Beyond the Typical Syndrome: Understanding Non-motor Features in Niemann-Pick Type C Disease

Rangel, Deborah Moreira; Melo, Matias Carvalho Aguiar; Pedroso, José Luiz; Barsottini, Orlando Graziani Póvoas; Sobreira-Neto, Manoel Alves; Braga‐Neto, Pedro

doi:10.1007/s12311-020-01156-0

Cited by 6 publications

(2 citation statements)

References 85 publications

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“…Sleep disorders have been rarely described within NPC [ 17 , 36 ]. Limited evidence include chronic insomnia, probable and confirmed obstructive sleep apnea, REM sleep behavior disorders, restless leg syndrome, and excessive daytime sleepiness, which has been occasionally reported to as an initial symptom of the disease [ 36 ]. We attempted to characterize excessive daytime somnolence by the use of the Epworth Sleepiness Scale [ 37 ].…”

Section: Dksmentioning

confidence: 99%

Clinical correlates of movement disorders in adult Niemann-Pick type C patients measured via a Personal KinetiGraph

et al. 2022

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Background Niemann-Pick type C (NPC) is an autosomal recessive progressive neurodegenerative disorder caused by mutations in the NPC1 or NPC2 genes. Patients with this disorder have variable phenotypic presentations that often include neuropsychiatric manifestations, cognitive decline, and movement disorders. There is considerable interpatient variation in movement disorders, with limited quantitative measurements describing the movements observed. Objective measurements using wearable sensors provide clinically applicable monitoring of patients with Parkinson’s disease, and hence may be utilized in patients with NPC. Objective To explore the relationship between objective measurements of movement obtained via the use of the Personal KinetiGraph (PKG) with the clinical information obtained via questionnaires and clinical rating tools of patients with Niemann-Pick type C. Methods Twelve patients with Niemann-Pick type C were recruited who wore the PKG for 6 days during regular activities. A 6-day output was provided by the manufacturer, which provided bradykinesia (BK) and dyskinesia (DK) scores. BK and DK scores were further divided into their interquartile ranges. A fluctuation score (FDS), percentage time immobile (PTI), and percent time with tremors (PTT) were also provided. Clinical assessments included Abnormal Involuntary Movement Scale (AIMS), Epworth Sleepiness Score (ESS), Falls, Neuropsychiatric Unit Assessment Tool (NUCOG), Parkinson’s disease questionnaire (PDQ), and modified Unified Parkinson’s Disease Rating Scale (UPDRS) which were performed over telehealth within 2 weeks of PKG use. Pearson’s correlation analyses were utilized to explore the relationship between DK and BK quartiles and clinical measures. Results We found bradykinesia to be a feature among this cohort of patients, with a median BKS of 22.0 (7.4). Additionally, PTI scores were elevated at 4.9 (8.2) indicating elevated daytime sleepiness. Significant correlations were demonstrated between BK25 and Falls (r = − 0.74, 95% CI = [− 0.95, − 0.08]), BK50 and Falls (r = − 0.79, 95% CI = [− 0.96, − 0.19]), and BK75 and Falls (r = − 0.76, 95% CI = [− 0.95, − 0.11]). FDS correlated with PDQ (r = − 0.7, 95% CI = [− 0.92, − 0.18]), UPDRS IV (r = − 0.65, 95% CI = [− 0.90, − 0.09]), UPDRS (r = − 0.64, 95% CI = [− 0.9, − 0.06]), and AIMS (r = − 0.96, 95% CI = [− 0.99, − 0.49]). DK25 in comparison with NUCOG-A (r = 0.72, 95% CI = [0.17, 0.93]) and DK75 in comparison with NUCOG (r = 0.64, 95% CI = [0.02, 0.91]) and NUCOG-A (r = 0.63, 95% CI = [0.01, 0.90]) demonstrated significant correlations. Additionally, duration of illness in comparison with PTI (r = 0.72, 95% CI = [0.22, 0.92]) demonstrated significance. Conclusions Utilization of PKG measures demonstrated that bradykinesia is under recognized among NPC patients, and the bradykinetic patients were less likely to report concerns regarding falls. Additionally, the FDS rather than the DKS is sensitive to the abnormal involuntary movements of NPC—reflecting a differing neurobiology of this chorea compared to levodopa-induced dyskinesias. Furthermore, dyskinetic individuals performed better in cognitive assessments of attention which may indicate an earlier timepoint within disease progression.

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Section: Dksmentioning

confidence: 99%

Clinical correlates of movement disorders in adult Niemann-Pick type C patients measured via a Personal KinetiGraph

et al. 2022

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“…Dysfunction of either protein causes intracellular accumulation of unesterified cholesterol (Pentchev et al, 1985;Vanier et al, 1991) and other lipids (Altuzar et al, 2023;Fan et al, 2013;Lloyd-Evans et al, 2008;Malathi et al, 2004;Sugimoto et al, 2001;Taniguchi et al, 2001;te Vruchte et al, 2004;Zervas et al, 2001a), and impairs lysosomal (Elrick et al, 2012;Ko et al, 2001;Lloyd-Evans et al, 2008;Shen et al, 2012;Zhang et al, 2001) and mitochondrial function (Colaco et al, 2020;Li et al, 2005;Marí et al, 2006;Torres et al, 2017;Yambire et al, 2019;Yu et al, 2005), and autophagy (Ko et al, 2005;Liao et al, 2007;Pacheco et al, 2007). Patients present distinct forms of the disease depending on the onset of neurovisceral symptoms (Bolton et al, 2022;Geberhiwot et al, 2018;Patterson, 2020;Rangel et al, 2020). The most common forms are characterized by infantile onset at two months to six years of age presenting hepatosplenomegaly, delayed motor and speech development, and progressive neurologic symptoms including dysphagia, ataxia, clumsiness, seizures, and cataplexy.…”

Section: Introductionmentioning

confidence: 99%

Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

Parente,

Barthelemy,

Tonini

et al. 2023

Preprint

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Niemann-Pick type C disease (NPCD) is a lysosomal disorder whith patients presenting highly variable onset, neurovisceral symptoms and life spans due to defective lipid homeostasis. At present, therapeutic options are limited to palliative and disease-modifying drugs, and there is a continued need for new approaches. Here, we explored bromodomain and extraterminal (BET) proteins as new drug target for NPCD using patient-derived fibroblasts. Treatment of cells with JQ1, a prototype BET inhibitor, enhanced the level of NPC1 protein and increased its presence in lysosomes, diminished lysosomal expansion and cholesterol accumulation and induced extracellular release of lysosomal components in a time- and dose-dependent manner. The reversal of pathologic changes in an established cell model suggest inhibition of BET protein as new therapeutic approach for NPCD.

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The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism

Pfrieger

2023

Progress in Lipid Research

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Beyond the Typical Syndrome: Understanding Non-motor Features in Niemann-Pick Type C Disease

Cited by 6 publications

References 85 publications

Clinical correlates of movement disorders in adult Niemann-Pick type C patients measured via a Personal KinetiGraph

Clinical correlates of movement disorders in adult Niemann-Pick type C patients measured via a Personal KinetiGraph

Reversal of pathologic changes in fibroblasts from Niemann-Pick type C disease patients by inhibition of bromodomain and extraterminal proteins

The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism

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