Child ; Humans ; Gaucher Disease/therapy*

Humans ; Gaucher Disease/pathology*

Child ; Consensus ; Gaucher Disease/therapy* ; Humans

Ceramide metabolism is known to be an essential etiology for various diseases, such as atopic dermatitis and Gaucher disease. Glucosylceramide synthase (GCS) is a key enzyme for the synthesis of glucosylceramide (GlcCer), which is a main ceramide metabolism pathway in mammalian cells. In this article, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine GCS activity using synthetic non-natural sphingolipid C8-ceramide as a substrate. The reaction products, C8-GlcCer for GCS, could be separated on a C18 column by reverse-phase high-performance liquid chromatography (HPLC). Quantification was conducted using the multiple reaction monitoring (MRM) mode to monitor the precursor-to-product ion transitions of m/z 588.6 → 264.4 for C8-GlcCer at positive ionization mode. The calibration curve was established over the range of 0.625–160 ng/mL, and the correlation coefficient was larger than 0.999. This method was successfully applied to detect GCS in the human hepatocellular carcinoma cell line (HepG2 cells) and mouse peripheral blood mononuclear cells. We also evaluated the inhibition degree of a known GCS inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) on GCS enzymatic activity and proved that this method could be successfully applied to GCS inhibitor screening of preventive and therapeutic drugs for ceramide metabolism diseases, such as atopic dermatitis and Gaucher disease.
Animals ; Calibration ; Carcinoma, Hepatocellular ; Cell Line ; Chromatography, Liquid ; Dermatitis, Atopic ; Gaucher Disease ; Humans ; Mass Screening ; Mass Spectrometry ; Metabolism ; Methods ; Mice

BACKGROUND AND OBJECTIVES: The antioxidant ebselen will be able to limit or prevent the ototoxicity arising from 2-hydroxypropyl-β-cyclodextrin (HPβCD). Niemann-Pick Type C (NPC) disease is a disorder of lysosomal storage manifested in sphingolipidosis. Recently, it was noted that experimental use of HPβCD could partially resolve the symptoms in both animals and human patients. Despite its desirable effect, HPβCD can induce hearing loss, which is the only major side effect noted to date. Understanding of the pathophysiology of hearing impairment after administration of HPβCD and further development of preventive methods are essential to reduce the ototoxic side effect. The mechanisms of HPβCD-induced ototoxicity remain unknown, but the resulting pathology bears some resemblance to other ototoxic agents, which involves oxidative stress pathways. To indirectly determine the involvement of oxidative stress in HPβCD-induced ototoxicity, we tested the efficacy of an antioxidant reagent, ebselen, on the extent of inner ear side effects caused by HPβCD. MATERIALS AND METHODS: Ebselen was applied prior to administration of HPβCD in mice. Auditory brainstem response thresholds and otopathology were assessed one week later. Bilateral effects of the drug treatments also were examined. RESULTS: HPβCD-alone resulted in bilateral, severe, and selective loss of outer hair cells from base to apex with an abrupt transition between lesions and intact areas. Ebselen co-treatment did not ameliorate HPβCD-induced hearing loss or alter the resulting histopathology. CONCLUSIONS: The results indirectly suggest that cochlear damage by HPβCD is unrelated to reactive oxygen species formation. However, further research into the mechanism(s) of HPβCD otopathology is necessary.
Animals ; Ear, Inner ; Evoked Potentials, Auditory, Brain Stem ; Hair Cells, Auditory, Outer ; Hearing Loss ; Hearing ; Humans ; Mice ; Oxidative Stress ; Pathology ; Reactive Oxygen Species ; Sphingolipidoses ; Tight Junctions

Gaucher Disease ; Humans

Gaucher disease is the most common of the lysosomal storage diseases caused by a defect in the lysosomal enzyme βglucocererbrosidase resulting in multi-organ involvement. The presence of cholelithiasis has been rarely observed among patients with non-neuronopathic type of Gaucher disease and the exact pathophysiology is still unknown. We report a Filipino child with chronic neuronopathic Gaucher Disease noted to have cholelithiasis on routine whole abdominal ultrasonography as part of the regular monitoring of the disease.
Gaucher Disease ; Cholelithiasis ; Gaucher Disease

Farber disease (FD) is a rare lysosomal storage disorder that shows autosomal recessive inheritance. We report the case of a 58-month-old girl with FD, who was misdiagnosed with epithelioid hemangioendothelioma. The patient had undergone five surgeries for sacrococcygeal masses and three surgeries for scalp masses owing to misdiagnosis. Here, we describe this rare case of FD.
Diagnostic Errors ; Farber Lipogranulomatosis* ; Female ; Hemangioendothelioma* ; Hemangioendothelioma, Epithelioid ; Humans ; Scalp ; Wills

PURPOSE: Gaucher disease (GD) is the most common lysosomal storage disease caused by beta-glucocerebrosidase (GBA) deficiency. Oral substrate reduction therapy with miglustat (Zavesca®) was approved for the treatment of adults with GD type 1, for whom enzyme replacement therapy (ERT) is unsuitable or not a therapeutic option. In this study, we report the effect of miglustat (Zavesca®) in three Korean GD patients. MATERIALS AND METHODS: Clinical findings comprising age at diagnosis, presenting signs, laboratory findings at diagnosis, GBA activity and mutations, and clinical courses of the three patients were reviewed. RESULTS: Miglustat was administered to three patients who reported allergic reactions during intravenous imiglucerase infusions. One patient withdrew after 15 months of miglustat administration owing to continuous elevation of disease biomarker levels (chitotriosidase, acid phosphatase, and angiotensin-converting enzyme). Poor adherence to medication was suspected but was denied by the patient. In the other two patients, platelet count and levels of hemoglobin and other biomarkers remained stable during miglustat administration. However, they suffered from severe diarrhea and weight loss, which led to miglustat discontinuation after 1 and 12 months of administration. CONCLUSION: Our study shows that although miglustat is suggested to GD patients as an alternative treatment to ERT, significant adverse reactions may lead to discontinuation of miglustat. In addition, it is difficult to monitor the drug adherence.
Acid Phosphatase ; Adult ; Biomarkers ; Diagnosis ; Diarrhea ; Enzyme Replacement Therapy ; Gaucher Disease* ; Glucosylceramidase ; Humans ; Hypersensitivity ; Lysosomal Storage Diseases ; Platelet Count ; Weight Loss

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficiency of acid β-glucosidase. The diminished enzyme activity leads to the accumulation of substrates and results in multi-systemic manifestations including hepatosplenomegaly, anemia, thrombocytopenia, and bone diseases. Enzyme replacement therapy (ERT) by infusion of recombinant protein has been the standard treatment for over 20 years. Despite the successful long-term treatment with ERT, several unmet needs remain in the treatment of GD1 such as severe pulmonary and skeletal manifestations. Substrate reduction therapy (SRT) reduces the accumulation of substrates by inhibiting their biosynthesis. Eliglustat, a new oral SRT, was approved in United States and Europe as a first-line therapy for treating adult patients with GD1 who have compatible CYP2D6 metabolism phenotypes. Although eliglustat is not yet available in Korea, introduction and summary of this new treatment modality are provided in this paper by review of literatures. Despite the fact that there are only limited studies to draw resolute conclusions, the current data demonstrated that eliglustat is not inferior to ERT in terms of its clinical efficacy. The approval of eligustat enables eligible adult GD1 patients to have the option of oral therapy although it still needs further studies on long-term outcomes. The individual patient should be assessed carefully for the choice of treatment modality when eliglustat becomes available in Korea. Furthermore, the clinical guidelines for Korean patients with GD1 regarding the use of eliglustat needs to be developed in near future.
Adult ; Anemia ; Bone Diseases ; Cytochrome P-450 CYP2D6 ; Enzyme Replacement Therapy ; Europe ; Gaucher Disease* ; Humans ; Korea ; Metabolism ; Phenotype ; Thrombocytopenia ; Treatment Outcome ; United States