title: Clinical Spectrum and Genetic Variability in Bulgarian Patients with Niemann-Pick Disease Type C.
abstract: BACKGROUND
  Niemann-Pick disease type C (NP-C) is a rare autosomal-recessive lysosomal storage disorder caused by mutations in either the NPC1 (in 95% of cases) or the NPC2 gene.
  
  
  METHODS
  In a prospective, observational cohort study, all Bulgarian patients diagnosed with NP-C to date (since 2010) underwent detailed neurological examination and neuro-ophthalmological, neuropsychological and psychiatric evaluations, as well as brain MRI, abdominal ultrasound and hearing tests. Plasma chitotriosidase was also measured, when possible.
  
  
  RESULTS
  The Bulgarian national NP-C cohort comprised 11 patients who were diagnosed based on molecular genetic analysis (n = 9) and/or filipin staining of skin fibroblasts (n = 3). The mean age at onset was 14.4 (SD 8.3). Diagnoses were achieved 1-23 years after initial clinical presentation. All patients who underwent genetic mutation analysis were compound heterozygotes: a total of 12 NPC1 mutations were recorded, 5 of which were novel. Two patients had late-infantile onset, 4 had juvenile onset, and the remaining 5 had the adult-onset form of NP-C. Initial symptoms were neurological in 9 patients, visceral in one, and predominantly psychiatric in another. Vertical gaze palsy was present in all patients. Dysarthria, pyramidal involvement, cognitive impairment, and organomegaly with varied severity were observed in 10 of them. Ataxia was present in 9 and dystonia in 7. Four patients had epileptic seizures, and gelastic cataplexy was reported in 5. Brain MRI revealed hyperintense white matter lesions in 5 patients and cortical and/or cerebellar atrophy in 4.
  
  
  CONCLUSIONS
  This Bulgarian NP-C cohort showed wide variability in terms of NPC1 mutations and predominant forms of neurological involvement. Diagnosing NP-C is challenging, and it was often delayed in this cohort due to the heterogeneity of patients' clinical signs and symptoms.
authors.affiliation: Department of Neurology, Sofia Medical University, Sofia, Bulgaria.
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.forename: Andrey
authors.initials: A
authors.lastname: Kirov
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Tihomir
authors.initials: T
authors.lastname: Todorov
authors.forename: Veneta
authors.initials: V
authors.lastname: Bojinova
authors.forename: Sashka
authors.initials: S
authors.lastname: Zhelyazkova
authors.forename: Jean
authors.initials: J
authors.lastname: Samuel
authors.forename: Melania
authors.initials: M
authors.lastname: Radionova
authors.forename: Stayko
authors.initials: S
authors.lastname: Sarafov
authors.forename: Sylvia
authors.initials: S
authors.lastname: Cherninkova
authors.forename: Stefan
authors.initials: S
authors.lastname: Krastev
authors.forename: Albena
authors.initials: A
authors.lastname: Todorova
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
mesh_terms: D000328:Adult; D017668:Age of Onset; D002031:Bulgaria; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009460:Neurologic Examination; D052556:Niemann-Pick Disease, Type C / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology*; D011446:Prospective Studies