Peripheral neuropathy as a very rare symptom in a patient with Niemann-Pick type C with negative enzymatic evaluation: a case report.

BACKGROUND: Niemann-Pick is a rare metabolic disease distinguished by lysosomal storage defects. This disease is characterized by sphingomyelinase acid deficiency, causing its accumulation in various organs such as the kidneys, spleen, liver, brain, and nerves. Niemann-Pick disease is categorized into four groups: A, B, C, and D. Peripheral neuropathy is an extremely rare complication in patients with Niemann-Pick type C, which certainly leads to neurologic deterioration. CASE PRESENTATION: We report a case of Niemann-Pick type C disease in a 3-year-old Iranian Azeri female patient who was hospitalized twice. The first time was at 1 month of age with symptoms of splenomegaly, jaundice, and elevated liver enzymes, and the second time was at around age 2 for loss of mental and physical abilities. The patient presented with failure to thrive. According to paraclinical examinations, mildly delayed myelination along with a nonspecific periventricular hypersignal intensity was seen. Interestingly, the patient's Niemann-Pick type C enzymatic function was evaluated twice and was negative on both occasions, while she was positive for NPC1 and NPC2 gene examinations. CONCLUSIONS: In this study, despite the enzymatic study being negative, Niemann-Pick type C disease was finally confirmed, revealing the importance of mutations in Niemann-Pick type C pathogenesis. Besides, peripheral neuropathy was diagnosed in this patient as a very rare symptom of Niemann-Pick type C.

Acid sphingomyelinase deficiency exacerbates LPS-induced experimental periodontitis.

BACKGROUND: Mutation of the gene for acid sphingomyelinase (ASMase) causes Niemann-Pick disease. However, the effect of ASMase deficiency on periodontal health is unknown. Periodontal disease is a disease resulting from infection and inflammation of periodontal tissue and alveolar bone that support the teeth. The goal of this study was to determine the role of ASMase deficiency in periodontal inflammation and alveolar bone loss. METHODS: We induced periodontitis in wild-type and ASMase-deficient (ASMase-/- ) mice with periodontal lipopolysaccharide (LPS) injection and compared the alveolar bone loss and periodontal inflammation between these mice. RESULTS: Results showed that ASMase deficiency did not significantly change metabolic parameters, but exacerbated LPS-induced alveolar bone loss, osteoclastogenesis, and periodontal tissue inflammation. To understand the mechanisms by which ASMase deficiency aggravates LPS-induced periodontitis, we analyzed sphingolipids in periodontal tissues. Results showed that ASMase deficiency led to increases in not only sphingomyelin, but also ceramide (CER), a bioactive sphingolipid known to promote inflammation. Results further showed that ASMase deficiency increased CER de novo synthesis. CONCLUSION: ASMase deficiency exacerbated LPS-induced alveolar bone loss and periodontal inflammation. ASMase deficiency leads to an unexpected CER increase by stimulating de novo synthesis CER, which is likely to be involved in the ASMase deficiency-exacerbated periodontitis.

Cathepsin S contributes to microglia-mediated olfactory dysfunction through the regulation of Cx3cl1-Cx3cr1 axis in a Niemann-Pick disease type C1 model.

Microglia can aggravate olfactory dysfunction by mediating neuronal death in the olfactory bulb (OB) of a murine model of Niemann-Pick disease type C1 (NPC1), a fatal neurodegenerative disorder accompanied by lipid trafficking defects. In this study, we focused on the crosstalk between neurons and microglia to elucidate the mechanisms underlying extensive microgliosis in the NPC1-affected brain. Microglia in the OB of NPC1 mice strongly expressed CX3C chemokine receptor 1 (Cx3cr1), a specific receptor for the neural chemokine C-X3-C motif ligand 1 (Cx3cl1). In addition, a high level of Cx3cl1 was detected in NPC1 mouse-derived CSF due to enhanced catalytic activity of Cathepsin S (Ctss), which is responsible for Cx3cl1 secretion. Notably, nasal delivery of Cx3cl1 neutralizing antibody or Ctss inhibitor could inhibit the Cx3cl1-Cx3cr1 interaction and support neuronal survival through the suppression of microglial activation, leading to an improvement in the olfactory function in NPC1 mice. Relevant in vitro experiments revealed that intracellular cholesterol accumulation could act as a strong inducer of abnormal Ctss activation and, in turn, stimulated the Cx3cl1-Cx3cr1 axis in microglia via p38 mitogen-activated protein kinase signaling. Our data address the significance of Cx3cl1-Cx3cr1 interaction in the development of microglial neurotoxicity and suggest that Ctss is a key upstream regulator. Therefore, this study contributes to a better understanding of the crosstalk between neurons and microglia in the development of the neurodegeneration and provides a new perspective for the management of olfactory deficits and other microglia-dependent neuropathies. GLIA 2016;64:2291-2305.

Types A and B Niemann-Pick disease.

Two distinct metabolic abnormalities are encompassed under the eponym Niemann-Pick disease (NPD). The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM). Patients with ASM deficiency are classified as having types A and B Niemann-Pick disease (NPD). Type A NPD patients exhibit hepatosplenomegaly in infancy and profound central nervous system involvement. They rarely survive beyond two years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no central nervous system signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Recently, patients with phenotypes intermediate between types A and B NPD also have been identified. These individuals represent the expected continuum caused by inheriting different mutations in the ASM gene (SMPD1). Patients in the second NPD category are designated as having types C and D NPD. These patients may have mild hepatosplenomegaly, but the central nervous system is profoundly affected. Impaired intracellular trafficking of cholesterol causes types C and D NPD, and two distinct gene defects have been found. In this chapter only types A and B NPD will be discussed.

Improvement of biochemical and behavioral defects in the Niemann-Pick type A mouse by intraventricular infusion of MARCKS.

Niemann-Pick disease type A (NPDA) is a fatal disease due to mutations in the acid sphingomyelinase (ASM) gene, which triggers the abnormal accumulation of sphingomyelin (SM) in lysosomes and the plasma membrane of mutant cells. Although the disease affects multiple organs, the impact on the brain is the most invalidating feature. The mechanisms responsible for the cognitive deficit characteristic of this condition are only partially understood. Using mice lacking the ASM gene (ASMko), a model system in NPDA research, we report here that high sphingomyelin levels in mutant neurons lead to low synaptic levels of phosphoinositide PI(4,5)P2 and reduced activity of its hydrolyzing phosphatase PLCγ, which are key players in synaptic plasticity events. In addition, mutant neurons have reduced levels of membrane-bound MARCKS, a protein required for PI(4,5)P2 membrane clustering and hydrolysis. Intracerebroventricular infusion of a peptide that mimics the effector domain of MARCKS increases the content of PI(4,5)P2 in the synaptic membrane and ameliorates behavioral abnormalities in ASMko mice.

Acid sphingomyelinase deficiency contributes to resistance of scleroderma fibroblasts to Fas-mediated apoptosis.

BACKGROUND: Scleroderma (SSc) is characterized by excess production and deposition of extracellular matrix (ECM) proteins. Activated fibroblasts play a key role in fibrosis in SSc and are resistant to Fas-mediated apoptosis. Acid sphingomyelinase (ASMase), a major sphingolipid enzyme, plays an important role in the Fas-mediated apoptosis. OBJECTIVE: We investigated whether dysregulation of ASMase contributes to Fas-mediated apoptosis resistance in SSc fibroblasts. METHODS: Fibroblasts were isolated from SSc patients and healthy controls. Western blot was performed to analyze protein levels and quantitative real time RT-PCR was used to determine mRNA expression. Cells were transiently transfected with siRNA oligos against ASMase or transduced with adenoviruses overexpressing ASMase. Apoptosis was induced using anti-Fas antibody (1 µg/mL) and analyzed using caspase-3 antibody or Cell Death Detection ELISA. RESULTS: SSc fibroblasts showed increased resistance to Fas-mediated apoptosis. ASMase expression was decreased in SSc fibroblasts and Transforming Growth Factor beta (TGFß), the major fibrogenic cytokine involved in the pathogenesis of SSc, downregulated ASMase in normal fibroblasts. Forced expression of ASMase in SSc fibroblasts restored sensitivity of these cells to Fas-mediated apoptosis while blockade of ASMase was sufficient to induce partial resistance to Fas-induced apoptosis in normal fibroblasts. In addition, ASMase blockade decreased activity of protein phosphatase 2A (PP2A) through phosphorylation on Tyr(307) and resulted in activation of extracellular regulated kinase 1/2 (Erk1/2) and protein kinase B (Akt/PKB). CONCLUSION: In conclusion, this study suggests that ASMase deficiency promotes apoptosis resistance and contributes to activation of profibrotic signaling in SSc fibroblasts.