BACKGROUND: Niemann-Pick disease Type C (NP-C) is difficult to diagnose due to heterogeneous and nonspecific clinical presentation. The NP-C Suspicion Index (SI) was developed to identify patients with a high likelihood of NP-C; however, it was less reliable in patients aged <4 years. METHODS: An early-onset NP-C SI was constructed following retrospective chart review of symptom presentation in 200 patients from nine centres comprised of 106 NP-C cases, 31 non-cases and 63 controls. Statistical analyses defined strength of association between symptoms and a diagnosis of NP-C and assigned risk prediction scores to each symptom. RESULTS: Visceral symptoms were amongst the strongest predictors. Except for gelastic cataplexy and vertical supranuclear gaze palsy, central nervous system symptoms were not discriminatory in this population. Performance of the early-onset NP-C SI was superior versus the original NP-C SI in patients aged ≤4 years. CONCLUSIONS: The early-onset NP-C SI can help physicians, especially those with limited knowledge of NP-C, to identify patients aged ≤4 years who warrant further investigation for NP-C.

• Klíčová slova
• Diagnosis, Diagnostics, Early-onset, Infant, NP-C, Niemann-Pick disease Type C, Paediatric, Screening, Suspicion Index,
• MeSH
• hodnocení rizik MeSH
• kojenec MeSH
• lidé MeSH
• logistické modely MeSH
• metody pro podporu rozhodování * MeSH
• Niemannova-Pickova nemoc typu C diagnóza   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• senzitivita a specificita MeSH
• studie případů a kontrol MeSH
• ukazatele zdravotního stavu * MeSH
• věkové faktory MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: To assess the effects of the modified amino acid acetyl-dl-leucine (AL) on cerebellar ataxia, eye movements, and quality of life of patients with Niemann-Pick type C (NP-C) disease. METHODS: Twelve patients with NP-C disease were treated with AL 3 g/d for 1 week and then with 5 g/d for 3 weeks with a subsequent washout period of 1 month. The Scale for the Assessment and Rating of Ataxia (SARA), the Spinocerebellar Ataxia Functional Index (SCAFI), the modified Disability Rating Scale (mDRS), EuroQol 5Q-5D-5L, and the visual analog scale (VAS) were administered. Measurements took place at baseline, after 1 month of therapy, and after 1 month of washout. RESULTS: The SARA score changed from the baseline (median [±SD, interquartile range]) of 10.8 (11.2, 8-24.6) to 7.0 (10.7, 5.6-19.6) on medication (difference: 3.8 points) and 10.5 (11.5, 7.1-23.9) after washout (difference: 3.5 points) (p = 0.000412; post hoc p = 0.003 between baseline and on medication, and on medication and washout p = 0.005). The SCAFI subscore 9-Hole Peg Test for dominant hand, mDRS score, and VAS score also improved on medication. No side effects except transient dizziness in one patient were reported. CONCLUSIONS: Treatment with AL improved ataxic symptoms in patients with NP-C without relevant side effects, thus showing a reasonable risk-benefit profile. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that AL improves cerebellar symptoms and quality of life in patients with NP-C.

• MeSH
• dospělí MeSH
• kvalita života psychologie   MeSH
• leucin analogy a deriváty   terapeutické užití   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Niemannova-Pickova nemoc typu C diagnóza   farmakoterapie   psychologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylleucine MeSH Prohlížeč
• leucin MeSH

A case is described of Niemann-Pick type C2 disease presenting an infantile pneumopathic phenotype known to occur in this recently established, second, minor complementation group of Niemann-Pick type C (NPC) disease. However, the pulmonary involvement was unique, being dominated, in addition to the usual storage macrophage infiltration of the alveolar and septal compartments, by irregular emphysema attributed to storage cell migration into the bronchiolar lumen. The latter modified considerably the X-ray findings and hindered the initial clinical diagnosis. Otherwise, the storage phenotype, including the range of stored lipids, storage distribution, and cell and organ pathology, was found to be identical to that in the whole Niemann-Pick type C disease group dominated by NPC1. The biochemical findings (cholesterol esterification level) corresponded to the classical biochemical phenotype. Emphysema should thus be considered as a variant of the pulmonary NPC2 storage process, governed most probably by an epigenetic mechanism responsible for storage macrophage migration into the bronchiolar compartment.

• MeSH
• emfyzém diagnóza   etiologie   genetika   MeSH
• fatální výsledek MeSH
• glykosfingolipidy metabolismus   MeSH
• intersticiální plicní nemoci diagnóza   etiologie   genetika   MeSH
• lidé MeSH
• makrofágy metabolismus   patologie   MeSH
• neurony metabolismus   patologie   MeSH
• Niemannova-Pickova nemoc komplikace   diagnóza   genetika   MeSH
• novorozenec MeSH
• plíce patologie   MeSH
• rentgendiagnostika hrudníku MeSH
• respirační insuficience MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• glykosfingolipidy 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

A multi-approach study in a series of 25 Czech and Slovak patients with acid sphingomyelinase deficiency revealed a broad phenotypic variability within Niemann-Pick disease types A and B. The clinical manifestation of only 9 patients fulfilled the historical classification: 5 with the rapidly progressive neurovisceral infantile type A and 4 with a slowly progressive visceral type B. Sixteen patients (64%) represented a hitherto scarcely documented 'intermediate type' (IT). Twelve patients showed a protracted neurovisceral course with overt or mild neurological symptoms, three a rapidly progressing fatal visceral affection with rudimentary neurological lesion. One patient died early from a severe visceral disease. The genotype in our patients was represented by 4 frameshift and 14 missense mutations. Six were novel (G166R, R228H, A241V, D251E, D278A, A595fsX601). The Q292K mutation (homoallelic, heteroallelic) was strongly associated with a protracted neurovisceral phenotype (10 of 12 cases). The sphingomyelin loading test in living fibroblasts resulted in total degradation from less than 2% in classical type A to 70-80% in classical type B. In the IT group it ranged from 5% to 49% in a 24 h chase. The liver storage showed three patterns: diffuse, zonal (centrolobular), and discrete submicroscopic. Our series showed a notable variability in both the neurological and visceral lesions as well as in their proportionality and synchrony, and demonstrates a continuum between the historical 'A' and 'B' phenotypes of ASM deficiency. This points to a broad phenotypic potential of ASM deficiency, suggesting the existence of still unknown factors independently controlling the storage level in the visceral and neuronal compartments. This report highlights the important position of the IT in the ASM deficiency phenotype classification. We define IT as a cluster of variants combining clinical features of both the classical types. The protracted neuronopathic variant with overt, borderline or subclinical neurology prevails and is important in view of future enzyme replacement therapy. It appears more common in central Europe. The visceral, rapidly progressing early fatal type has been recognized rarely so far.

• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• fibroblasty cytologie   fyziologie   MeSH
• genotyp MeSH
• hydrolýza MeSH
• játra metabolismus   MeSH
• kojenec MeSH
• kůže cytologie   MeSH
• lidé MeSH
• missense mutace MeSH
• mladiství MeSH
• mutageneze cílená MeSH
• Niemannova-Pickova nemoc genetika   mortalita   patofyziologie   MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• posunová mutace MeSH
• předškolní dítě MeSH
• prevalence MeSH
• sfingomyelinfosfodiesterasa genetika   metabolismus   MeSH
• stupeň závažnosti nemoci MeSH
• transformované buněčné linie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Slovenská republika epidemiologie   MeSH
• Názvy látek
• sfingomyelinfosfodiesterasa MeSH

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies.

• Klíčová slova
• Association study, Dementia with Lewy bodies, NPC1, Niemann-Pick disease type C, Parkinson’s disease, REM-sleep behavior disorder,
• MeSH
• demence s Lewyho tělísky * genetika   MeSH
• lidé MeSH
• Parkinsonova nemoc * genetika   MeSH
• porucha chování v REM spánku * genetika   MeSH
• protein NPC1 MeSH
• spánek MeSH
• synukleinopatie * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• NPC1 protein, human MeSH Prohlížeč
• protein NPC1 MeSH