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BACKGROUND: Once dystonia or dysmetria occurs in patients with schizophrenia, we usually know that antipsychotics might have induced these involuntary movements. However, some of these patients have severe neurological symptoms to be considered as adverse effects. In fact, we were able to identify probable Niemann–Pick disease type C (NPC) in such patients. NPC is a rare, progressive genetic disorder characterized by the inability of the body to transport cholesterol and other fatty substances (lipids) inside the cells. The symptoms are varied, such as jaundice, splenomegaly, hepatomegaly, vertical supranuclear gaze palsy, cerebellar ataxia, dystonia, dysphagia, resistant psychotic symptoms, and slow-progressive impairment of intellectual ability. NPC is difficult to diagnose, particularly adult-onset NPC. Diagnosis of NPC is confirmed by staining skin cells (fibroblasts) or by bone marrow smears of the affected individual for determining the level of cholesterol accumulation (filipin staining) and identifying known mutations in the NPC1 or NPC2 gene (gene sequencing). Recently, some studies have reported on the probable biomarkers for NPC. In the present study, we measured some biological markers of NPC in plasma and urine. Furthermore, the mRNA expression levels of NPC1 and NPC2, which are pathological genes of NPC, were compared between patients with schizophrenia and normal controls. METHODS: Blood and clinical data were obtained with the approval of the institutional review boards of Dokkyo Medical University School of Medicine. The study design followed the ethical norms of the Ministry of Health, Labor, and Welfare of Japan. We obtained written informed consents from all patients in this study. Five patients with neurological symptoms were evaluated using the NPC Suspicion Index. Furthermore, several biological markers were measured. In addition, mRNA expression levels of NPC1 and NPC2 were measured and analyzed in patients with schizophrenia and healthy controls. We measured bile acid content in urine with LC/MS/MS and serum oxysterol with Q-TOF LC/MS in five patients with neurological symptoms. In addition, whole-genome sequences were analyzed in one patient by a particular company. The mRNA expression levels of NPC1 and NPC2 were measured using the TaqMan method and we performed their semi-quantitative assessment with beta-actin. The Mann–Whitney U test was performed to compare mRNA expression levels between patients with schizophrenia and normal controls by using SPSS Statistics. RESULTS: One patient had significantly high biological marker levels for NPC. No patients without this patient have significantly high biological markers as the disease. The mRNA expression levels of NPC1 and NPC2 in patients with schizophrenia were significantly higher than that in normal controls. DISCUSSION: The mRNA expression levels of both NPC1 and NPC2 in patients with schizophrenia were higher than those in healthy controls. Further investigation is required, including resequencing of NPC1 and NPC2, to understand the implications of the results.

Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep–wake syndrome (N-24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock-gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR-based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferroni’s corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59–38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.