Novel compound heterozygous mutations of the NPC1 gene associated with Niemann-pick disease type C: a case report and review of the literature.

BACKGROUND: Niemann-Pick Disease type C is a fatal autosomal recessive lipid storage disorder caused by NPC1 or NPC2 gene mutations and characterized by progressive, disabling neurological deterioration and hepatosplenomegaly. Herein, we identified a novel compound heterozygous mutations of the NPC1 gene in a Chinese pedigree. CASE PRESENTATION: This paper describes an 11-year-old boy with aggravated walking instability and slurring of speech who presented as Niemann-Pick Disease type C. He had the maternally inherited c.3452 C > T (p. Ala1151Val) mutation and the paternally inherited c.3557G > A (p. Arg1186His) mutation using next-generation sequencing. The c.3452 C > T (p. Ala1151Val) mutation has not previously been reported. CONCLUSIONS: This study predicted that the c.3452 C > T (p. Ala1151Val) mutation is pathogenic. This data enriches the NPC1 gene variation spectrum and provides a basis for familial genetic counseling and prenatal diagnosis.

Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C.

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.).

Challenges in the Definitive Diagnosis of Niemann-Pick Type C-Leaky Variants and Alternative Transcripts.

Niemann-Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Other than the detailed clinical history, the typical diagnostic work-up for NPC includes the quantification of pathognomonic metabolites. However, the molecular basis diagnosis is still of utmost importance to fully characterize the disorder. Here, the authors provide an overview of splicing variants in the NPC1 and NPC2 genes and propose a new workflow for NPC diagnosis. Splicing variants cover a significant part of the disease-causing variants in NPC. The authors used cDNA analysis to study the impact of such variants, including the collection of data to classify them as leaky or non-leaky pathogenic variants. However, the presence of naturally occurring spliced transcripts can misdiagnose or mask a pathogenic variant and make the analysis even more difficult. Analysis of the NPC1 cDNA in NPC patients in parallel with controls is vital to assess and detect alternatively spliced forms. Moreover, nonsense-mediated mRNA decay (NMD) analysis plays an essential role in evaluating the naturally occurring transcripts during cDNA analysis and distinguishing them from other pathogenic variants' associated transcripts.

[Argentinean Consensus on the Diagnosis and Treatment of Niemann- Pick Disease Type C]. / Consenso argentino sobre diagnóstico y tratamiento de la enfermedad de Niemann-Pick Tipo C.

Niemann-Pick type C (NPC) is a disorder of the lysosomal metabolism due to biallelic pathogenic variants in NPC1 or NPC2. Intracellular deposit of lipids, mainly unesterified cholesterol, gives rise to oxidative damage in several tissues, mainly neurons, spleen and liver. This, in turn, is associated with a myriad of neurological / psychiatric and visceral symptoms, with wide variability in age of presentation, from prenatal / neonatal to adult-onset forms of the disease. The last few years have seen considerable progress in understanding this disease and its management. In this consensus, current approaches to the diagnosis, follow-up and treatment of NPC (including the use of miglustat, the only specific drug approved at the time) are discussed by an Argentinian panel of experts.

La enfermedad de Niemann-Pick tipo C (NPC) es un trastorno del metabolismo lisosomal que se debe a la presencia de variantes patogénicas bialélicas en los genes NPC1 o NPC2. El depósito intracelular de lípidos, especialmente colesterol no esterificado, provoca daño oxidativo en diversos tejidos, especialmente neuronas, bazo e hígado. Esto, a su vez, induce la aparición de un conjunto de síntomas neurológicos / psiquiátricos y viscerales, con una amplia variabilidad de edad de aparición, desde formas prenatales / neonatales hasta otras de aparición en la vida adulta. En los últimos años ha habido avances considerables en la comprensión sobre esta enfermedad y su manejo. En el presente consenso un grupo de expertos argentinos abordan los enfoques actuales de diagnóstico, seguimiento y tratamiento de NPC, incluyendo el uso de miglustat como única terapia específica aprobada en la actualidad.

Neonatal onset of Niemann-Pick disease type C in a patient with cholesterol re-accumulation in the transplanted liver and inflammatory bowel disease.

BACKGROUND: Niemann-Pick disease type C (NPC) is an autosomal recessive inherited and neurodegenerative disorder. Approximately 10% of NPC patients have acute liver failure and sometimes need liver transplantation (LT), and 7% reportedly develop inflammatory bowel disease (IBD). We report the case of a girl with NPC who had a re- accumulation of cholesterol in the transplanted liver and NPC-related IBD. CASE REPORT: The patient underwent living donor liver transplantation (LDLT) due to severe acute liver failure caused by an unknown etiology inherited from her father. At 1 year and 6 months (1Y6M), she developed neurological delay, catalepsy, and vertical supranuclear gaze palsy. The foam cells were found in her skin, and fibroblast Filipin staining was positive; hence, she was diagnosed with NPC. It was identified that her father had NPC heterozygous pathogenic variant. At 2 years, she had anal fissure, skin tag and diarrhea. She was diagnosed with NPC-related IBD, using a gastrointestinal endoscopy. Three years after LT, liver biopsy revealed foam cells and numerous fatty droplets. At 8 years, broken hepatocytes and substantial fibrosis were observed. She died from circulation failure due to hypoalbuminemia at 8Y2M. CONCLUSIONS: In NPC, load of cholesterol metabolism is suggested to persist even after LT. LDLT from NPC heterozygous variant donor was insufficient to metabolize cholesterol overload. In NPC patients, the possibility of cholesterol re-accumulation should be considered when LT is performed. NPC-related IBD should be considered when NPC patients have anorectal lesions or diarrhea.

N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal disease characterized by multiple symptoms such as progressive cerebellar ataxia and cognitive decline. The modified amino acid N-acetyl-leucine has been associated with positive symptomatic and neuroprotective, disease-modifying effects in various studies, including animal models of NPC, observational clinical case studies, and a multinational, rater-blinded phase IIb clinical trial. Here, we describe the development of a study protocol (Sponsor Code "IB1001-301") for the chronic treatment of symptoms in adult and pediatric patients with NPC. METHODS: This multinational double-blind randomized placebo-controlled crossover phase III study will enroll patients with a genetically confirmed diagnosis of NPC patients aged 4 years and older across 16 trial sites. Patients are assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 followed by placebo or vice versa. Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia, and secondary outcomes include cerebellar functional rating scales, clinical global impression, and quality of life assessments. DISCUSSION: Pre-clinical as well as observational and phase IIb clinical trials have previously demonstrated that IB1001 rapidly improved symptoms, functioning, and quality of life for pediatric and adult NPC patients and is safe and well tolerated. In this placebo-controlled cross-over trial, the risk/benefit profile of IB1001 for NPC will be evaluated. It will also give information about the applicability of IB1001 as a therapeutic paradigm for other rare and common neurological disorders. TRIAL REGISTRATIONS: The trial (IB1001-301) has been registered at www. CLINICALTRIALS: gov (NCT05163288) and www.clinicaltrialsregister.eu (EudraCT: 2021-005356-10). Registered on 20 December 2021.

The experience of living with Niemann-Pick type C: a patient and caregiver perspective.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare inherited lysosomal storage disease typified by accumulation of cholesterol and other lipids in late endosomes/lysosomes, thereby resulting in a spectrum of neurological, psychiatric, and systemic symptoms (notably liver disease). Though it is well-known that NPC exacts a physical and emotional toll on both patients and caregivers, the burden of NPC can vary between patients, while the challenges of living with NPC can evolve over time (i.e., from time of diagnosis to the present day). To further grasp patient and caregiver perceptions and experiences with NPC, we carried out focus group discussions with pediatric and adult individuals with NPC (N = 19), with partial or full representation of the patient by their caregiver. Furthermore, we utilized our NPC focus group discussion to provide guidance on study design parameters and feasibility of prospective investigations aiming to characterize the central manifestations of NPC using neuroimaging, specifically, magnetic resonance imaging (MRI) methodology. RESULTS: Focus group discussions revealed that neurological signs, including declining cognition, memory loss, and psychiatric symptoms, as well as increasingly impaired mobility and motor function, are among the most pressing past and current concerns for patients and caregivers. Moreover, several participants also expressed concern over a loss of independence, social exclusion, and uncertainty for what the future holds. Caregivers described the challenges that participation in research poses, which included logistical difficulties mainly due to traveling with medical equipment and the need for sedation in a minority of patients when undergoing MRI. CONCLUSIONS: The findings derived from focus group discussions highlight the outstanding challenges that NPC patients and their caregivers face daily, while also providing direction on the potential scope and feasibility of future studies focusing on the central phenotypes of NPC.

Niemann-Pick type C disease: Case report and review of the literature.

Niemann-Pick type C (NPC) disease is an autosomal recessive disease of lysosomal lipid storage disorder caused by mutations in either the NPC1 (95%) or the NPC2 (5%) gene. We report a case of a 23-year-old woman who initially showed ataxia, altered gait and tremor. She subsequently developed cognitive decline and psychiatric symptoms. She had asphyxia at birth and was diagnosed as hypoxic-ischemic encephalopathy and cerebral palsy before. The chest computed tomography (CT) incidentally showed splenomegaly. Brain magnetic resonance imaging (MRI) showed no significant abnormalities. Genetic analysis revealed compound heterozygous mutations of NPC1. The clinical picture of NPC can be markedly variable, so comprehensive clinical evaluation, neurological examination and laboratory test are quite important for the diagnosis of NPC.

Current advancements in therapy for Niemann-Pick disease: progress and pitfalls.

INTRODUCTION: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, lysosomal storage disorder. To combat the progressive neurodegeneration in NPC, disease-modifying treatment needs to be introduced early in the course of the disease. The only approved, disease-modifying treatment is a substrate-reduction treatment, miglustat. Given miglustat's limited efficacy, new compounds are under development, including gene therapy; however, many are still far from clinical use. Moreover, the phenotypic heterogeneity and variable course of the disease can impede the development and approval of new agents. AREAS COVERED: Here, we offer an expert review of these therapeutic candidates, with a broad scope not only on the main pharmacotherapies, but also on experimental approaches, gene therapies, and symptomatic strategies. The National Institute of Health (NIH) database PubMed has been searched for the combination of the words 'Niemann-Pick type C'+ 'treatment' or 'therapy' or 'trial.' The website clinicaltrials.gov has also been consulted. EXPERT OPINION: We conclude a combination of treatment strategies should be sought, with a holistic approach, to improve the quality of life of affected individuals and their families.

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

Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.

A Retrospective Multicentric Study of 34 Patients with Niemann-Pick Type C Disease and Early Liver Involvement in France.

OBJECTIVE: To describe the clinical features and course of liver involvement in a cohort of patients with Niemann-Pick type C disease (NP-C), a severe lysosomal storage disorder. STUDY DESIGN: Patients with genetically confirmed NP-C (NPC1, n = 31; NPC2, n = 3) and liver involvement before age 6 months were retrospectively included. Clinical, laboratory test, and imaging data were collected until the last follow-up or death; available liver biopsy specimens were studied using anti-CD68 immunostaining. RESULTS: At initial evaluation (median age, 17 days of life), all patients had hepatomegaly, 33 had splenomegaly, and 30 had neonatal cholestasis. Portal hypertension and liver failure developed in 9 and 4 patients, respectively. Liver biopsy studies, performed in 16 patients, revealed significant fibrosis in all 16 and CD68+ storage cells in 15. Serum alpha-fetoprotein concentration measured in 21 patients was elevated in 17. Plasma oxysterol concentrations were increased in the 16 patients tested. Four patients died within 6 months of life, including 3 from liver involvement. In patients who survived beyond age 6 months (median follow-up, 6.1 years), cholestasis regressed in all, and portal hypertension regressed in all but 1; 25 patients developed neurologic involvement, which was fatal in 16 patients. CONCLUSIONS: Liver involvement in NP-C consisted of transient neonatal cholestasis with hepatosplenomegaly, was associated with liver fibrosis, and was responsible for death in 9% of patients. The combination of liver anti-CD68 immunostaining, serum alpha-fetoprotein measurement, and studies of plasma biomarkers should facilitate early identification of NP-C.

Central sleep apnea and daytime sleepiness in Niemann-Pick type C disease: a report of 2 cases.

Niemann-Pick disease type C (NPC) is an autosomal recessive hereditary disease in which sphingomyelin and cholesterol are deposited in various organs of the body. The clinical manifestations of NPC include neurologic symptoms and cataplexy; other symptoms related to sleep have seldom been reported. One previous study described various sleep disorders including chronic insomnia, obstructive sleep apnea, restless legs syndrome, and rapid eye movement sleep behavior disorder, thus suggesting that sleep disorders in patients with NPC are more prevalent than previously thought and warrant close attention. Here, we describe sleep disorders in 2 patients with NPC and discuss the clinical characteristics and, for the first time, discuss potential pathogenic mechanisms underlying sleep disorders in such patients. CITATION: Zhang Y, Cheng Y, Li N, et al. Central sleep apnea and daytime sleepiness in Niemann-Pick type C disease: a report of 2 cases. J Clin Sleep Med. 2023;19(2):409-414.

Cost-effectiveness of miglustat versus symptomatic therapy of Niemann-Pick disease type C.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a progressive neurodegenerative disorder with early infantile (< 2 years), late infantile (2-6 years), juvenile (7-15 years) and adolescent (> 15 years) onset. The mainstay of therapy for NP-C patients with neurological symptoms is miglustat, a drug that may modify the course of the disease. AIM: Our aim was to evaluate the cost-effectiveness of miglustat in comparison to symptomatic therapy in patients with NP-C in the socio-economic settings of the Republic of Serbia, an upper-middle-income European economy. METHOD: The perspective of the Serbian Republic Health Insurance Fund was chosen for this study, and the time horizon was eighty years. The main outcomes of the study were quality-adjusted life years gained with miglustat and comparator, and direct costs of treatment. The study was conducted through the generation and simulation of the Discrete-Event Simulation model. The model results were obtained after Monte Carlo microsimulation of a sample with 1000 virtual patients. RESULTS: Treatment with miglustat was not cost-effective when compared with symptomatic therapy and was associated with negative values of net monetary benefit regardless of the onset of neurological manifestations (- 110,447,627.00 ± 701,614.00 RSD, - 343,871,695.00 ± 2,577,441.00 RSD, - 1,397,908,502.00 ± 23,084,235.00 RSD and - 2,953,680,879.00 ± 33,297,412.00 RSD) for early infantile, late infantile, juvenile and adolescent cohorts, respectively). CONCLUSION: When traditional pharmacoeconomic evaluation is employed, miglustat is not a cost-effective option in comparison to symptomatic therapy for the treatment of NP-C. However, given the proven efficacy of miglustat, there is a need to find ways to make this drug available to all patients with NP-C.

Spectrum of Movement Disorders in Niemann-Pick Disease Type C.

Introduction: Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lipid storage disorder caused by mutations in the NPC 1 or 2 genes. Movement disorders can occur as the first symptom and as predominant symptom mainly in juvenile-onset. The frequency and heterogeneity of movement disorders in NPC are not well described. We studied the frequency and spectrum of movement disorders in patients with NPC of different age of onset. Methods: Retrospective chart review of patients with NPC diagnosed based on the Suspicion Index tool and demonstration of foamy macrophages/sea-blue histiocytes in bone marrow aspirate. Results: We report 9 cases of NPC with 2 patients of late-infantile, 4 juvenile-onset and 3 of adult-onset. The mean age at onset of symptoms was 11.7 ± 10.4 (range 4-38 years) and the median duration of illness was 4 years. Vertical supranuclear gaze palsy (VSGP) was noted in 8 patients and VSGP with slowing of saccade in 1 patient. Splenomegaly was seen in 5 patients. Movement disorders as the first symptom occurred in 4 patients. Dystonia was the first symptom in 2 patients and cerebellar ataxia in 2 patients. Cerebellar ataxia occurred during the course of illness in 5 patients, dystonia in 6 patients. One patient with late-infantile NPC had stimulus-sensitive myoclonus. Conclusion: Movement disorders are common in NPC and occur as a presenting symptom. Cerebellar ataxia and dystonia are the most common movement disorder in NPC. Vertical supranuclear gaze palsy along with the movement disorders should lead to clinical suspicion of NPC.

Development of a Highly Sensitive and Rapid Liquid Chromatography-Tandem Mass Spectrometric Method Using a Basic Mobile Phase Additive to Determine the Characteristics of the Urinary Metabolites for Niemann-Pick Disease Type C.

As Niemann-Pick disease type C (NPC) is difficult to diagnose owing to its various clinical symptoms; biomarker tests have been developed. Previously, we revealed urinary sulfated cholesterol metabolites as noninvasive biomarkers for NPC. However, LC/tandem mass spectrometry (LC/MS/MS) requires long separation time and large urine volumes. Recently, a basic mobile phase was reported to increase the MS intensity. Thus, we developed a highly sensitive and rapid LC/MS/MS method for analyzing urinary cholesterol metabolites using a basic mobile phase additive. 3ß-Sulfooxy-7ß-N-acetylglucosaminyl-5-cholenic acid, its glycine and taurine conjugates, 3ß-sulfooxy-7ß-hydroxy-5-cholenic acid, and 7-oxo form were measured, with selected reaction monitoring in negative ion mode. Oasis HLB and L-column 3 were used for column-switching LC/MS/MS and urine diluted 10-fold was employed as the sample. After trapping, gradient separation was performed using solutions containing 1% (v/v) ammonium solution. On average, a 16-fold increase in peak areas was observed compared to that obtained at pH 5.5 with the mobile phases. Although the previous method needed 60 min for separation from interference peaks, we succeeded to separate them in 7 min with optimized LC condition. Further, all compounds showed good linearity from 0.3-1000 ng/mL, with satisfactory intra- and inter-day reproducibility. The developed method was applied to the urinalysis of healthy participants and NPC patients. Overall, the concentrations of metabolites correlated with those obtained using the previous method. Therefore, we succeeded to increasing MS intensity and shorten LC running time; and the method is useful for the noninvasive diagnostic screening of patients with NPC.

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

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.

Backward leaning during gait: An underrecognized sign in Niemann-Pick type C.

Niemann-Pick type C (NPC) is a rare but treatable lysosomal disorder with heterogeneous clinical presentations including cognitive impairment, movement disorders and vertical gaze palsy. We illustrate five cases of genetically confirmed NPC and highlight backward leaning during gait as a relevant clinical sign and a useful diagnostic clue.

Niemann-Pick type C disease as proof-of-concept for intelligent biomarker panel selection in neurometabolic disorders.

AIM: Using Niemann-Pick type C disease (NPC) as a paradigm, we aimed to improve biomarker discovery in patients with neurometabolic disorders. METHOD: Using a multiplexed liquid chromatography tandem mass spectrometry dried bloodspot assay, we developed a selective intelligent biomarker panel to monitor known biomarkers N-palmitoyl-O-phosphocholineserine and 3ß,5α,6ß-trihydroxy-cholanoyl-glycine as well as compounds predicted to be affected in NPC pathology. We applied this panel to a clinically relevant paediatric patient cohort (n = 75; 35 males, 40 females; mean age 7 years 6 months, range 4 days-19 years 8 months) presenting with neurodevelopmental and/or neurodegenerative pathology, similar to that observed in NPC. RESULTS: The panel had a far superior performance compared with individual biomarkers. Namely, NPC-related established biomarkers used individually had 91% to 97% specificity but the combined panel had 100% specificity. Moreover, multivariate analysis revealed long-chain isoforms of glucosylceramide were elevated and very specific for patients with NPC. INTERPRETATION: Despite advancements in next-generation sequencing and precision medicine, neurological non-enzymatic disorders remain difficult to diagnose and lack robust biomarkers or routine functional testing for genetic variants of unknown significance. Biomarker panels may have better diagnostic accuracy than individual biomarkers in neurometabolic disorders, hence they can facilitate more prompt disease identification and implementation of emerging targeted, disease-specific therapies. WHAT THIS PAPER ADDS: Intelligent biomarker panel design can help expedite diagnosis in neurometabolic disorders. In Niemann-Pick type C disease, such a panel performed better than individual biomarkers. Biomarker panels are easy to implement and widely applicable to neurometabolic conditions.