Serum neurofilament light protein as a biomarker in Niemann-Pick disease, type C1.

Purpose: Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disease caused by pathological variants in . Analysis of serum neurofilament light (NfL), a marker of neuronal damage, could be useful as a biomarker for patient monitoring and clinical trial design.

Methods: We measured NfL levels in serum samples from 118 well-characterized individuals with NPC1 and analyzed them with respect to clinical measures and treatment status.

Biomarker Validation in NPC1: Foundations for Clinical Trials and Regulatory Alignment.

Niemann-Pick Type C1 (NPC1) disease is a rare, autosomal recessive, neurovisceral lysosomal storage disorder caused by mutations in the NPC1. This condition leads to defective intracellular cholesterol and lipid trafficking, resulting in the accumulation of unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes. Clinically, NPC1 manifests with a heterogeneous spectrum of progressive neurological symptoms, including ataxia, vertical supranuclear gaze palsy, dysarthria, cognitive decline, and dystonia, often accompanied by systemic signs such as hepatosplenomegaly and neonatal cholestasis.

Altered Cerebrospinal Fluid Proteins in Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz Syndrome (SLOS) is a rare, autosomal recessive, neurocognitive disorder caused by pathological variants in the 7-dehydrocholesterol reductase gene (), leading to impaired cholesterol biosynthesis. The biochemical results of these defects include the accumulation of the cholesterol precursor, 7-dehydrocholesterol (7-DHC), and typically reduced cholesterol. Individuals with SLOS present with a spectrum of developmental anomalies and neurocognitive impairments.

Convergent Validity of the Fine Motor, Speech, and Cognitive Domains of the 5-Domain Niemann-Pick Disease Type C Clinical Severity Scale.

The 5-Domain Niemann Pick Type C Clinical Severity Scale (5DNPCCSS) is used in clinical practice and trials. Although psychometric data support the clinical meaningfulness of the concepts and the scale's interrater reliability, more information is needed to support its construct validity. Here, we evaluated the convergent validity of the Cognition, Speech, and Fine Motor domains.

Efficacy results from a 12-month double-blind randomized trial of arimoclomol for treatment of Niemann-Pick disease type C (NPC): Presenting a rescored 4-domain NPC Clinical Severity Scale.

Background: In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (NCT02612129), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a primary endpoint in NPC-002, discusses its validation, and presents the results of the primary analysis.

Elevated Cerebrospinal Fluid Total Tau in Niemann-Pick Disease Type C1: Correlation With Clinical Severity and Response to Therapeutic Interventions.

Niemann-Pick disease, type C1 (NPC1) is an inborn error of intracellular cholesterol transport. Impaired function of NPC1 leads to endolysosomal accumulation of unesterified cholesterol, which results in progressive neurodegeneration. Although the age of onset is variable, classical NPC1 is a pediatric disease.

Prevalence of Neutralizing Antibodies to AAV2 and AAV9 in Individuals with Niemann-Pick Disease, Type C1.

Niemann-Pick disease, type C1 (NPC1), is a rare, fatal neurodegenerative disorder caused by pathological variations in . We and others have previously demonstrated the efficacy of systemic adeno-associated virus (AAV) gene therapy with AAV9 in murine models of NPC1. The presence of neutralizing antibodies (NAbs) caused by natural exposure to wildtype AAVs may impair AAV transduction efficacy and reduce or negate the benefit of gene therapy.

Changes in glycosphingolipid levels in plasma and cerebrospinal fluid of individuals with Lysosomal Free Sialic Acid Storage Disorder.

Lysosomal free sialic acid storage disorder (FSASD) is a rare, multisystem disease caused by biallelic pathogenic variants in , encoding the lysosomal transmembrane sialic acid exporter, sialin. Defective sialin function leads to sialic acid accumulation in lysosomes, contributing to neurodegeneration. While glycosphingolipid (GSL) metabolism is altered in other lysosomal storage disorders, its role in FSASD remains poorly understood, especially due to the restricted availability of biospecimens.

Cerebrospinal Fluid and Serum Neuron-Specific Enolase in Niemann-Pick Disease Type C1.

Niemann-Pick disease, type C1 (NPC1) is an ultra rare, autosomal recessive disorder characterized by impaired intracellular cholesterol trafficking. This study assessed neuron-specific enolase (NSE) as a biomarker for disease status and treatment response in individuals with NPC1. We also evaluated the concordance between serum and cerebrospinal fluid (CSF) NSE measurements.

Assessing Postnatal Mortality in Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder caused by pathological variants in DHCR7, resulting in a deficiency in the enzyme 7-dehydrocholesterol reductase. This results in elevated levels of cholesterol precursors and typically low cholesterol levels, leading to a range of physical and cognitive challenges. Mortality rates in infants with severe SLOS are high, due to congenital malformations.

Elevated cerebrospinal fluid glial fibrillary acidic protein levels in Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is a rare, multiple malformation/intellectual disability disorder caused by pathogenic variants of DHCR7. DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol in the final step of cholesterol biosynthesis. This results in accumulation of 7DHC and a cholesterol deficiency.

Accumulation of alkyl-lysophosphatidylcholines in Niemann-Pick disease type C1.

Lysosomal function is impaired in Niemann-Pick disease type C1 (NPC1), a rare and inherited neurodegenerative disorder, resulting in late endosomal/lysosomal accumulation of unesterified cholesterol. The precise pathogenic mechanism of NPC1 remains incompletely understood. In this study, we employed metabolomics to uncover secondary accumulated substances in NPC1.

Optimization of systemic AAV9 gene therapy in Niemann-Pick disease type C1 mice.

Niemann-Pick disease, type C1 (NPC1) is a rare, fatal neurodegenerative disorder caused by pathological variants in , which encodes a lysosomal cholesterol transport protein. There are no FDA approved treatments for this disorder. Both systemic and central nervous system delivery of AAV9- have shown significant disease amelioration in NPC1 murine models.

Swallowing characterization of adult-onset Niemann-Pick, type C1 patients.

Background: Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal disorder with progressive neurological manifestations, historically recognized as a pediatric disease. However, awareness of the adult-onset (AO) subtype is increasing, often with non-specific symptoms leading to delayed and misdiagnosis. Dysphagia, commonly recognized as a clinical morbidity in NPC1, raises concerns for swallowing safety and aspiration risk.

Sterol O-Acyltransferase 1 (): A Genetic Modifier of Niemann-Pick Disease, Type C1.

Niemann-Pick disease type C1 (NPC1) is a lysosomal disorder due to impaired intracellular cholesterol transport out of the endolysosomal compartment.. Marked heterogeneity has been observed in individuals with the same genotype, thus suggesting a significant effect of modifier genes.

Corrigendum to "Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency".

[This corrects the article DOI: 10.1016/j.ymgmr.

Characterization of seizures and EEG findings in creatine transporter deficiency due to SLC6A8 mutation.

Seizures occur in up to 59% of boys with creatine transporter deficiency (CTD). While seizure phenotypes have been previously described, electroencephalogram (EEG) findings have only been reported in several case reports. In this prospective observational study, we report seizure characteristics and EEG findings in combination with neurobehavioral and SLC6A8 pathogenic variants in twenty males with CTD.

Elevated amyloid beta peptides and total tau in cerebrospinal fluid in individuals with Creatine transporter deficiency.

Background: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aβ peptide containing amyloid plaques and tau neurofibrillary tangles.

Rare disease variant curation from literature: assessing gaps with creatine transport deficiency in focus.

Background: Approximately 4-8% of the world suffers from a rare disease. Rare diseases are often difficult to diagnose, and many do not have approved therapies. Genetic sequencing has the potential to shorten the current diagnostic process, increase mechanistic understanding, and facilitate research on therapeutic approaches but is limited by the difficulty of novel variant pathogenicity interpretation and the communication of known causative variants.

Elevated cerebrospinal fluid ubiquitin C-terminal hydrolase-L1 levels correlate with phenotypic severity and therapeutic response in Niemann-Pick disease, type C1.

Background: Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive disorder due to pathological variants of NPC1. The NPC1 phenotype is characterized by progressive cerebellar ataxia and cognitive impairment. Although classically a childhood/adolescent disease, NPC1 is heterogeneous with respect to the age of onset of neurological signs and symptoms.

Cerebrospinal Fluid Protein Biomarker Discovery in CLN3.

Syndromic CLN3-Batten is a fatal, pediatric, neurodegenerative disease caused by variants in , which encodes the endolysosomal transmembrane CLN3 protein. No approved treatment for CLN3 is currently available. The protracted and asynchronous disease presentation complicates the evaluation of potential therapies using clinical disease progression parameters.

Brain proton MR spectroscopy measurements in CLN3 disease.

Background: CLN3 is an autosomal recessive lysosomal disorder with intracellular accumulation of ceroid-lipofuscins. CLN3 classically has onset around 4-6 years of age involving vision loss, followed by developmental regression and seizures. Symptoms are progressive and result in premature death.

Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1.

: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal storage disorder characterized by the accumulation of multiple lipids in the late endosome/lysosomal system and reduced acidic store calcium. The lysosomal system regulates key aspects of iron homeostasis, which prompted us to investigate whether there are hematological abnormalities and iron metabolism defects in NPC1. : Iron-related hematological parameters, systemic and tissue metal ion and relevant hormonal and proteins levels, expression of specific pro-inflammatory mediators and erythrophagocytosis were evaluated in an authentic mouse model and in a large cohort of NPC patients.

Identification of cerebral spinal fluid protein biomarkers in Niemann-Pick disease, type C1.

Background: Niemann-Pick disease, type C1 (NPC1) is an ultrarare, recessive, lethal, lysosomal disease characterized by progressive cerebellar ataxia and cognitive impairment. Although the NPC1 phenotype is heterogeneous with variable age of onset, classical NPC1 is a pediatric disorder. Currently there are no therapies approved by the FDA and therapeutics trials for NPC1 are complicated by disease rarity, heterogeneity, and the relatively slow rate of neurological decline.