT02004691/EudraCT 2015-000371-26) enrolled 36 adults with ASMD randomized 1:1 to receive olipudase alfa or placebo intravenously every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary efficacy endpoints were percent change from baseline to week 52 in percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume (combined with splenomegaly-related score in the United States). Read More

Zhejiang Da Xue Xue Bao Yi Xue Ban 2021 Mar 25;50(7):1-5. Epub 2021 Mar 25.

To establish cut-off values of lysosomal storage disease (LSD)-related enzymes by tandem mass spectrometry. A total of 26 689 newborns and 7 clinically confirmed LSD children underwent screening for LSDs (glycogen storage disease typeⅡ, Fabry disease, mucopolysaccharidosis type Ⅰ, Krabbe disease, Niemann-Pick disease A/B and Gaucher disease). The activities of LSD-related enzymes were detected by tandem mass spectrometry. Read More