• MeSH
• diferenciální diagnóza MeSH
• lidé středního věku MeSH
• lidé MeSH
• Niemannova-Pickova nemoc diagnóza   patologie   MeSH
• syndrom histiocytů barvy mořské modři diagnóza   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• kazuistiky MeSH

Acid sphingomyelinase deficiency (ASMd, Niemann-Pick disease A/B) and Niemann-Pick type C disease (NPC) share core clinical symptoms. Initial diagnostic discrimination of these two rare lysosomal storage diseases is thus difficult. As sphingomyelin accumulates in ASMd as well as NPC, lysosphingomyelin (sphingosylphosphorylcholine) and its m/z 509 analog were suggested as biomarkers for both diseases. Herein we present results of simultaneous LC-ESI-MS/MS measurements of lysosphingomyelin and lysosphingomyelin 509 in plasma and dried blood spots (DBS) collected from ASMd and NPC patients and suggest that the plasma but not DBS levels of the two analytes allow differential biochemical screening of ASMd and NPC.

• Klíčová slova
• Lysosphingomyelin, Mass spectrometry, Niemann-Pick A/B, Niemann-Pick C, Screening, Sphingosylphosphorylcholine,
• MeSH
• biologické markery krev   MeSH
• chromatografie kapalinová metody   MeSH
• fosforylcholin analogy a deriváty   krev   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací metody   MeSH
• lidé MeSH
• Niemannova-Pickova nemoc typu A krev   diagnóza   MeSH
• Niemannova-Pickova nemoc typu B krev   diagnóza   MeSH
• Niemannova-Pickova nemoc typu C krev   diagnóza   MeSH
• sfingosin analogy a deriváty   krev   MeSH
• studie případů a kontrol MeSH
• tandemová hmotnostní spektrometrie metody   MeSH
• test suché kapky krve metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• biologické markery MeSH
• fosforylcholin MeSH
• sfingosin MeSH
• sphingosine phosphorylcholine MeSH Prohlížeč

Acid sphingomyelinase (ASM) deficiency (ASMD) is a spectrum that includes Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). ASMD is characterized by intracellular accumulation of unesterified cholesterol and gangliosides within the endosomal-lysosomal system. It is caused by different mutations in SMPD1 gene that result in reduction or complete absence of acid sphingomyelinase activity in the cells. Herein, four unrelated consanguineous families with two NPD A and three NPD B patients were assessed for their genotypes via sequencing of the SMPD1 gene and their acid sphingomyelinase enzymatic activity. Among the eight identified mutations, three were novel and reported for the first time in Jordanian families (c.120_131delGCTGGCGCTGGC or c.132_143delGCTGGCGCTGGC, c.1758T > G, and c.1344T > A). All the patients displayed ASM activity lower than 1.3 µmol/l/h (P < 0.001). Genotyping and enzymatic assessment might play a significant role in disease identification in people at risk to facilitate genetic counseling in the future.

• Klíčová slova
• ASMD, Acid sphingomyelinase, Acid sphingomyelinase deficiency, Gangliosides, Genotype, Jordan, Sphingomyelin phosphodiesterase,
• MeSH
• dítě MeSH
• fatální výsledek MeSH
• kojenec MeSH
• lidé MeSH
• mutace genetika   MeSH
• Niemannova-Pickova nemoc typu A enzymologie   genetika   MeSH
• Niemannova-Pickova nemoc typu B enzymologie   genetika   MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sfingomyelinfosfodiesterasa chemie   genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Geografické názvy
• Jordánsko MeSH
• Názvy látek
• sfingomyelinfosfodiesterasa MeSH
• SMPD1 protein, human MeSH Prohlížeč

Deuterium-labeled cholesterol-dextran particles (d4-CholDex), prepared by co-precipitation, were internalized by cultured human skin fibroblasts and HEK293 cells. Subcellular particles from d4-CholDex-treated HEK293 cells were fractionated on iodixanol gradients. More than 60% of d4-cholesterol (d4-UC) in the gradient co-fractionated with lysosomal markers and NPC1. This and formation of d4-cholesteryl esters (d4-CE) in the cells suggests that d4-CholDex is lysosomally processed. In accordance with these findings, we observed an increase in lysosomal cholesterol content by fluorescence microscopy in CholDex-loaded cells. Fibroblast cultures including 13 NPC1-deficient, four heterozygous and six control lines were treated with d4-CholDex at final d4-UC concentration of 0.05 mg/ml (127.98 μmol/L) for 3 h and chased for 48 h in medium without d4-CholDex. Concentrations of d4-UC and d4-CE in harvested cells were measured by tandem mass spectrometry (MS/MS). d4-UC/d4-CE ratios were elevated in NP-C lines compared to controls (n = 6, mean = 4.36, range = 1.89-8.91), with the highest ratios in severe NP-C1 phenotypes and the lowest in adolescent/adult type patients. There were overlaps between NP-C1 forms: early infantile (n = 1, mean = 48.6), late infantile (n = 4, mean = 36.3, range = 20.6-54.0), juvenile (n = 5, mean = 24.7, range = 13.4-38.3), adolescent/adult (n = 3, mean = 14.5, range = 11.7-19.8). The ratios in NP-C1 heterozygotes were mildly elevated (n = 4, mean = 16.4, range = 14.9-17.4) and comparable to patients with adolescent/adult NP-C1. The test can be useful in evaluation of suspected NP-C patients with inconclusive results of biomarker or molecular tests. Its advantages include standardized preparation of particles with longer shelf life at 4 °C, quantitative results, and no requirement for radioactive chemicals.

• Klíčová slova
• Niemann-Pick type C disease, cholesterol, cholesterol trafficking, cholesterol-dextran particles, cholesteryl ester, loading test,
• MeSH
• buněčné kultury MeSH
• cholesterol metabolismus   MeSH
• dextrany metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mladiství MeSH
• Niemannova-Pickova nemoc typu C * diagnóza   genetika   metabolismus   MeSH
• protein NPC1 genetika   MeSH
• tandemová hmotnostní spektrometrie MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholesterol MeSH
• dextrany MeSH
• protein NPC1 MeSH

We present the third case of Niemann-Pick disease type C without neurological symptoms. The patient was a 53-year-old woman without significant prior health problems who died of acute pulmonary embolism. Autopsy findings of hepatosplenomegaly, lymphadenopathy and ceroid-rich foam cells raised the suspicion of the visceral form of acid sphingomyelinase deficiency (Niemann-Pick disease type B; NPB) or a much rarer disorder, variant adult visceral form of Niemann-Pick disease type C (NPC). To verify the histopathological findings, SMPD1, NPC1 and NPC2 genes were analysed. Two novel sequence variants, c.1997G>A (S666N) and c.2882A>G (N961S) were detected in the NPC1 gene. No pathogenic sequence variants were found either in the SMPD1 gene mutated in NPB or in NPC2 gene. The pathogenicity of both NPC1 variants was supported by their location in regions important for the protein function. Both variations were not found in more than 300 control alleles. Identified sequence variations confirm the diagnosis of the extremely rare adult visceral form of Niemann-Pick disease type C, which is otherwise dominated by neurovisceral symptoms. Although only three patients have been reported, this (most probably underdiagnosed) form of NPC should be considered in differential diagnosis of isolated hepatosplenomegaly with foam cells in adulthood.

• MeSH
• glykoproteiny genetika   MeSH
• intracelulární signální peptidy a proteiny MeSH
• játra patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny genetika   MeSH
• molekulární sekvence - údaje MeSH
• mozek patologie   MeSH
• mutace MeSH
• Niemannova-Pickova nemoc typu C diagnóza   genetika   patologie   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• protein NPC1 MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• sfingomyelinfosfodiesterasa genetika   MeSH
• slezina patologie   MeSH
• transportní proteiny genetika   MeSH
• vezikulární transportní proteiny MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• glykoproteiny MeSH
• intracelulární signální peptidy a proteiny MeSH
• membránové glykoproteiny MeSH
• NPC1 protein, human MeSH Prohlížeč
• NPC2 protein, human MeSH Prohlížeč
• protein NPC1 MeSH
• sfingomyelinfosfodiesterasa MeSH
• transportní proteiny MeSH
• vezikulární transportní proteiny MeSH

• Klíčová slova
• AMAUROTIC FAMILIAL IDIOCY *, GAUCHER'S DISEASE *, HYPERLIPEMIA *, LIPID METABOLISM *, LIPOCHONDRODYSTROPHY *, LIPOIDOSIS *, NIEMANN-PICK DISEASE *, SKIN *,
• MeSH
• Gaucherova nemoc * MeSH
• hyperlipidemie * MeSH
• kůže * MeSH
• lidé MeSH
• lipidózy * MeSH
• metabolismus lipidů * MeSH
• mukopolysacharidóza I * MeSH
• Niemannova-Pickova nemoc * MeSH
• Tay-Sachsova nemoc * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• Gaucherova nemoc diagnóza   MeSH
• genetický kód MeSH
• glykosaminoglykany metabolismus   MeSH
• heterozygot MeSH
• lidé MeSH
• mentální retardace diagnóza   MeSH
• mukopolysacharidóza IV diagnóza   MeSH
• mukopolysacharidózy genetika   MeSH
• nemoci centrálního nervového systému diagnóza   etiologie   MeSH
• Niemannova-Pickova nemoc diagnóza   MeSH
• prenatální diagnóza MeSH
• vrozené poruchy metabolismu aminokyselin diagnóza   MeSH
• vrozené poruchy metabolismu sacharidů diagnóza   MeSH
• vrozené poruchy metabolismu diagnóza   etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• glykosaminoglykany MeSH

BACKGROUND: Acid sphingomyelinase deficiency (ASMD), due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, is divided into infantile neurovisceral ASMD (Niemann-Pick type A), chronic neurovisceral ASMD (intermediate form, Niemann-Pick type A/B) and chronic visceral ASMD (Niemann-Pick type B). We conducted a long-term observational, single-center study including 16 patients with chronic visceral ASMD. RESULTS: 12 patients were diagnosed in childhood and 4 others in adulthood, the oldest at the age of 50. The mean time of follow-up was approximately 10 years (range: 6 months - 36 years). Splenomegaly was noted in all patients at diagnosis. Hepatomegaly was observed in 88% of patients. Moderately elevated (several-fold above the upper limit of normal values) serum transaminases were noted in 38% of patients. Cherry-red spots were found in five Gypsy children from one family and also in one adult Polish patient, a heterozygote for p.delR610 mutation. Dyslipidemia was noted in 50% of patients. Interstitial lung disease was diagnosed in 44% of patients. Plasmatic lysosphingomyelin (SPC) was elevated in all the patients except one with p.V36A homozygosity and a very mild phenotype also presenting with elevated plasmatic SPC-509 but normal chitotriosidase activity. The most common variant of SMPD1 gene was p.G166R. We found a previously unreported variant in exon 2 (c.491G > T, p.G164 V) in one patient. CONCLUSIONS: Chronic visceral ASMD could constitute a slowly progressing disease with a relatively good outcome. The combined measurement of lysosphingomyelin (SPC) and lysospingomyelin-509 (SPC-509) is an essential method for the assessment of ASMD course.

• Klíčová slova
• Acid sphingomyelinase, Chitotriosidase, Chronic visceral acid sphingomyelinase deficiency, Hepatosplenomegaly, Lysosphingomyelin, Lysosphingomyelin-509,
• MeSH
• dítě MeSH
• dospělí MeSH
• exony genetika   MeSH
• hexosaminidasy genetika   metabolismus   MeSH
• homozygot MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace genetika   MeSH
• následné studie MeSH
• Niemannova-Pickova nemoc typu A genetika   metabolismus   MeSH
• předškolní dítě MeSH
• sfingomyelinfosfodiesterasa genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Polsko MeSH
• Názvy látek
• chitotriosidase MeSH Prohlížeč
• hexosaminidasy MeSH
• sfingomyelinfosfodiesterasa MeSH