Niemann-Pick Disease, Type C1 (NPC1) is a neurodegenerative lysosomal disease in which the first manifestation is often cholestatic liver disease at birth. The neurodegenerative symptoms typically manifest later. The aim of this study was to see if the presence and severity of liver disease at birth predicted whether a participant would develop liver disease later and if there was any correlation with the age of onset of neurological symptoms. Liver disease was characterized in 93 individuals with NPC1 using FibroScan, abdominal ultrasound, and plasma liver function tests at baseline and longitudinally over up to a four-year period. This information was correlated with the presence or absence of liver disease noted at birth. Higher liver stiffness measurement scores, suggesting increased risk for liver fibrosis, were associated with a history of significant liver disease in infancy (p = 0.001). A history of absent or mild/moderate liver disease at birth had no correlation with differences in liver stiffness measurements The presence of any degree of liver disease at birth corresponded to earlier onset of neurological symptoms compared to having no liver disease at birth (p = 0.002). Those with no history of neonatal liver disease had an average age of 10.3 years at time of neurological symptoms, compared to 5.9 years for those with mild/moderate disease and 3.6 years for those with severe disease (p = 0.002). The presence of liver disease at birth can provide prognostic information on when individuals with NPC1 may manifest neurologic symptoms. In addition, individuals who had severe liver disease at birth are at higher risk for developing clinically significant liver disease after the neonatal period. Given multiple reports of hepatocellular carcinoma in individuals with NPC1, those with a history of severe liver disease should be closely monitored.

When patients with schizophrenia on antipsychotic medication present neurological symptoms, it is often considered to be side effects of antipsychotics. In contrast, Niemann-Pick disease type C (NPC) has a wide variety of symptoms, and the diagnosis of adult-onset NPC is difficult. In this study, we measured novel biomarkers of NPC and examined the possibility of NPC in patients diagnosed with schizophrenia. Five patients with schizophrenia and neurological symptoms were evaluated using the NPC Suspicion Index, and urinary bile acid and blood oxysterol levels were measured by LC-MS/MS and Q-TOF LC/MS. Lysosphingomyelin (SPC) and Lyso-SM-509(PPCS), reported as novel biomarkers for NPC, were measured in the plasma of 163 patients with schizophrenia and 111 healthy controls using LC-MS/MS. NPC1 and NPC2 gene analyses were performed on 124 patients using the next-generation sequencer. In one patient, Filipin staining was performed using skin fibroblasts. Among the five patients, one patient had an abnormal urinary bile acid level. Levels of SPC were significantly higher in patients than in healthy controls. Genetic analysis revealed no genetic mutations associated with the etiology. The patient who underwent Filipin staining had cholesterol-stained pale and was determined to be a variant type. However, it would be more accurate to state that no patients were identified as NPC based on these biomarkers. Among the patients with schizophrenia, there were no cases that were definitively diagnosed as NPC, but some patients had features of NPC. It is important to evaluate mental and neurological symptoms in light of this possibility. Niemann-Pick disease type C (NPC) is a slowly progressive lysosomal disorder in which the principal manifestations are age dependent. Perinatal period and infancy: The initial presentation is predominantly visceral with hepatosplenomegaly, cholestatic jaundice, and (in some instances) pulmonary infiltrates. Many infants succumb at this stage; however, of those who survive, some are hypotonic and have delayed psychomotor development, whereas others may have complete resolution of disease manifestations, only to present with neurologic disease many years later. Mid- to late childhood onset: The initial presentation is dominated by neurologic manifestations. The youngest children may present with hypotonia and developmental delay, with the subsequent emergence of ataxia, dysarthria, dysphagia, and, in some individuals, epileptic seizures, dystonia, and gelastic cataplexy. Although cognitive impairment may be subtle at first, it eventually becomes apparent as progressive dementia. Death from aspiration pneumonia usually occurs in the late second or third decade. Adolescent to adult onset: The initial presentation may be neurologic manifestations like those in childhood, but with a much slower rate of progression and longer life expectancy. In others, the initial presentation can be predominantly early-onset dementia or psychiatric manifestations. The diagnosis of NPC is established in a proband with suggestive findings and biallelic pathogenic variants in either NPC1 or NPC2 identified by molecular genetic testing. Targeted therapies: Treatment for the neurologic manifestations of NPC can include miglustat (approved in several countries but not currently FDA approved for standalone treatment of NPC), arimoclomol (approved for use in combination with miglustat), and levacetylleucine (standalone treatment approved by FDA). Supportive care: No curative therapy for NPC exists. Supportive therapy is provided by specialists from multiple disciplines including neurology, physical therapy, occupational therapy, speech therapy, nutrition, feeding, psychology, social work, and clinical genetics. Surveillance: Regularly scheduled follow up is recommended for multidisciplinary specialists to monitor disease progression, emergence of new disease manifestations, and response to supportive management including psychosocial support. For those on miglustat therapy, regularly scheduled follow up is recommended to monitor adherence, side effects, and conditions that would prompt discontinuation of therapy. Agents/circumstances to avoid: Drugs that cause excessive salivation or may exacerbate seizures directly by interacting with anti-seizure medication; alcohol as well as many drugs that exacerbate ataxia. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk sibs of an affected individual in order to identify as early as possible those who might benefit from targeted therapy for NPC. NPC is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an NPC-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes may manifest clinical and biochemical abnormalities. Once the NPC-causing pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

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. Identification of biomarkers that correlate with clinical phenotype and respond to therapeutic interventions will be essential for developing effective therapeutic interventions. Aβ peptides and Tau protein are primary components of amyloid plaques and neurofibrillary tangles, respectively, which are major pathological features in neurodegenerative disorders. Cerebrospinal fluid (CSF) levels of total Tau, a biomarker of axonal damage, were elevated ~3-fold (p < 0.0001) in 106 individuals with Niemann-Pick disease, type C1, relative to age-appropriate comparison samples. Baseline CSF total Tau levels correlated with clinical measures of disease severity. Specifically, CSF total Tau levels decreased with increased age of neurological onset (rs = -0.42, FDR adj. p < 0.0001) and increased with increased Annual Severity Increment Score (rs = 0.52, FDR adj. p < 0.0001). Baseline CSF total Tau levels were decreased 40% (p = 0.0066) in individuals being treated with miglustat, and longitudinal analysis substantiated this observation with a 40% decrease (p < 0.0001, 95% CI 32%-47.4%). Longitudinal analysis also showed a significant (p = 0.004) decrease of 19% (95% CI 7%-30%) in total Tau levels associated with intrathecal 2-hydroxypropyl-β-cyclodextrin therapy. These data show that CSF total Tau levels are significantly increased in individuals with NPC1, positively correlated with increased disease severity, and respond to therapeutic interventions.

Niemann-Pick Disease Type C (NPC) is an ultra-rare disorder characterized by progressive psychiatric and neurologic manifestations, with late infantile, juvenile, and adolescent/adult presentations. We examined morphological properties of the choroid plexus, a protective blood-cerebrospinal fluid barrier, in NPC, and their relationship with neurodegeneration, clinical status, and circulatory markers. This study also determined whether choroid plexus morphology differentiates between NPC and more prevalent illnesses, schizophrenia (SZ) and bipolar disorder (BD), which have overlapping psychiatric symptoms with adolescent and adult-onset NPC and are associated with misdiagnosis. Patients with NPC were assessed using neuroimaging, clinical instruments, and plasma protein quantification focusing on inflammatory markers. Morphological properties (i.e., choroid plexus volumes) were compared between patients with NPC (n = 17), SZ (n = 20), BD (n = 24), and healthy controls (HCs, n = 106). Choroid plexus enlargement (p < 0.05) and reduced thalamic volumes (p < 0.05) were observed in NPC patients versus HCs and SZ or BD patients. A logistic regression model with choroid plexus and thalamic volumes as predictors yielded high prediction accuracy for NPC vs. HCs, NPC vs. SZ, and NPC vs. BD (area under the receiver operating characteristics curve [AUROC] of 1). Choroid plexus volumes were negatively correlated with left (p = 0.009-0.012) and right (p = 0.007-0.025) thalamic volumes, left (r = -0.69, p = 0.003) and right (r = -0.71, p = 0.002) crus I of the cerebellum, and greater severity on the NPC-Suspicion Index psychiatric subscale (ρ = 0.72, p = 0.042). Targeted protein expression quantification revealed differential expression of TGFA, HLA-DRA, TNFSF12, EGF, INFG, and IL-18 in NPC patients vs. HCs (p < 0.05), with higher choroid plexus volumes correlating with IL-18 levels (ρ = 0.71, p = 0.047). The choroid plexus may play a critical role in NPC neuropathogenesis and serve as a novel biomarker for monitoring neurodegenerative and inflammatory processes in NPC.

In search of disease-modifying treatments for the Niemann-Pick disease type C (NPC), this Phase II single-arm clinical trial evaluated the safety and efficacy of efavirenz, a reverse transcriptase inhibitor that potentially ameliorates neuronal cholesterol turnover, typically impaired in this rare lysosomal storage disorder. Patients 14 years of age or older with genetically confirmed NPC received efavirenz 25 mg/day (Weeks 1-26) or 100 mg/day (Weeks 27-52) orally on top of standard care including miglustat. The primary endpoint was the proportion of response, defined as lack of deterioration in a composite outcome of cognitive performance. Secondary endpoints included the quantitative scores of several clinical neuropsychological assessment tools, some relevant neurological signs and symptoms, and imaging and biological specimen-based biomarkers. Measures were taken repeatedly over time and were analyzed using generalized linear mixed models. Sixteen patients 15-60 years of age were enrolled. All (100.0 %, 95 % exact confidence interval: 79.4-100.0 %) met the primary endpoint response criterion at Week 52. Quantitative neuropsychological assessments yielded more nuanced results, with relative preservation of learning, memory and executive control, and subtle impairments of verbal fluency, selective and divided attention, and cognitive inhibition. Some patients had better responses than others, allowing us to set two well-differentiated subgroups that differed essentially in the time since symptoms onset. No efavirenz-related or serious adverse events were reported. Efavirenz appears to be a safe, easy-to-use, new targeted therapeutic option which slows the rate of NPC progression. The benefits of efavirenz are greater if started earlier. Registered on the European Union Clinical Trials Register (EurdraCT) on December 20th, 2019 under the number: 2019-004498-18 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004498-18/ES/). The first patient was enrolled on May 25th, 2022.