Dataset Information

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.

ABSTRACT: Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.

SUBMITTER: Las Heras M

PROVIDER: S-EPMC10421955 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.

Las Heras Macarena M Szenfeld Benjamín B Ballout Rami A RA Buratti Emanuele E Zanlungo Silvana S Dardis Andrea A Klein Andrés D AD

NPJ genomic medicine 20230811 1

Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC ...[more]

PMID: 37567876

Similar Datasets

Project description:BACKGROUND:Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively. CASE PRESENTATION:In Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C?>?T (p.P474L), a known causative mutation, and c.3722 T?>?C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient's 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C?>?T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation. CONCLUSIONS:Marked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.

Project description:BackgroundNiemann-Pick disease type C1 (NPC1) is a rare autosomal recessive disease characterized by endolysosomal accumulation of unesterified cholesterol with progressive deterioration in swallowing, often leading to premature death. Although documented, the natural history of NPC1 swallowing dysfunction has yet to be delineated systematically. This manuscript aims to provide a comprehensive characterization of the phenotypic spectrum and progression of swallowing dysfunction in NPC1.MethodologyThe National Institutes of Health (NIH) NPC1 natural history study (NCT00344331) enrolled 120 patients, who underwent comprehensive interpretative swallow assessments for swallowing safety, dietary modifications, and aspiration risk. Longitudinal statistical modeling accounted for all outcomes with NPC1 disease covariates (first symptom onset, age at neurological symptom onset, seizure history, duration of neurological symptoms) as well as miglustat use (a glucosylceramide synthase inhibitor) and NIH study duration (NIHSD; the length of time an individual participated in the NIH study). Probabilities for disease progression and time to swallowing decline were conducted for the entire cohort.ResultsTime to swallowing decline with American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH-adapted Penetration Aspiration Scale (NIH-PAS) were identified: [Formula: see text] person-years and [Formula: see text] person-years, respectively. NIHSD and seizure history consistently and significantly were associated with decline (ORNIHSD = 1.34-2.10, 95% CI 1.04-3.4, p = 0.001-0.026; ORSeizure = 3.26-18.22, 1.03-167.79; p = 0.001-0.046), while miglustat use revealed protection (ORMiglustat = 0.01-0.43, 0.007-0.98; p = 0.001-0.044). The probability of decline with NPC1 neurological severity scale and annual severity increment scale were established with the aforementioned covariates, varying amongst subgroups.ConclusionThis study represents the most extensive collection of prospective, instrumental swallowing assessments in NPC1 to date with an interpretive analysis providing an improved understanding of NPC1 disease progression with swallowing function-serving as a foundation for clinical management and future NPC1 therapeutics.

Project description:Increasing evidence implicates lysosomal dysfunction in the pathogenesis of neurodegenerative diseases, including the rare inherited lysosomal storage disorders (LSDs) and the most common neurodegenerative diseases, such as Alzheimer's and Parkinson's disease (AD and PD). Although the triggers of the lysosomal impairment may involve the accumulated macromolecules or dysfunction of the lysosomal enzymes, the role of the lysosomal glycocalyx in the lysosomal (dys)function has not been studied. The goal of this work was to analyze whether there are changes in the lysosomal glycocalyx in a cellular model of a LSD Niemann-Pick type C disease (NPC). Using the ferrofluid nanoparticles we isolated lysosomal organelles from NPC1-null and CHOwt cells. The magnetically isolated lysosomal fractions were enriched with the lysosomal marker protein LAMP1 and showed the key features of NPC disease: 3-fold higher cholesterol content and 4-5 fold enlarged size of the particles compared with the lysosomal fractions of wt cells. These lysosomal fractions were further processed to isolate lysosomal membrane proteins using Triton X-114 and their N-glycome was analyzed by HILIC-UPLC. N-glycans presented in each chromatographic peak were elucidated using MALDI-TOF/TOF-MS. We detected changes in the N-glycosylation pattern of the lysosomal glycocalyx of NPC1-null versus wt cells which involved high-mannose and sialylated N-glycans. To the best of our knowledge this study is the first to report N-glycome profiling of the lysosomal glycocalyx in NPC disease cellular model and the first to report the specific changes in the lysosomal glycocalyx in NPC1-null cells. We speculate that changes in the lysosomal glycocalyx may contribute to lysosomal (dys)function. Further glycome profiling of the lysosomal glycocalyx in other LSDs as well as the most common neurodegenerative diseases, such as AD and PD, is necessary to better understand the role of the lysosomal glycocalyx and to reveal its potential contribution in lysosomal dysfunction leading to neurodegeneration.

Project description:BackgroundNiemann-Pick disease Type C (NP-C) is a rare, progressive neurodegenerative disorder characterized by progressive neurodegeneration and premature death. We report data at closure of the NPC Registry that describes the natural history, disease course and treatment experience of NP-C patients in a real-world setting.MethodsThe NPC Registry was a prospective observational cohort study that ran between September 2009 and October 2017. Patients with a confirmed diagnosis of NP-C were enrolled regardless of treatment status. All patients underwent clinical assessments and medical care as determined by their physicians; data were collected through a secure internet-based portal.ResultsAt closure on October 19, 2017, 472 patients from 22 countries were enrolled in the NPC Registry. Mean (standard deviation) age at enrollment was 21.2 (15.0) years, and 51.9% of patients were male. First neurological symptom onset occurred during the early-infantile (< 2 years), late-infantile (2 to < 6 years), juvenile (6 to < 15 years), or adolescent/adult (≥ 15 years) periods in 13.5, 25.6, 31.8, and 29.1% of cases, respectively. The most frequent neurological manifestations prior to enrollment included ataxia (67.9%), vertical supranuclear gaze palsy (67.4%), dysarthria (64.7%), cognitive impairment (62.7%), dysphagia (49.1%), and dystonia (40.2%). During infancy, splenomegaly and hepatomegaly were frequent (n = 199/398 [50%] and n = 147/397 [37.0%], respectively) and persisted in most affected patients. Of the 472 enrolled patients, 241 were continuously treated with miglustat during the NPC Registry observation period, of whom 172 of these 241 patients were treated continuously for ≥12 months. A composite disability score that assesses impairment of ambulation, manipulation, language, and swallowing was highest in the early-infantile population and lowest in the adolescent/adult population. Among the continuous miglustat therapy population, 70.5% of patients had improved or had stable disease (at least 3 of the 4 domains having a decreased or unchanged score between enrollment and last follow-up). The NPC Registry did not identify any new safety signals associated with miglustat therapy.ConclusionsThe profiles of clinical manifestations in the final NPC Registry dataset agreed with previous clinical descriptions. Miglustat therapy was associated with a stabilization of neurological manifestations in most patients. The safety and tolerability of miglustat therapy was consistent with previous reports.

Dataset Information

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.

Publications

Understanding the phenotypic variability in Niemann-Pick disease type C (NPC): a need for precision medicine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets