Identification of Niemann–Pick type C disease in the group of ataxias of unclear origin in adults
Authors: Klyushnikov Sergey A. , Proshlyakova Tatiana Yu. , Baydakova Galina V. , Nuzhnyi Evgenii P. , Nikolaeva Natalya S. , Goncharova Zoya A. , Fomina-Chertousova Neonila A. , Degtereva Elena V. , Chernikova Victoria V. , Gorshkova Kristina V. , Artemova Natalya S. , Shperling Larisa P. , Antipova Lyudmila N. , Tsyplugina Olga Yu. , Ivanova Irina L. , Chepkasova Lyubov V. , Illarioshkin Sergey N. 
Published: January 2025

Introduction. NiemannPick type C disease (NPC) is a rare neurovisceral lysosomal storage disease with an autosomal recessie type of inheritance that develops as a result of abnormal intracellular transport of cholesterol and other lipids. The possibility of pathogenetic therapy makes it very important to screen the population and identify new cases of the disease.
Objective. Conducting biochemical and genetic screening in the group of adult patients with early-onset ataxia of unclear origin to detect new cases of NPC, with subsequent initiation of pathogenetic substrate reduction therapy and studies of clinical, genetic and biochemical characteristics the disease.
Materials and methods. Ninety-five persons (1840 years of age), both males and females, from different regions of Russia suffering from primary ataxia of unknown origin, associated with other neurological symptoms and/or visceral and psychiatric disorders, were examined. Patients underwent neurological examination and neuropsychological testing. During biochemical screening, the concentrations of blood plasma oxysterols (cholestane-3,5,6-triol and 7-ketocholesterol) and chitotriosidase were examined. The presence of pathogenic mutations in the NPC1 and NPC2 genes was detected by total sequencing of all exons of these genes.
Results. On biochemical screening, 3 patients were identified whose cholestane-3,5,6-triol concentration and chitotriosidase activity were significantly higher than the reference norm, and 7-ketocholesterol concentration was either higher or at the level of the upper limit of the norm. On sequencing of the NPC1 gene, two unrelated patients (21-year-old woman and 37-year-old man) were found to carry 2 pathogenic compound heterozygous mutations each, and these findings confirm the diagnosis of NPC. The clinical picture was represented by a combination of neurological, psychiatric and visceral symptoms. In both patients, cerebellar ataxia was accompanied by dystonia and other extrapyramidal disorders, as well as vertical supranuclear gaze palsy, and bulbar and pseudobulbar symptoms. There were also affective disorders and progressive cognitive decline up to dementia of the frontal type. Both patients had ultrasound signs of isolated splenomegaly. The score for the NPC suspicion index was 200 points. Thus, in the studied group, NPC was detected in 2.1% of patients.
Conclusions. Biochemical screening of oxysterols and chitotriosidase of blood plasma is a quick and inexpensive method for biochemical diagnosis of NPC, the diagnostic value of which is unquestionable in the case of integrated assessment of the history of the disease, the clinical picture and the results of instrumental diagnostic exams. Adult patients with early-onset ataxia associated with visceral and psychiatric disorders are at risk group for having NPC. They should primarily be sent to screening biochemical studies, and, in case of positive results, to carry out mutation screening of NPC1 and NPC2 genes.