Novel GALC Mutations Cause Adult-Onset Krabbe Disease With Myelopathy in Two Chinese Families: Case Reports and Literature Review.

Krabbe disease (KD), also referred to as globoid cell leukodystrophy, is a rare autosomal recessive lysosomal storage disorder caused by ß-galactocerebrosidase (GALC) deficiency. Most patients affected by this disease are infants, and <10% of cases suffer from adult-onset KD. In this study, two Chinese males presented with long-term progressive weakness in their limbs. Magnetic resonance imaging of the brain and spinal cord of these patients revealed lesions with abnormally high signal intensity on T2-weighted (T2W) and T2W fluid-attenuated inversion recovery images. Whole-exome sequencing was performed for both patients, and four GALC mutations were identified. Case 1 carried a novel deletion mutation (p.T633Tfs*2) and a known missense mutation (p.T529M), while case 2 carried a novel missense mutation (p.W355C) and a known missense mutation (p.P154H). Previous literature has rarely reported myelopathy in patients with KD; in this study, we report two cases of adult-onset KD who both experienced myelopathy. We also conducted a literature review of KD and its association with myelopathy. Our findings provide a better understanding of the phenotypic and genotypic profiles associated with adult-onset KD. We recommend that physicians consider KD as a possible diagnosis in cases showing progressive motor dysfunction or gait disorder in association with typical myelopathy.

The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

Genetic analysis of N6-methyladenosine modification genes in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease with a relatively unclear etiology. Previous studies have shown that N6-methyladenosine (m6A) is a vital RNA modification enriched in brain tissue, and that the genes involved in m6A modification are implicated in various neurologic diseases. Here, we conducted a comprehensive genetic analysis using targeted sequencing with molecular inversion probes (MIPs) to identify m6A-modification genes (including METTL3, METTL14, WTAP, FTO, ALKBH5, YTHDF1, YTHDF2, YTHDF3, HNRNPC, and ELAVL1) in a total of 1647 sporadic PD patients and 1372 controls of Han Chinese origin. PD patients were divided into early-onset PD (EOPD) and late-onset PD (LOPD) based on whether the onset of motor symptoms occurred before or after 50 years of age. Rare variants were subjected to gene-based burden tests and common variants were subjected to single-variant association analyses. As a result, we identified 214 rare variants in all 10 m6A-modification genes and 16 common variants in 7 genes. Gene-wise association analyses of rare variants in each m6A-modification gene did not achieved a p value of less than 0.05 in either total cohorts or 2 age groups. In fact, p values greater than 0.05 were found when conducting single-variant association analyses on common variants of these genes between PD and control patients. Our comprehensive analyses of m6A-modification genes suggest that there is no significant association between these 10 m6A-modification genes and the risk of sporadic PD.

Engineering Properties of Engineered Cementitious Composite and Multi-Response Optimization Using PCA-Based Taguchi Method.

The engineered cementitious composite (ECC) mixtures were prepared with Portland cement, ground fly ash, silica sand, and polyvinyl alcohol (PVA) fibers. Accordingly, four mix design factors with five levels each were designed using the Taguchi method. The engineering properties of ECC (flow expansion, compressive strength, flexural strength, charge passed, and maximum freeze-thaw cycle) were evaluated, and the single-response optimizations were conducted separately. Unlike other studies assigning a relative weighting parameter to each response, the principal component analysis (PCA) was innovatively introduced to optimize the ECC's multiple responses so that the single principal performance was obtained from the most objective perspective. Furthermore, the weighting parameters for utility concept were determined by the PCA. Thereafter, an optimum mix formulation was estimated using the PCA-based Taguchi method and the updated utility concept, which provided the most desired balance of these engineering properties. Finally, the contribution of each mix design factor to the principal performance of ECC was examined, and the estimated mix formulation was verified via an additional experiment.

Investigation on the Failure Behavior of Engineered Cementitious Composites under Freeze-Thaw Cycles.

This paper investigates the freeze-thaw performance of engineered cementitious composites (ECC) reinforced with polyvinyl alcohol (PVA) fibers, by applying an innovative criterion for judging the specimen's working state mutation. The ECC materials are prepared into 25 mixtures using the Taguchi method. Then, the fundamental transverse frequency, the flexural performance and the internal strain variation of ECC specimens subjected to freeze-thaw cycles are measured. Unlike the existing studies, this investigation focuses on the failure behavior of ECC materials in the process of freeze-thaw. The Mann-Kendall (M-K) criterion is introduced to detect the ECC specimen's working state leap feature, leading to the updated definition of frost-induced failure concept. Furthermore, the three-level model for evaluating the freeze-thaw performance of ECC materials is established according to the revealed essential leap feature. Thus, the effect of each individual mix design factor on the frost-induced failure indices is perceived from the signal-to-noise (S/N) ratio analysis and the analysis of variance (ANOVA). Finally, a mix formulation estimated based on Taguchi method is recommended for its optimum resistance against frost-induced failure, which is verified by the confirmation experiment.

Association of HIF1A and Parkinson's disease in a Han Chinese population demonstrated by molecular inversion probe analysis.

Parkinson's disease (PD) is a common neurodegenerative disorder with multiple factors contributing to disease pathogenesis. Previous studies implicated the involvement of the transcription factor hypoxia inducible factor 1 alpha (HIF1A) in PD through its transcriptional regulation of PD-associated genes. This study uses molecular inversion probes (MIPs) followed by high-throughput sequencing for the genetic analysis of HIF1A in a large cohort including 1692 ethnic Han Chinese PD patients and 1419 neurologically normal control subjects matched for age, gender, and ethnicity. Common HIF1A variant rs11549465 was found to be associated with increased late-onset PD (LOPD) risk (OR (95%CI) = 1.531(1.068-2.194), P = 0.03828 for trend test, P = 0.03948 for analyses using the allelic model and P = 0.04196 for logistic regression analyses (sex + age as covariates)). Though the gene-based variants burden test is negative, seven rare non-synonymous, predicted-pathogenic point variants were identified. In conclusion, our study further indicates that HIF1A plays a role in PD pathogenesis.

Genetic analysis of DNA methylation and hydroxymethylation genes in Parkinson's disease.

DNA methylation is an important regulatory mechanism of Parkinson's disease (PD). To investigate the relationship between DNA methylation and hydroxymethylation genes and PD, we performed gene-targeted sequencing using molecular inversion probes in a Chinese PD population. We sequenced 12 genes related to DNA methylation and hydroxymethylation in 1657 patients and 1394 control subjects. We conducted genewise association analyses of rare variants detected in the present study and identified the TET1 gene as important in PD (p = 0.0037738, 0.013, 0.019521 (b.collapse test, variable threshold test, and skat-o test, respectively; sex + age as covariates). However, no positive results were observed when conducting association analyses on common variants in these genes. We performed a comprehensive analysis of associations between variants of DNA methylation and hydroxymethylation genes and PD, resulting in determination that TET1 might play a role in PD.