BACKGROUND: Niemann-Pick disease type C is a rare lysosomal storage disorder. We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C. METHODS: In this double-blind, placebo-controlled, crossover trial, we randomly assigned patients 4 years of age or older with genetically confirmed Niemann-Pick disease type C in a 1:1 ratio to receive NALL for 12 weeks, followed by placebo for 12 weeks, or to receive placebo for 12 weeks, followed by NALL for 12 weeks. NALL or matching placebo was administered orally two to three times per day, with patients 4 to 12 years of age receiving weight-based doses (2 to 4 g per day) and those 13 years of age or older receiving a dose of 4 g per day. The primary end point was the total score on the Scale for the Assessment and Rating of Ataxia (SARA; range, 0 to 40, with lower scores indicating better neurologic status). Secondary end points included scores on the Clinical Global Impression of Improvement, the Spinocerebellar Ataxia Functional Index, and the Modified Disability Rating Scale. Crossover data from the two 12-week periods in each group were included in the comparisons of NALL with placebo. RESULTS: A total of 60 patients 5 to 67 years of age were enrolled. The mean baseline SARA total scores used in the primary analysis were 15.88 before receipt of the first dose of NALL (60 patients) and 15.68 before receipt of the first dose of placebo (59 patients; 1 patient never received placebo). The mean (±SD) change from baseline in the SARA total score was -1.97±2.43 points after 12 weeks of receiving NALL and -0.60±2.39 points after 12 weeks of receiving placebo (least-squares mean difference, -1.28 points; 95% confidence interval, -1.91 to -0.65; P<0.001). The results for the secondary end points were generally supportive of the findings in the primary analysis, but these were not adjusted for multiple comparisons. The incidence of adverse events was similar with NALL and placebo, and no treatment-related serious adverse events occurred. CONCLUSIONS: Among patients with Niemann-Pick disease type C, treatment with NALL for 12 weeks led to better neurologic status than placebo. A longer period is needed to determine the long-term effects of this agent in patients with Niemann-Pick disease type C. (Funded by IntraBio; ClinicalTrials.gov number, NCT05163288; EudraCT number, 2021-005356-10.).

• MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• klinické křížové studie MeSH
• látky ovlivňující centrální nervový systém * aplikace a dávkování   terapeutické užití   MeSH
• leucin analogy a deriváty   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Niemannova-Pickova nemoc typu C * komplikace   diagnóza   farmakoterapie   genetika   MeSH
• předškolní dítě MeSH
• sběr dat MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

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.

• 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

• Klíčová slova
• Zavesca (miglustatum),
• MeSH
• biologické markery krev   metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• neurologické manifestace MeSH
• Niemannova-Pickova nemoc typu C * enzymologie   epidemiologie   genetika   patofyziologie   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• časná diagnóza MeSH
• dítě MeSH
• koordinovaný terapeutický postup organizace a řízení   MeSH
• lidé MeSH
• mladiství MeSH
• Niemannova-Pickova nemoc typu C * diagnóza   genetika   patofyziologie   terapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH

• MeSH
• 1-deoxynojirimycin analogy a deriváty   aplikace a dávkování   terapeutické užití   MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• lyzozomální střádavé nemoci v nervovém systému diagnóza   epidemiologie   genetika   metabolismus   MeSH
• mladiství MeSH
• neurologické manifestace MeSH
• Niemannova-Pickova nemoc typu C * epidemiologie   etiologie   genetika   klasifikace   terapie   MeSH
• prognóza MeSH
• vzácné nemoci MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH

Niemannova-Pickova choroba typu C je autosomálně recesivně dědičné střídavé onemocnění vyskytující se panetnicky s incidencí cca 1 : 150 000. Genetická mutace genu NPC1 nebo NPC2 má za následek poruchu transportu a esterifikace cholesterolu uvnitř buňky. V lyzosomech se hromadí neesterifikovaný cholesterol, sfingomyelin, fosfolipidy a glykosfingolipidy Klinická manifestace Niemannovy-Pickovy choroby typu C je závislá na věku a projevy onemocnění zahrnují kromě hepatosplenomegalie mentální retardaci, poruchy chůze, kataplexii a ataxii doprovázené parézou vertikálního pohledu. Onemocnění nebývá pro variabilitu klinických projevů rozpoznáno, je nesprávně diagnostikováno nebo je zjištěno opožděně a postiženým bývá podávána nevhodná léčba. Plnému rozvoji onemocnění mohou předcházet psychotické příznaky, halucinace nebo agresivní chování. Vzhledem k tomu, že existuje léčba, je nezbytné zvýšit povědomí o této chorobě a její diagnostice tak, aby mohla být včas zahájena její adekvátní terapie.

Niemann-Pick disease type C is a rare and fatal inherited autosomal recessive disease caused by mutations in either the NPC1 or NPC2 genes and leads to the inhibition of unesterified cholesterol glycosphingolipids transport and intracellular accumulation in the brain, liver and spleen. Disease affects both infants and adults with neurological symptoms varying with age of onset. Symptoms include mental retardation, gait problems, cataplexy and ataxia with the most common characteristic being vertical supranuclear gaze palsy. People suffering from Niemann-Pick disease presenting with neuropsychiatric symptoms in combination with delayed onset are often misdiagnosed as other major psychiatric disorders and may thus be prescribed inappropriate treatments. Non-motor signs often precede the first notable clinical motor symptoms in adult Niemann-Pick disease including neuropsychiatric illness in the form of schizophrenia-like psychotic disorders, hallucinations or/and aggressive behaviours. Improved awareness of Niemann-Pick disease and its symptoms among clinicians is essential for better disease detection, since patients diagnosed with chronic psychiatric illness and concomitant neurological impairments managed with antipsychotic drugs may have this disease.

• Klíčová slova
• gen NPC2, gen NPC1, neuropsychiatrická onemocnění,
• MeSH
• 1-deoxynojirimycin analogy a deriváty   terapeutické užití   MeSH
• genetická predispozice k nemoci genetika   MeSH
• glykosfingolipidy MeSH
• lidé MeSH
• lyzozomální nemoci z ukládání diagnóza   terapie   MeSH
• membrány MeSH
• neurologické manifestace MeSH
• Niemannova-Pickova nemoc typu C diagnóza   genetika   metabolismus   MeSH
• pohyby očí genetika   MeSH
• psychotické poruchy epidemiologie   etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Niemannova-Pickova choroba typ C (NPC) je zriedkavé autozomálne recesívne neuroviscerálne ochorenie zo skupiny lyzozómových porúch, zapríčinené defektom v lipidovom metabolizme. Najčastejšou formou je neskorá detská a juvenilná forma NPC. Diagnóza je založená na stanovení akumulácie voľného cholesterolu v lyzozómoch a na redukcii cholesterolovej esterifikácie vo fibroblastoch (Filipínový test). Ochorenie je podmienené mutáciou génu NPC1 (95 %) a NPC2 (4 %). V liečbe sa uplatňuje miglustat na princípe redukcie patologického substrátu s cieľom zastaviť progresiu ochorenia.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurovisceral disease from the group of lysosomal disorders caused by a defect in lipid metabolism. The most common forms are late-infantile and juvenile NPC. The diagnosis is based on the assessment of build-up of free cholesterol in lysosomes and the reduction in cholesterol esterification in fibroblasts (Filipin test). The disease is caused by mutations in the NPC1 (95 %) and NPC2 (4 %) genes. The treatment employs miglustat aimed at reducing the pathological substrate in order to stop the progression of the disease.

• MeSH
• 1-deoxynojirimycin aplikace a dávkování   MeSH
• dospělí MeSH
• lidé MeSH
• Niemannova-Pickova nemoc typu C dietoterapie   farmakoterapie   genetika   MeSH
• patologické stavy, příznaky a symptomy MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• kazuistiky 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
• 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
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• sfingomyelinfosfodiesterasa genetika   MeSH
• slezina patologie   MeSH
• transportní proteiny * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• kazuistiky MeSH