Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.

Ollier disease (OD) and Maffucci Syndrome (MS) are rare disorders characterized by multiple enchondromas, commonly causing bone deformities, limb length discrepancies, and pathological fractures. MS is distinguished from OD by the development of vascular anomalies. Both disorders are cancer predisposition syndromes with malignancies developing in ~50% of the individuals with OD or MS. Somatic gain-of-function variants in IDH1 and IDH2 have been described in the enchondromas, vascular anomalies and chondrosarcomas of approximately 80% of the individuals with OD and MS. To date, however, no investigation of germline causative variants for these diseases has been comprehensively performed. To search for germline causative variants, we performed whole exome sequencing or whole genome sequencing of blood or saliva DNA in 94 unrelated probands (68 trios). We found that 7 had rare germline missense variants in HIF1A, 6 had rare germline missense variants in VHL, and 3 had IDH1 variants including 2 with mosaic IDH1-p.Arg132His variant. A burden analysis using 94 probands assigned as cases and 2,054 unrelated individuals presenting no OD- or MS-related features as controls, found that variants in HIF1A, VHL, and IDH1 were all significantly enriched in cases compared to controls. To further investigate the role of HIF-1 pathway in the pathogenesis of OD and MS, we performed RNA sequencing of fibroblasts from 4 probands with OD or MS at normoxia and at hypoxia. When cultured in hypoxic conditions, both proband and control cells showed altered expression of a subset of HIF-1 regulated genes. However, the set of differentially expressed genes in proband fibroblasts included a significantly reduced number of HIF-1 regulated genes compared to controls. Our findings suggest that germline or early post-zygotic variants identified in HIF1A, VHL, and IDH1 in probands with OD and MS underlie the development of the phenotypic abnormalities in a subset of individuals with OD and MS, but extensive functional studies are needed to further confirm it.

Preliminary analysis of Huntington's Disease in South Korea.

BACKGROUND: There have been epidemiological studies of Huntington's disease (HD) in various populations and nations. Only a few studies describing clinical characteristics have been reported in Asia. OBJECTIVE: To conduct preliminary analyses of demographic, clinical and genetic characteristics of HD in South Korea. METHODS: From 1994 to 2011, thirty six subjects were diagnosed as HD in Seoul National University Hospital. Demographic, clinical and genetic data were carefully analyzed in all subjects. RESULTS: Mean age of onset was 46.5 ± 12.7 years and mean expanded CAG repeat size was 45.4 ± 4.7. Twenty-eight subjects (80%) had a family history of HD. Chorea was the most frequent symptom at first visit (89%). Proportion of cognitive decline (36%) and psychiatric symptom (28%) at first visit were lower than proportion of previous reports. A negative correlation (Pearson correlation coefficient -0.757, p = 0.001) was found between expanded CAG repeat size and age of onset. Seven subjects without family history of HD had higher mean age of onset (54.0 ± 8.1) and smaller expanded CAG repeat size (42.4 ± 2.7). Cognitive problems at first visit of subjects without family history were more prominent than those with family history (86% vs. 25%). CONCLUSIONS: This study is the first demographic, clinical and genetic analyses in South Korea. These results will be helpful to stimulate more large-scale research in South Korea and other Asian nations.

Association between parkinsonism and participation in agriculture in Korea.

BACKGROUND AND PURPOSE: Environmental factors might influence the pathogenesis of Parkinson's disease (PD) or multiple-system atrophy (MSA), and previous examinations of pesticide exposure, well-water drinking, and farming have produced inconclusive results. Because agriculture has been of considerable importance to Korean society, and hence the risk of exposure to pesticides was high in Korea, this study investigated whether such exposure is associated with elevated risks of developing PD and MSA. METHODS: Two hundred and thirty-five PD patients, 133 MSA patients, and 77 normal control subjects were examined. Data concerning environmental factors were collected by face-to-face interviews using a structured questionnaire. Odds ratios (ORs) were calculated by binary logistic regression. RESULTS: ORs for environmental risk factors for developing PD were 1.06 [95% confidence interval (CI) = 1.02-1.10] for age and 2.37 (95% CI = 1.32-4.27) for rural well-water drinking for >10 years. Smoking >10 pack-years (OR = 0.31; 95% CI = 0.11-0.64) was a preventable factor for developing PD in this study. However, no significant risk factors were identified for MSA. CONCLUSIONS: These results suggest that exposure to certain environmental risk factors plays a role in the development of PD. However, the development of MSA appears to be independent of environmental risk factors in Korean patients.

Importance of low-range CAG expansion and CAA interruption in SCA2 Parkinsonism.

OBJECTIVES: To examine the presence of an ATXN2 mutation in patients with parkinsonism in the Korean population and to find the difference in the ATXN2 mutation between ataxic and parkinsonian phenotypes. DESIGN: Survey. SETTING: Seoul National University Hospital (a referral center). Patients Patients with Parkinson disease (PD) (n = 468) and the Parkinson variant of multiple system atrophy (MSA-P) (n = 135) who were seen at our Department of Neurology during the past 3 years. MAIN OUTCOME MEASURES: CAG expansion in spinocerebellar ataxia type 2 (SCA2) alleles was assessed by polymerase chain reaction amplification and fragment analysis, and its size and interruption were verified by cloning and sequencing. SCA2 was tested also in the family members of the probands. Striatal dopamine transporter (DAT) and D(2) receptor status were evaluated in the probands and their SCA2-positive family members using iodine I 123 [(123)I]-radiolabeled fluoropropyl (FP) 2-carbomethoxy-3-(4-iodophenyl) tropane (CIT) with single-photon emission computed tomography (SPECT) and carbon C 11 [(11)C]-radiolabeled raclopride positron emission tomography (PET). RESULTS: We found 3 patients with apparently sporadic disease with expanded CAG repeats in the ATXN2 locus. Two patients had a PD phenotype. The third patient showed an MSA-P phenotype. The CAG repeats in the ATXN2 locus of the patients were 35/22, 34/22, and 32/22, respectively (range in normal population, 19-27). The size of repeats was lower than the CAG repeats (38-51) in ataxic SCA2 in our population. The sequence of expanded CAG repeats was interrupted by CAA as (CAG)(n)(CAA)(CAG)(8) in all the patients. DNA analyses in 2 families showed 2 asymptomatic carriers in each family. In the patient with the PD phenotype, striatal DAT loss was more severe in the putamen than the caudate, and [(11)C]raclopride PET showed an increased relative putamen-caudate binding ratio. The patient with the MSA-P phenotype had severe DAT loss throughout the striatum. Two of 3 asymptomatic carriers had striatal DAT loss. CONCLUSIONS: This study demonstrates that SCA2 is one of the genetic causes of PD and MSA-P. All 3 patients had apparently sporadic disease, emphasizing the need to screen even in patients with nonfamilial disease. CAG repeats were in the low expansion range and interrupted by CAA in all patients in the low-range expansion. Therefore, accurate determination of CAG expansion and ATXN2 sequencing are warranted. [(123)I]FP-CIT SPECT and [(11)C]raclopride PET provide a useful way to evaluate the degree of nigrostriatal dopaminergic damage in SCA2-related parkinsonism and gene carriers.