Clinical features and genetic spectrum of a multicenter Chinese cohort with myotonic dystrophy type 1.

BACKGROUND: As the most common subtype of adult muscular dystrophy worldwide, large cohort reports on myotonic dystrophy type I (DM1) in China are still lacking. This study aims to analyze the genetic and clinical characteristics of Chinese Han DM1 patients. METHODS: Based on the multicenter collaborating effort of the Pan-Yangtze River Delta Alliance for Neuromuscular Disorders, patients with suspected clinical diagnoses of DM1 were genetically confirmed from January 2020 to April 2023. Peak CTG repeats in the DMPK gene were analyzed using triplet repeat-primed PCR (TP-PCR) and flanking PCR. Time-to-event analysis of onset age in females and males was performed. Additionally, detailed clinical features and longitudinal changes from the disease onset in 64 DM1 patients were retrospectively collected and analyzed. The Epworth Sleepiness Scale and Fatigue Severity Scale were used to quantify the severity of daytime sleepiness and fatigue. RESULTS: Among the 211 genetically confirmed DM1 patients, the mean age at diagnosis was 40.9 ± 12.2 (range: 12-74) with a male-to-female ratio of 124:87. The average size of CTG repeats was 511.3 (range: 92-1945). Among the DM1 patients with comprehensive clinical data (n = 64, mean age 41.0 ± 12.0), the age at onset was significantly earlier in males than in females (4.8 years earlier, p = 0.026). Muscle weakness (92.2%), myotonia (85.9%), and fatigue (73.4%) were the most prevalent clinical features. The predominant involved muscles at onset are hands (weakness or myotonia) (52.6%) and legs (walking disability) (42.1%). Of them, 70.3% of patients had daytime sleepiness, 14.1% had cataract surgery, 7.8% used wheelchairs, 4.7% required ventilatory support, and 1.6% required gastric tubes. Regarding the comorbidities, 4.7% of patients had tumors, 17.2% had diabetes, 23.4% had dyspnea, 28.1% had intermittent insomnia, 43.8% experienced dysphagia, and 25% exhibited cognitive impairment. Chinese patients exhibited smaller size of CTG repeats (468 ± 139) than those reported in Italy (613 ± 623), the US (629 ± 386), and Japan (625 [302, 1047]), and milder phenotypes with less multisystem involvement. CONCLUSION: The Chinese Han DM1 patients presented milder phenotypes compared to their Caucasian and Japanese counterparts. A male predominance and an early age of onset were identified in male Chinese Han DM1 patients.

[Clinical and genetic analysis of a patient with Desminopathy manifesting initially with myalgia after lower limb activity].

OBJECTIVE: To explore the clinical characteristics and genetic variant of a patient with desminopathy manifesting with atypical symptoms. METHODS: A patient who was admitted to the Department of Neurology of Jing'an District Central Hospital on February 24, 2021 was selected as the study subject. Clinical data, laboratory tests, muscle pathology, muscle magnetic resonance imaging (MRI) and genetic testing of the patient were retrospectively analyzed. RESULTS: The patient had developed myalgia after lower limb activity, and gradually developed asymmetrical muscle weakness and atrophy of the lower limbs. Cardiac examination revealed atrioventricular block and decreased left ventricular diastolic function. Muscle MRI showed that semitendinosus, sartorius, gracilis, fibula, gastronemius and supinator muscles were selectively involved at the early stage. Muscle biopsy confirmed pathological changes of desmin positive myofibrils. Genetic testing revealed that the patient has harbored a c.1024A>G (p.n342d) missense variant in exon 6 of the DES gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic (PS4_moderate+PM2_supporting+PP3_moderate+PP1). CONCLUSION: Desmin disease has a great clinical heterogeneity. Postexercise myalgia of lower limbs is a rare clinical phenotype. For patients harboring the c.1024A>G (p.n342d) variant of the DES gene, in addition to semitendinosus and fibula, Cardiac involvement is relatively insidious and easy to be ignored in clinic. Timely muscle MRI, muscle biopsy and gene detection will help the early diagnosis of the disease.

Classifying mild cognitive impairment and Alzheimer's disease by constructing a 14-gene diagnostic model.

BACKGROUND: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are two neurodegenerative diseases. Most patients with MCI will develop AD. Early detection of AD and MCI is a crucial issue in terms of secondary prevention. Therefore, more diagnostic models need to be developed to distinguish AD patients from MCI patients. METHODS: In our research, the expression matrix and were screened from Gene Expression Omnibus (GEO) databases. A 14-gene diagnostic model was constructed with lasso logistic analysis. The efficiency and accuracy of diagnostic model have also been validated. In order to clarify the expression differences of 14 genes in health donor, AD and MCI, the blood samples of patients and healthy individuals were collected. The mRNA expression of the 14 genes in blood sample were detected. The SH-SY5Y cell injury model was constructed and biological function of POU2AF1 and ANKRD22 in SH-SY5Y have been proved. RESULTS: We obtained 16 genes which have an area under curve (AUC) ≥0.6. After that, a diagnostic model based on 14 genes was constructed. Validation in independent cohort showed that the diagnostic model has a good diagnostic efficiency. The expressions of 6 genes in AD patients were significantly lower than those in healthy individuals and MCI patients, while the expressions of 8 genes in AD patients were significantly higher than those in healthy individuals and MCI patients. In in vitro experiments, we found that two key genes POU2AF1 and ANKRD22 could regulate neuronal development by regulating cell viability and IL-6 expression. CONCLUSION: The diagnostic model established in this study has a good diagnose efficiency. Most of these genes in diagnostic model also showed diagnostic value in AD patients. This research also can help doctors make better diagnosis for the treatment and prevention of AD.

Association of ATG5 gene polymorphism with Parkinson's disease in a Han Chinese population.

PURPOSE: There is growing evidence that autophagy-related gene 5 (ATG5) is involved in neural development, neuronal differentiation, and neurodegenerative diseases. The purpose of this study was to investigate the association between ATG5 gene single-nucleotide polymorphisms (SNPs) and Parkinson's disease (PD) in the Han population. METHODS: A case-control study was conducted in 120 PD patients and 100 healthy volunteers. MassArray platform was used to analyze polymorphisms in three different regions of ATG5 gene (rs510432, rs573775 and rs17587319). In the included subjects, 50 PD patients and 50 healthy volunteers were selected, and the plasma ATG5 concentration was detected by enzyme-linked immunosorbent assay (ELISA). The allele and genotype frequencies of SNPs were assessed using the SHEsis program. RESULTS: We found a significant correlation between rs17587319 and PD, and the subcomponent showed a high correlation between rs17587319 with cognitive impairment and age at onset in PD patients. At the same time, the total plasma ATG5 level of PD patients and the plasma ATG5 expression level of early-onset Parkinson's disease (EOPD) patients were significantly higher than the control group, while there was no significant difference of ATG5 expression between late-onset Parkinson's disease (LOPD) patients and the control group. CONCLUSION: These findings suggest that genetic variations in the ATG5 gene and low levels of the ATG5 protein are associated with susceptibility to PD and with cognitive impairment in PD patients. ATG5 could be a potential biomarker to assess the severity and prognosis of PD.

Effects of strain on the electronic, optical, and ferroelectric transition properties of HfO2:ab initiosimulation study.

The amazing ferroelectricity observed in Hafnium oxide (HfO2) thin films is due to the existence of non-centrosymmetric orthorhombicPca21phase. In this study, the structural, electronic, optical, and polarization switching properties of the orthorhombicPca21phase with various strains are investigated by employing density functional theory (DFT) calculations based on the DFT. Out-of-plane and in-plane strains are taken into consideration. The results indicate that the band-gap values of orthorhombic HfO2increase at first and then decrease from compressive strain to tensile strain due to the variation of the valence band maximum and the conduction band minimum. Moreover, orthorhombic HfO2transforms into a direct bandgap material when compressive strain along thezdirection is larger than or equal to 5%. A red-shift occurs under both tensile and compressive strains in the absorption edge compared with instinct HfO2in the absorption spectra. The absorption intensity of the strained HfO2is enhanced with the energy below 5.5 eV. The energy barriers of path A and path B of the polarization switching mediated by non-polar tetragonal phase are 116.8 and 91.2 meV per formula unit (meV/f.u.), respectively. In polarization switching without mediated by non-polar phase, the energy barriers decrease with the increasing of out-of-plane compressive strain along thexdirection and tensile strain along theydirection compared with strain free structures.

Nanocrystal-Embedded-Insulator (NEI) Ferroelectric FETs for Negative Capacitance Device and Non-Volatile Memory Applications.

We report a novel nanocrystal-embedded-insulator (NEI) ferroelectric field-effect transistor (FeFET) with very thin unified-ferroelectric/dielectric (FE/DE) insulating layer, which is promising for low-voltage logic and non-volatile memory (NVM) applications. The ferroelectric nature of the NEI layers comprising orthorhombic ZrO2 nanocrystals embedded in amorphous Al2O3 is proved by polarization voltage measurements, piezoresponse force microscopy, and electrical measurements. The temperature dependent performance and endurance behavior of a NEI negative capacitance FET (NCFET) are investigated. A FeFET with 3.6 nm thick FE/DE achieves a memory window larger than 1 V, paving a pathway for ultimate scaling of FE thickness to enable three-dimensional FeFETs with very small fin pitch.

Development and Standardization of a New Cognitive Assessment Test Battery for Chinese Aphasic Patients: A Preliminary Study.

BACKGROUND: Nonlinguistic cognitive impairment has become an important issue for aphasic patients, but currently there are few neuropsychological cognitive assessment tests for it. To get more information on cognitive impairment of aphasic patients, this study aimed to develop a new cognitive assessment test battery for aphasic patients, the Non-language-based Cognitive Assessment (NLCA), and evaluate its utility in Chinese-speaking patients with aphasia. METHODS: The NLCA consists of five nonverbal tests, which could assess five nonlinguistic cognitive domains such as visuospatial functions, attention test, memory, reasoning, and executive functions of aphasic patients. All tests are modified from the nonverbal items of the current existed tests with some changes to the characteristics of Chinese culture. The NLCA was tested in 157 participants (including 57 aphasic patients, 50 mild cognitive impairment (MCI) patients, and 50 normal controls), and was compared with other well-established relative neuropsychological tests on the reliability, validity, and utility. RESULTS: The NLCA was fully applicable in the MCI patients and the normal controls, almost working in the aphasic patients (57/62 patients, 91.9%). The NLCA scores were 66.70 ± 6.30, 48.67 ± 15.04, and 77.58 ± 2.56 for the MCI group, the aphasic group, and the control group, respectively , and a significant difference was found among three groups (F = 118.446, P < 0.001). The Cronbach's alpha of the NLCA as an index of internal consistency was 0.805, and the test-retest and interrater reliability was adequate (r=0.977 and r= 0.970, respectively). The correlations of the cognitive subtests and their validation instruments were between 0.540 and 0.670 (all P < 0.05). Spearman's correlation analysis indicated that the coefficient of internal consistency of each subtest itself was higher than other subtests. When choosing the Montreal Cognitive Assessment score of <26 as the diagnostic criteria of cognitive impairment, the area under the curve for all participants in the control and MCI groups was 0.942 (95% confidence interval: 0.895-0.989), and an optimal cutoff point of 75.00 seemed to provide the best balance between sensitivity and specificity. Age (r = -0.406, P < 0.001) was the main influence factor for the NLCA. CONCLUSIONS: The NLCA could efficiently differentiate the cognitive impairment patients from the normal controls and is a reliable and valid cognitive assessment test battery to specially find nonlinguistic cognitive function for aphasic patients.

[Neurolinguistic features during recovery of a Chinese patient with pure alexia].

OBJECTIVE: To analyze the neurolinguistic features of a Chinese patient with pure alexia in acute and convalescent stages. METHODS: We assessed the reading and writing abilities of the patient with the Aphasia Battery of Chinese (ABC), the reading examination of Chinese characters (1999, Lin) and the Chinese agraphia battery (CAB). RESULTS: In the ABC examination in the acute phase, the patient performed well in oral expression and comprehension, and the prominent linguistic abnormalities were alexia and merging agraphia; in the convalescent phase, the recovery of alexia was better than that of agraphia. In reading examination of Chinese characters, shape errors were the main reading disorders in the acute phase with a few semantic errors, regularization errors and mistakes in pronunciation, but only shape errors reappeared in the recovery period. CAB examination showed impairment of writing for pictures and dictation abilities in the recovery period but recovery of other writing abilities. The writing disorder was manifested as aphasic agraphia, with obvious dysorthography and lexical errors; the patient was capable of spontaneous writing only after spontaneous speech, and was able to read the written words. CONCLUSION: The linguistic components of the Chinese patient with pure alexia showed different patterns of damage and recovery, suggesting the difference in their respective neuropsychological pathways.