Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively.Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes.Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected.We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.
Various studies have used stem cells in the field of bone tissue engineering to repair bone defects. Dental pulp stem cells (DPSCs) have multipotent properties and can be acquired in a noninvasive manner; therefore, they are frequently used in experiments in regenerative medicine. The objective of this study was to investigate the odontogenic/osteogenic differentiation of human DPSCs (hDPSCs) using propofol, a widely used intravenous anesthetic agent. Alkaline phosphatase (ALP) staining was used to investigate the effects of various concentrations of propofol (5, 20, 50 and 100 μM) on the osteogenic differentiation of hDPSCs. Real-time qPCR and Western blot analysis were used to detect the effect of propofol on the expression of odontogenic/osteogenic genes, such as DMP1, RUNX2, OCN, and BMP2. Odontogenic/osteogenic differentiation of hDPSCs was estimated at days 7 and 14. ALP staining of hDPSCs was significantly decreased by propofol treatment. The mRNA expression of DMP1, RUNX2, OCN, and BMP2 decreased after propofol treatment for 14 days. The protein expression of DMP1 and BMP2 was decreased by propofol at days 7 and 14, and that of RUNX2 was decreased by propofol at day 14 only. Propofol attenuated odontogenic/osteogenic differentiation of hDPSCs in vitro. This result suggests that propofol, which is widely used for dental sedation, may inhibit the odontogenic/osteogenic differentiation of hDPSCs.
This study aimed to determine the underlying pathogenesis of Meniere's disease (MD) using transcriptome analysis.Total RNA was extracted from the peripheral blood mononuclear cells of 39 patients with MD and 39 controls. Through microarray analysis for nine patients and controls, the differentially expressed genes (DEGs) of those two groups were screened based on cut-off criteria (|fold changes| > 2.0 and adjusted p-value < 0.05). The functional enrichment analysis of DEGs was performed using Gene Ontology (GO).There were 996 DEGs identified in the MD group: 415 were upregulated and 581 were downregulated. A functional enrichment analysis indicated that the downregulated DEGs were significantly enriched in terms related to immune system processes. Among them, 17 genes were enriched in terms for the major histocompatibility complex (MHC) protein complex, and the relative messenger RNA (mRNA) levels of three markedly downregulated DEGs [fold changes < -5: human leukocyte antigen (HLA)-DMA, HLA-DRB1, and HLA-DPB1] were significantly decreased in another 30 patients with MD compared with normal controls by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). However, there were no correlations between the expression levels of these three genes and clinical data, such as age, onset age, time course, or hearing threshold.Our transcriptome analysis showed that the downregulated DEGs in MD were mainly associated with the immune system pathways including the MHC protein complex in MD. Remarkably, a breakdown in immunological tolerance mediated by MHC class II may contribute to the MD development, which has implications for targeted treatment.
The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between CSF Aβ 1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer’s disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aβ 1-42 , t-tau, and p-tau levels were analyzed in 203 individuals [27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases] consecutively recruited from two dementia clinics. We used both visual and standardized uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aβ 1-42 and t-tau/Aβ 1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aβ 1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aβ 1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aβ 1-42 . However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aβ 1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aβ 1-42 and amyloid PET, baseline CSF Aβ 1-42 better predicted AD conversion.
To analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations.Twenty-three patients with prepubertal NS treated at Pusan National University Children's Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11, RAF1, and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11, RAF1, SOS1, KRAS, and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy.The mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11, RAF1, and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group.The 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11, RAF1, and SOS1 groups.
Myotonia congenita (MC) is a form of nondystrophic myotonia caused by a mutation of CLCN1, which encodes human skeletal muscle chloride channel (CLC-1).We performed sequence analysis of all coding regions of CLCN1 in patients clinically diagnosed with MC, and identified 10 unrelated Korean patients harboring mutations.Detailed clinical analysis was performed in these patients to identify their clinical characteristics in relation to their genotypes.The CLCN1 mutational analyses revealed nine different point mutations.Of these, six (p.M128I, p.S189C, p.M373L, p.P480S, p.G523D, and p.M609K) were novel and could be unique among Koreans.While some features including predominant lower extremity involvement and normal to slightly elevated creatine kinase levels were consistently observed, general clinical features were highly variable in terms of age of onset, clinical severity, aggravating factors, and response to treatment.Our study is the first systematic study of MC in Korea, and shows its expanding clinical and genetic spectrums.
Background: Infantile nystagmus syndrome (INS) is a genetically heterogeneous disorder. Identifying genetic causes of INS would help clinicians to facilitate clinical diagnosis and provide appropriate treatment. The aim of this study was to determine the diagnostic utility of targeted next-generation sequencing (NGS) for INS.Materials and methods: We recruited 37 patients who were referred to the Neuro-ophthalmology clinics for evaluations of INS. NGS was performed using a targeted panel that included 98 candidate genes associated with INS. We identified pathogenic variants according to guidelines of the American College of Medical Genetics and Genomics. We also calculated the sensitivity and specificity of each clinical sign to assess the diagnostic yield of our gene panel.Results: After variant filtering, annotation, and interpretation, the potential pathogenic variants were detected in 13 of the 37 patients, achieving a molecular diagnostic rate of 35%. The identified genes were PAX6 (n = 4), FRMD7 (n = 4), GPR143 (n = 2), CACNA1F (n = 1), CNGA3 (n = 1) and GUCY2D (n = 1). In approximately 30% (n = 4) of the patients, the initial clinical diagnosis was revised after a molecular diagnosis was performed. The presence of a family history had the highest predictive power for a molecular diagnosis (sensitivity = 61.5%, specificity = 91.7%), and the sensitivity increased when the family history was considered together with one of two clinical signs such as pendular nystagmus waveforms or anterior segment dysgenesis.Conclusions: Our study shows that targeted NGS can be useful to determine a molecular diagnosis for patients with INS. Targeted NGS also helps to confirm a clinical diagnosis in atypical phenotypes or unresolved cases.
Received December 29, 2005 Accepted February 27, 2006 *Dae-Seong Kim, M.D., Ph.D. Department of Neurology, Pusan National University Hospital 10 Amidong-1ga, Seo-gu, Busan, 602-739, Korea Tel: +82-51-240-7672 Fax: +82-51-245-2783 E-mail: dskim@pusan.ac.kr Myoadenylate deaminase (muscle AMP deaminase; 이하 AMPD) 결핍은 대사성근육병의 가장 흔한 원인으로 알려져 있 다. 환자의 상당수는 운동에 의해 유발되는 근육경련이나 근육 통(exercise-induced muscle cramps or myalgia)을 호소하 는데, 격렬한 운동을 하여도 혈중 암모니아가 증가되지 않을 때 임상적으로 AMPD 결핍을 의심할 수 있다. 상염색체 열성으로 유전되는 AMPD 결핍은 대부분 AMPD1 유전자의 엑손 2에 존 재하는 34번 염기 cytosine이 thymidine으로 치환(c.34 C>T) 되어 12번째 아미노산인 글루타민이 정지 코돈으로 변하는 무 의미돌연변이(nonsense mutation)에 의해 발병하는데 흥미롭 게도 백인이나 흑인들의 경우 c.34 C>T의 돌연변이 대립유전 자가 인구의 12~18%에서 발견되며 무려 2% 정도가 돌연변이 대립유전자의 동형접합체(homozygote)라는 사실이 알려져 있 다. 이에 저자들은 한국인 AMPD1 유전자의 c.34 C>T 돌연변 이 대립유전자 빈도를 알아보고자 본 연구를 시행하였다.
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