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.

Niemann-Pick type C (NPC) is a rare, autosomal recessive, neurodegenerative disorder caused by biallelic pathogenic variants in the NPC1 or NPC2 genes, leading to lysosomal lipid accumulation. NPC has an incidence of 1 in 100,000 live births and presents with a wide range of symptoms affecting visceral organs and the central nervous system. We aim to describe the diverse clinical presentations of NPC through case studies. We report seven NPC patients from five families, showcasing the variability in clinical manifestations. The most common finding was hepatosplenomegaly (70 %), followed by prolonged jaundice (57 %) and neonatal cholestasis. Pulmonary alveolar proteinosis (PAP) was observed in three patients with biallelic pathogenic variants in the NPC2 gene. Neurological symptoms, including vertical gaze palsy and epilepsy, were noted in patients with juvenile onset form. Genetic analyses identified a novel homozygous c.315del (p.Thr106ProfsTer5) variant in the NPC2 gene, associated with early infantile onset. NPC presents with diverse clinical findings across ages. Early hepatic symptoms in infants and neuropsychiatric issues in older patients warrant a high index of suspicion for NPC in such cases. A multidisciplinary approach is crucial for patient management, and further research is needed to clarify genotype-phenotype relationships in NPC.

Niemann-Pick type C (NPC) disease is a lysosomal storage disease with visceral organ involvement and neurological and psychiatric symptoms. This study presents the clinical and laboratory findings of NPC cases involving three novel variants. The clinical and laboratory findings were reviewed retrospectively between February 2006 and December 2022. There were nine females and five males. The median age of diagnosis of the patients was 5 months (range: 1 month to 38 years). The clinical phenotypes of the patients were early infantile (n = 7), late infantile (n = 4), juvenile (n = 2), and adult (n = 1). The visceral findings were splenomegaly (100%), hepatomegaly (78.6%), neonatal jaundice (42.8%), and hepatic failure (14.3%). The neurological findings were developmental delay (71.4%), seizures (50%), vertical supranuclear gaze palsy (28.6%), ataxia (28.6%), dysarthria (28.6%), dysphagia (21.4%), dystonia (21.4%). Cataplexy (14.3%) and psychiatric manifestations (14.3%) were recorded in juvenile and adult-onset patients. Three novel variants were detected (p.Asn524LysfsTer39, p.Val1023Phe, and p.Asn906Tyr). Miglustat treatment was received by 64.3% of patients but had no clear effect on the disease course. The median duration of use was 3 years (with a range from 1-13 years). Miglustat's adverse effects were low platelet count (35.7%) and diarrhea (7.1%). Niemann-Pick type C disease should be considered in the presence of visceral organ involvement and progressive neurological findings. It is essential to support the diagnosis with laboratory and genetic analysis.

Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for 'swallowing' and 'seizure'. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Niemann Pick type C is an autosomal recessive lysosomal storage disorder caused by mutations in NPC1 and NPC2 genes. It is a neuro-visceral disease with a heterogeneous phenotype. Clinical features depend on the age at onset. Visceral manifestations are more prominent in the early onset (infantile) form, while neuro-psychiatric symptoms are more prominent in the late disease onset (juvenile and adult forms). A total number of 150 patients have been screened for changes in NPC1 and NPC2 gene at the Neurology Clinic, University Clinical Centre of Serbia in the period 2012-2020. Clinical data were extracted for patients with biallelic mutations. Fifteen patients carried biallelic mutations in the NPC1. Out of eight different reported NPC1 variants, four are novel (c.1204_1205TT>GC, p.F402A; c.2486T>G, p.L829R; c.2795+5 G>C; c.3722T>A, p.L1241*). The mean age at the disease onset was 20.3 ± 11.9 years with the average diagnostic delay of 7.7 ± 4.3 years. Movement disorders and psychiatric or cognitive disturbances were the most common initial symptoms (in 33% and 28% patients, respectively). The average age at the first neurological manifestation was 21 ± 12.0 years. At the last examination, eye movement abnormalities (vertical slow saccades or vertical supranuclear gaze palsy), and ataxia were present in all patients, while dystonia was common (in 78.6% of patients). Presence of c.2861C>T, p.S954L mutation in homozygous state was associated with older age at the neurological symptom onset. Clinical findings were in line with the expected, but the diagnostic delay was common. We hypothesize that the presence of c.2861C>T, p.S954L mutation may contribute to the phenotype attenuation.