- MeSH
- Niemann-Pick Diseases MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Child MeSH
- Humans MeSH
- Niemann-Pick Disease, Type C MeSH
- Niemann-Pick Diseases etiology classification pathology MeSH
- Child, Preschool MeSH
- Prenatal Diagnosis MeSH
- Vitamin E therapeutic use MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
Součásti Niemannovy-Pickovy nemoci typu C je postižení centrálního nervového systému, projevující se při MR zobrazení a v 1H MR spektru mozku známkami atrofie a demyelinizace se zvýšením signálu lipidů. Autoři shrnují tyto nálezy u vlastního pozorování a diskutují některé rozdíly proti údajům známým z písemnictví.
Part of type C of Niemann-Pick disease is affection of the central nervous system, manifested during MR images and in the 1H MR spectrum of the brain by signs of atrophy and demyelinization with an increased lipid signal. The authors summarize these findings in their own observation and discuss some difierences as compared with those known from the literature.
Niemann-Pick typ C predstavuje veľmi vzácne a závažné lyzozómové ochorenie. Diagnostika tohto ochorenia je komplementárna a žiadny z testov sám o sebe nemusí stačiť pre jednoznačné stanovenie diagnózy. Tento príspevok opisuje, ako sa od pozorovania prvých príznakov krok za krokom prišlo k stanoveniu konečnej diagnózy, a ktoré vyšetrenia boli pre diagnostiku potrebné. Pozornosť bude venovaná aj dôrazu na potrebu genetického vyšetrenia v prípade potvrdenia tejto diagnózy u rodičov ako prevencia prepuknutia ochorenia u ďalších súrodencov.
The Niemann-Pick type C is a very rare and serious lysosomal storage disease. The diagnosis of this disease is complex, and none of the tests alone is sufficient to confirm the diagnosis. This thesis describes the diagnosis from initial observation of first symptoms to confirmation of the final diagnosis. We also list all the test required to establish the diagnosis. We also focus on importance of genetic testing of parents as a preventative approach to disease onset of other children.
- MeSH
- Child MeSH
- Lysosomal Storage Diseases, Nervous System MeSH
- Niemann-Pick Disease, Type C diagnostic imaging diagnosis genetics physiopathology therapy MeSH
- Splenomegaly MeSH
- Check Tag
- Child MeSH
- Publication type
- Case Reports 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.
Cílem sdělení je shrnutí současného přístupu k diagnostice Niemann-Pickovy choroby typu C (NP-C) s důrazem na nové laboratorní techniky. NP-C je závažné autozomálně recesivní neuroviscerální onemocnění a aktuální dostupnost terapie ovlivňující průběh nemoci zvyšuje důležitost její včasné diagnostiky. Dědičně podmíněný deficit transportního proteinu pro cholesterol (NPC1 nebo NPC2) u NP-C vede k poruše transportu lipidů uvnitř buňky. Ověření klinického podezření na NP-C se proto opírá o biochemické a/nebo molekulárně genetické metody. Nové metody využívajících analýzu biomarkerů v krevním séru nebo plazmě a pokročilé sekvenační techniky mají nyní v diagnostice NP-C důležitou roli. U části pacientů je pro ověření diagnózy nutné použít více vzájemně se doplňujících vyšetření, vč. v článku diskutovaných pokročilých buněčných a biochemických technik. Ty proto musí být k disposici ve specializované laboratoři.
This review provides a summary of current approaches to Niemann-Pick disease type C (NP-C) dianostics with an emphasis on novel laboratory techniques. NP-C is a severe autosomal recessive neurovisceral disorder and the recent availability of disease-modifying therapies increases the importance of its timely diagnosis. The hereditary deficiency of cholesterol transporter proteins (NPC1 or NPC2) in NP-C leads to abnormal intracellular lipid trafficking. Clinical suspicion for NP-C has to be confirmed by biochemical and/or molecular genetic methods. Novel biomarkers in serum or plasma and advanced sequencing techniques now have a prominent role in NP-C diagnostics. In a subset of patients, it is necessary to use several complementary techniques for confirmation of NP-C diagnosis, including advanced biochemical and cellular assays discussed in the paper. These methods therefore have to be available in a specialized laboratory.
- Keywords
- filipinový test, lyzosfingolipidy, intracelulární transport cholesterolu,
- MeSH
- Biomarkers MeSH
- Humans MeSH
- Niemann-Pick Disease, Type C * diagnosis MeSH
- Oxysterols MeSH
- Check Tag
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Niemann-Pickova choroba typ C je autozomálně recesivně dědičné lysozomální onemocnění, klinicky charakterizované věkově specifickou symptomatologií, s možností manifestace od novorozeneckého věku do pozdní dospělosti. S výjimkou neonatální formy s cholestázou, respiračním selháním a hepatosplenomegalií jde v dalších věkových kategoriích o nemoc vysloveně neurodegenerativní, často doprovázenou splenomegalií. Příčinou je funkční porucha membránového systému pozdního endozomu/lysozomu s akumulací neesterifikovaného cholesterolu a glykosfingolipidů v důsledku mutací v genech NPC1 (95 % případů) nebo NPC2 (5 % případů), kódujících lysozomální membránový protein NPC1 a solubilní protein NPC2. Základem diagnostiky je správné zhodnocení klinických symptomů s přihlédnutím k věku nemocného. Podezření potvrdí specifické testy v tkáňové kultuře fibroblastů a/nebo molekulárně genetická analýza uvedených genů. Aktuální možnost léčby spočívá v podávání reverzibilního inhibitoru glukosylceramidsyntázy (miglustat), potenciálně stabilizujícího průběh nemoci, experimentálně slibná aplikace cyklodextrinu vstupuje do fáze klinického testování. Komplexní diagnostika je v ČR dostupná prostřednictvím Ústavu dědičných metabolických poruch (diagnóza stanovena u 67 pacientů, z toho 42 českých).
Niemann-Pick disease type C is an autosomal recessive lysosomal disorder clinically characterized by age-specific symptomatology with possible manifestation any time from neonatal age to late adulthood. Except for its neonatal form with cholestasis, respiratory failure and hepatosplenomegaly, the disease presents as a neurodegenerative disorder, frequently with splenomegaly. Pathophysiology involves dysfunction of the late endosome/lysosome membraneous system with accumulation of unesterified cholesterol and glycosphingolipids due to mutations in the NPC1 and NPC2 genes coding the corresponding lysosomal proteins. Results of clinical examination must be confirmed by specific loading tests in cultivated fibroblasts and/or molecular genetic analysis of the concerned genes. In the last years the disease is treated with a reversible glucosylceramide synthase inhibitor miglustat, potentially stabilizing its course. Recently, clinical testing of cyclodextrin has been initiated. In the Czech Republic, comprehensive diagnostics is available at The Institute of Inherited Metabolic Disorders (67 confirmed patients including 42 Czechs).
- Keywords
- neesterifikovaný cholesterol, gen NPC1, gen NPC2, miglustat, cyklodextrin, ZAVESCA,
- MeSH
- 1-Deoxynojirimycin analogs & derivatives therapeutic use MeSH
- Cholesterol metabolism MeSH
- Cyclodextrins therapeutic use MeSH
- Diagnostic Techniques and Procedures MeSH
- Esterification MeSH
- Financing, Organized MeSH
- Genetic Predisposition to Disease MeSH
- Disease Attributes MeSH
- Humans MeSH
- Membrane Glycoproteins genetics MeSH
- Niemann-Pick Disease, Type C diagnosis classification physiopathology MeSH
- Prenatal Diagnosis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- MeSH
- Cholesterol chemistry MeSH
- Child MeSH
- Esterification physiology MeSH
- Filipin diagnostic use MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Niemann-Pick Diseases diagnosis MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
BACKGROUND: Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). METHOD: The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. RESULTS: A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). CONCLUSION: The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.
- MeSH
- Child MeSH
- Adult MeSH
- Enzyme Inhibitors therapeutic use MeSH
- Humans MeSH
- Niemann-Pick Disease, Type C * drug therapy MeSH
- Infant, Newborn MeSH
- Prospective Studies MeSH
- Registries MeSH
- Retrospective Studies MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Niemann-Pick disease type C (NP-C) is a rare and progressive autosomal recessive disease leading to disabling neurological manifestation and premature death. The disease is prone to underdiagnosis because of its highly heterogeneous presentation. NP-C is characterized by visceral, neurological, and psychiatric manifestation, and its clinical picture varies according to age at onset. Although cataplexy is one of its characteristic symptoms, particularly in the late infantile and juvenile form, sleep disturbances are described only exceptionally. A combination of splenomegaly, vertical supranuclear gaze palsy, and cataplexy creates a most useful suspicion index tool for the disease. In adolescent and adult patients, when intellectual deterioration progresses and emotional reactions become flat, cataplexy usually disappears. Pathological findings in the brainstem in NP-C mouse model are compatible with the patients' symptoms including cataplexy. The authors observed cataplexy in 5 (3 with late infantile and 2 with juvenile form) out of 22 NP-C cases followed up in the past 20 years.
- MeSH
- Cataplexy diagnosis pathology physiopathology therapy MeSH
- Humans MeSH
- Niemann-Pick Disease, Type C diagnosis pathology physiopathology therapy MeSH
- Sleep Wake Disorders diagnosis pathology physiopathology therapy MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
