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.
Subject(s)
Niemann-Pick Disease, Type C/diagnosis , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/pathology , Adult , Age of Onset , Bulgaria , Cohort Studies , Female , Humans , Male , Middle Aged , Mutation , Neurologic Examination , Prospective StudiesSubject(s)
Bipolar Disorder/genetics , DNA-Binding Proteins/genetics , Nuclear Proteins/genetics , Polymorphism, Genetic , Age of Onset , Genetic Predisposition to Disease , Humans , Promoter Regions, Genetic , Regulatory Factor X Transcription Factors , Transcription Factors , X-Box Binding Protein 1ABSTRACT
Several studies provide suggestive evidence of a susceptibility locus for bipolar disorder at chromosome 21q22-23. In an attempt to replicate these findings, we have analyzed linkage to 11 polymorphic markers from this region in 18 Bulgarian pedigrees with affective disorder. Two-point linkage analysis under assumption of homogeneity and a dominant model with reduced penetrance produced modest positive values for some of the markers tested under a 'narrow' phenotype definition, including bipolar I and II, and schizoaffective disorder. The maximum two-point score (lod=1.76, theta=0.00) was at marker D21S1919. Non-parametric linkage analysis under the same phenotype model, yielded positive NPLall values (P<0.05) over the region between markers D21S211 and D21S416, with a peak at D21S1252 (NPL Zall=2.32, P=0.0003). The multipoint lod score (GENEHUNTER) reached a suggestive value for linkage (lod=2.10) also at marker D21S1252. The results under a recessive model were completely negative. These data add to the evidence for the existence of a susceptibility locus for bipolar affective disorder on chromosome 21q22.
Subject(s)
Bipolar Disorder/genetics , Chromosomes, Human, Pair 21/genetics , Genetic Predisposition to Disease/genetics , Bulgaria , Canada , Chromosome Mapping , Female , Humans , Jews , Lod Score , Male , Models, Genetic , Pedigree , United StatesABSTRACT
The serotonin transporter (5-HTT) is a suitable candidate gene to test for involvement in the pathogenesis of major psychiatric disorders. We used the method of family-based controls to test for association between disease and a variable number tandem repeat (VNTR) in intron 2 of the gene, which has received support for involvement in the pathogenesis of several psychiatric disorders. We analysed 413 proband-parent trios of Bulgarian origin: 266 had a schizophrenic proband, 103 had a bipolar proband and 44 had a schizoaffective proband. The results were analysed using the extended transmission disequilibrium test. Possible effects of different alleles on certain clinical variables were examined by correlation analysis. Three alleles were detected: STin2.9, STin2.10 and STin2.12. None of the three diagnostic samples showed preferential transmission of alleles that reached conventional levels of statistical significance. We could not confirm previous results that STin2.12 allele increases susceptibility to bipolar disorder type I. The rare STin2.9 showed a non-significant trend for preferential transmission in the sample as a whole: 18 transmitted versus 11 non-transmitted (P = 0.2). The VNTR polymorphism in the 5-HTT gene does not appear to be a major risk factor for increasing susceptibility to major psychiatric disorders.
