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Molecular Genetics and Metabolism 2017The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as... (Review)
Review
The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this disease. We will also discuss the current status of therapy for this disorder.
Topics: Age of Onset; Animals; Cholesterol; Disease Progression; Female; History, 20th Century; History, 21st Century; Humans; Male; Mutation; Niemann-Pick Diseases; Sphingomyelin Phosphodiesterase
PubMed: 28164782
DOI: 10.1016/j.ymgme.2016.12.008 -
Orphanet Journal of Rare Diseases Feb 2017Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically,... (Review)
Review
Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically, ASMD has been classified as Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). NPD A is associated with a uniformly devastating disease course, with rapidly progressing psychomotor degeneration, leading to death typically by the age of 3 years, most often from respiratory failure. In contrast, the clinical phenotype and life expectancy of patients with NPD B may vary widely. Almost all patients have hepatosplenomegaly and an atherogenic lipid profile, and most patients have interstitial lung disease with progressive impairment of pulmonary function and hematologic abnormalities including cytopenias. Other common clinical manifestations include liver dysfunction, heart disease, skeletal abnormalities and growth delays. Some patients with ASMD who survive beyond early childhood have intermediate phenotypes (variant NPD B) characterized by combinations of non-neurologic and mild to severe neurologic symptoms. The physical and psychosocial burden of illness in patients with NPD B is substantial. Common symptoms include shortness of breath, joint or limb pain, abdominal pain, bleeding and bruising. The disease often leads to chronic fatigue, limited physical or social activity and difficulties in performing daily activities or work. Many patients die before or in early adulthood, often from pneumonia/respiratory failure or liver failure. Available treatments are limited to symptom management and supportive care. An enzyme replacement therapy currently in clinical development is expected to be the first treatment addressing the underlying pathology of the disease. Early diagnosis and appropriate management are essential for reducing the risk of complications. While knowledge about ASMD is evolving, more evidence about ASMD and the natural history across the disease spectrum is needed, to improve disease recognition, timely diagnosis and appropriate disease management.
Topics: Cause of Death; Cost of Illness; Humans; Incidence; Niemann-Pick Diseases; Rare Diseases; Sphingomyelin Phosphodiesterase
PubMed: 28228103
DOI: 10.1186/s13023-017-0572-x -
Obesity Reviews : An Official Journal... Aug 2021Sphingolipids, in particular ceramides, play vital role in pathophysiological processes linked to metabolic syndrome, with implications in the development of insulin... (Review)
Review
Sphingolipids, in particular ceramides, play vital role in pathophysiological processes linked to metabolic syndrome, with implications in the development of insulin resistance, pancreatic ß-cell dysfunction, type 2 diabetes, atherosclerosis, inflammation, nonalcoholic steatohepatitis, and cancer. Ceramides are produced by the hydrolysis of sphingomyelin, catalyzed by different sphingomyelinases, including neutral sphingomyelinase 2 (nSMase2), whose dysregulation appears to underlie many of the inflammation-related pathologies. In this review, we discuss the current knowledge on the biochemistry of nSMase2 and ceramide production and its regulation by inflammatory cytokines, with particular reference to cardiometabolic diseases. nSMase2 contribution to pathogenic processes appears to involve cyclical feed-forward interaction with proinflammatory cytokines, such as TNF-α and IL-1ß, which activate nSMase2 and the production of ceramides, that in turn triggers the synthesis and release of inflammatory cytokines. We elaborate these pathogenic interactions at the molecular level and discuss the potential therapeutic benefits of inhibiting nSMase2 against inflammation-driven cardiometabolic diseases.
Topics: Atherosclerosis; Ceramides; Diabetes Mellitus, Type 2; Humans; Sphingolipids; Sphingomyelin Phosphodiesterase
PubMed: 33738905
DOI: 10.1111/obr.13248 -
Biomedicine & Pharmacotherapy =... Jul 2021Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can... (Review)
Review
Sphingomyelin (SM) can be converted into ceramide (Cer) by neutral sphingomyelinase (NSM) and acid sphingomyelinase (ASM). Cer is a second messenger of lipids and can regulate cell growth and apoptosis. Increasing evidence shows that NSM and ASM play key roles in many processes, such as apoptosis, immune function and inflammation. Therefore, NSM and ASM have broad prospects in clinical treatments, especially in cancer, cardiovascular diseases (such as atherosclerosis), nervous system diseases (such as Alzheimer's disease), respiratory diseases (such as chronic obstructive pulmonary disease) and the phenotype of dwarfisms in adolescents, playing a complex regulatory role. This review focuses on the physiological functions of NSM and ASM and summarizes their roles in certain diseases and their potential applications in therapy.
Topics: Animals; Cardiovascular Diseases; Humans; Neoplasms; Nervous System Diseases; Respiratory Tract Diseases; Sphingomyelin Phosphodiesterase
PubMed: 33957567
DOI: 10.1016/j.biopha.2021.111610 -
Molecular Psychiatry Jan 2022Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that... (Review)
Review
Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.
Topics: COVID-19; Ceramides; Humans; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; SARS-CoV-2; Sphingomyelin Phosphodiesterase
PubMed: 34608263
DOI: 10.1038/s41380-021-01309-5 -
FEBS Open Bio Dec 2021Bacterial phospholipases and sphingomyelinases are lipolytic esterases that are structurally and evolutionarily heterogeneous. These enzymes play crucial roles as... (Review)
Review
Bacterial phospholipases and sphingomyelinases are lipolytic esterases that are structurally and evolutionarily heterogeneous. These enzymes play crucial roles as virulence factors in several human and animal infectious diseases. Some bacterial phospholipases C (PLCs) have both phosphatidylcholinesterase and sphingomyelinase C activities. Among them, Listeria monocytogenes PlcB, Clostridium perfringens PLC, and Pseudomonas aeruginosa PlcH are the most deeply understood. In silico predictions of substrates docking with these three bacterial enzymes provide evidence that they interact with different substrates at the same active site. This review discusses structural aspects, substrate specificity, and the mechanism of action of those bacterial enzymes on target cells and animal infection models to shed light on their roles in pathogenesis.
Topics: Animals; Clostridium perfringens; Humans; Listeria monocytogenes; Phospholipases; Pseudomonas aeruginosa; Sphingomyelin Phosphodiesterase; Type C Phospholipases
PubMed: 34709730
DOI: 10.1002/2211-5463.13320 -
Biological Chemistry Jun 2015Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single... (Review)
Review
Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.
Topics: Animals; Ceramides; Humans; Inflammation; Mutation; Sphingomyelin Phosphodiesterase; Sphingomyelins
PubMed: 25803076
DOI: 10.1515/hsz-2015-0109 -
International Journal of Molecular... Nov 2021Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of... (Review)
Review
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of acid sphingomyelinase (ASM) enzyme, leading to the accumulation of varying degrees of sphingomyelin. Lipid storage leads to foam cell infiltration in tissues, and clinical features including hepatosplenomegaly, pulmonary insufficiency and in some cases central nervous system involvement. ASM enzyme replacement therapy is currently in clinical trial being the first treatment addressing the underlying pathology of the disease. Therefore, presently, it is critical to better comprehend ASMD to improve its diagnose and monitoring. Lung disease, including recurrent pulmonary infections, are common in ASMD patients. Along with lung disease, several immune system alterations have been described both in patients and in ASMD animal models, thus highlighting the role of ASM enzyme in the immune system. In this review, we summarized the pivotal roles of ASM in several immune system cells namely on macrophages, Natural Killer (NK) cells, NKT cells, B cells and T cells. In addition, an overview of diagnose, monitoring and treatment of ASMD is provided highlighting the new enzyme replacement therapy available.
Topics: Animals; Enzyme Replacement Therapy; Humans; Lung Diseases; Lysosomal Storage Diseases; Sphingomyelin Phosphodiesterase
PubMed: 34884674
DOI: 10.3390/ijms222312870 -
Neuro-Signals 2019In this review, we summarize implications of the acid sphingomyelinase/ ceramide system in ischemic stroke. Acid sphingomyelinase catalyzes the formation of the... (Review)
Review
In this review, we summarize implications of the acid sphingomyelinase/ ceramide system in ischemic stroke. Acid sphingomyelinase catalyzes the formation of the bioactive sphingolipid ceramide which coalesces into membrane platforms and has a pivotal role in inflammation, cell signaling and death. Cerebral ischemia increases acid sphingomyelinase activity and elevates brain ceramide levels, which has been associated with the exacerbation of ischemic injury and deterioration of stroke outcome. In view of the fact that lowering acid sphingomyelinase activity and ceramide level was shown to protect against ischemic injury and ameliorate neurological deficits, the acid sphingomyelinase/ ceramide system might represent a promising target for stroke therapies.
Topics: Animals; Antidepressive Agents; Brain Ischemia; Ceramides; Drug Delivery Systems; Humans; Signal Transduction; Sphingomyelin Phosphodiesterase; Stroke
PubMed: 31778304
DOI: 10.33594/000000184 -
Chemistry and Physics of Lipids Nov 1999Several physiologic and pathophysiologic processes in which sphingomyelinases (SMases) have been implicated may involve extracellular sphingomyelin (SM) hydrolysis. A... (Review)
Review
Several physiologic and pathophysiologic processes in which sphingomyelinases (SMases) have been implicated may involve extracellular sphingomyelin (SM) hydrolysis. A candidate enzyme for these processes is a recently discovered SMase called secretory SMase, or S-SMase. S-SMase arises from the acid sphingomyelinase (ASM) gene via differential protein trafficking of a common protein precursor; this precursor can be targeted to either lysosomes or the Golgi secretory pathway. S-SMase is activated by physiologic levels of Zn2+, although the S-SMase from endothelial cells, which secrete abundant amounts of the enzyme, is partially Zn2+-independent. S-SMase functions best at acid pH but can hydrolyze certain physiologic substrates, such as atherogenic lipoproteins, at neutral pH. In endothelial cells, the secretion of S-SMase is regulated at the level of protein trafficking by inflammatory cytokines. Current work implicates a role for S-SMase in atherogenesis, and future work will be directed at understanding the potential roles of S-SMase in other processes, such as ceramide-mediated cell-signaling and the host inflammatory response.
Topics: Animals; Humans; Isoenzymes; Sphingomyelin Phosphodiesterase
PubMed: 11001566
DOI: 10.1016/s0009-3084(99)00080-8