Temporal variations of bacterial and eukaryotic community in coastal waters-implications for aquaculture.

Despite increased attention to the aquaculture environment, there is still a lack of understanding regarding the significance of water quality. To address this knowledge gap, this study utilized high-throughput sequencing of 16S rRNA and 18S rRNA to examine microbial communities (bacteria and eukaryotes) in coastal water over different months through long-term observations. The goal was to explore interaction patterns in the microbial community and identify potential pathogenic bacteria and red tide organisms. The results revealed significant differences in composition, diversity, and richness of bacterial and eukaryotic operational taxonomic units (OTUs) across various months. Principal coordinate analysis (PCoA) demonstrated distinct temporal variations in bacterial and eukaryotic communities, with significant differences (P = 0.001) among four groups: F (January-April), M (May), S (June-September), and T (October-December). Moreover, a strong association was observed between microbial communities and months, with most OTUs showing a distinct temporal preference. The Kruskal-Wallis test (P < 0.05) indicated significant differences in dominant bacterial and eukaryotic taxa among months, with each group exhibiting unique dominant taxa, including potential pathogenic bacteria and red tide organisms. These findings emphasize the importance of monitoring changes in potentially harmful microorganisms in aquaculture. Network analysis highlighted positive correlations between bacteria and eukaryotes, with bacteria playing a key role in network interactions. The key bacterial genera associated with other microorganisms varied significantly (P < 0.05) across different groups. In summary, this study deepens the understanding of aquaculture water quality and offers valuable insights for maintaining healthy aquaculture practices. KEY POINTS: • Bacterial and eukaryotic communities displayed distinct temporal variations. • Different months exhibited unique potential pathogenic bacteria and red tide organisms. • Bacteria are key taxonomic taxa involved in microbial network interactions.

Biological soil crust elicits microbial community and extracellular polymeric substances restructuring to reduce the soil erosion on tropical island, South China Sea.

Soil erosion stands as the preeminent environmental concern globally, attaining heightened significance, particularly within islands where land resources prove notably scarce. Biological soil crusts, referred to as biocrusts, assume a pivotal ecological role in soil conservation. Notably, they augment the horizontal stability of the substrate through the exudation of microbial extracellular polymeric substances (EPS), thereby shielding the soil against shear stress, exemplified in the form of water erosion. While extant research has delved into the anti-erosion mechanisms of biocrusts in arid landscapes, a conspicuous lacuna persists in the exploration of coral island environments. In this study, we collected and assessed 30 samples encompassing dark biocrusts, light biocrusts, and bare soil to scrutinize the potential anti-erosion efficacy of tropical coral island biocrusts within the South China Sea. Employing a cohesive strength meter, we quantified soil shear stress across various stages of biocrust development, revealing a discernible enhancement in soil erosion resistance during the formation of biocrusts. Relative to the exposed bare soil, the soil shear stress exhibited an escalation from 0.33 N m-2 to 0.61 N m-2 and 1.31 N m-2 in the light biocrusts and dark biocrusts, respectively. Mechanistically, we assayed microbial EPS contents, exposing a positive correlation between EPS and soil anti-erodibility, encompassing extracellular protein and polysaccharide. Concurrently, bacterial abundance displayed a significant augmentation commensurate with biocrust formation and development. In pursuit of elucidating the origin of EPS, high-throughput amplicon sequencing was executed to identify microorganisms contributing to biocrust development. Correlation analysis discerned Cyanobacteria, Chloroflexi, Deinococcota, and Patescibacteria as potential microbials fostering EPS production and fortifying erosion resistance. Collectively, our study presents the first evidence that biocrust from tropical coral reef island in the South China Sea promotes resistance to soil erosion, pinpointing key EPS-producing microbials against soil erosion. The findings would provide insights for island environment restoration.

Origin and evolution of pentanucleotide repeat expansions at the familial cortical myoclonic tremor with epilepsy type1 - SAMD12 locus.

Familial cortical myoclonic tremor with epilepsy type 1 (FCMTE1) is caused by (TTTTA)exp(TTTCA)exp repeat expansions in SAMD12, while pure (TTTTA)exp is polymorphic. Our investigation focused on the origin and evolution of pure (TTTTA)exp and (TTTTA)exp(TTTCA)exp at this locus. We observed a founder effect between them. The phylogenetic analysis suggested that the (TTTTA)exp(TTTCA)exp might be generated from pure (TTTTA)exp through infrequent transformation events. Long-read sequencing revealed somatic generation of (TTTTA)exp(TTTCA)exp from pure (TTTTA)exp, likely via long segment (TTTCA) repeats insertion. Our findings indicate close relationships between the non-pathogenic (TTTTA)exp and the pathogenic (TTTTA)exp(TTTCA)exp, with dynamic interconversions. This sheds light on the genesis of pathogenic repeat expansions from ancestral premutation alleles. Our results may guide future studies in detecting novel repeat expansion disorders and elucidating repeat expansion mutational processes, thereby enhancing our understanding of human genomic variation.

Seizures and electrophysiological features in familial cortical myoclonic tremor with epilepsy 1.

OBJECTIVES: To investigate and characterize epileptic seizures and electrophysiological features of familial cortical myoclonic tremor with epilepsy (FCMTE) type 1 patients in a large Chinese cohort. METHODS: We systematically evaluated 125 FCMTEtype 1 patients carrying the pentanucleotide (TTTCA) repeat expansion in the SAMD12 gene in China. RESULTS: Among the 28 probands, epileptic seizures (96.4%, 27/28) were the most common reason for an initial clinic visit. Ninety-seven (77.6%, 97/125) patients had experienced seizures. The seizures onset age was 36.5 ± 9.0 years, which was 6.9 years later than cortical tremors. The seizures were largely rare (<1/year, 58.8%) and occasional (1-6/year, 37.1%). Prolonged prodromes were reported in 57.7% (56/97). Thirty-one patients (24.8%, 31/125) reported photosensitivity history, and 79.5% (31/39) had a photoparoxysmal response. Interictal epileptiform discharges (IEDs) were recorded in 69.1% (56/81) of patients. Thirty-three patients showed generalized IEDs and 72.7% (24/33) were occipitally dominant, while 23 patients presented with focal IEDs with 65.2% (15/23) taking place over the occipital lobe. Overnight EEG of FCMTE patients displayed paradoxical sleep-wake fluctuation, with a higher average IED index of 0.82 ± 0.88/min during wakefulness and a lower IED index of 0.04 ± 0.06/min during non-rapid eye movement sleep stages I-II. INTERPRETATION: FCMTE type 1 has a benign course of epilepsy and distinct clinical and electrophysiological features. In addition to a positive family history and cortical myoclonus tremor, the seizure prodromes, specific seizure triggers, photosensitivity, distribution of IEDs, and unique fluctuations during sleep-wake cycle are cues for proper genetic testing and an early diagnosis of FCMTE.

Retinal Thinning as a Marker of Disease Severity in Progressive Supranuclear Palsy.

OBJECTIVE: Progressive supranuclear palsy (PSP) involves a variety of visual symptoms that are thought to be partially caused by structural abnormalities of the retina. However, the relationship between retinal structural changes, disease severity, and intracranial alterations remains unknown. We investigated distinct retinal thinning patterns and their relationship with clinical severity and intracranial alterations in a PSP cohort. METHODS: We enrolled 19 patients with PSP (38 eyes) and 20 age-matched healthy controls (40 eyes). All of the participants underwent peripapillary and macular optical coherence tomography. Brain 11C-2ß-carbomethoxy-3ß-(4-fluorophenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography imaging were also performed in patients with PSP. We investigated the association between retinal thickness changes and clinical features, striatal dopamine transporter availability, and cerebral glucose metabolism. RESULTS: The peripapillary retinal nerve fiber layer (pRNFL) and macula were significantly thinner in patients with PSP than in controls. The thickness of the superior sector of the pRNFL demonstrated a significant negative relationship with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and Hoehn and Yahr staging scale scores. A significant negative correlation was found between outer inferior macular thickness and disease duration. Outer temporal macular thickness was positively correlated with Montreal Cognitive Assessment scores. In PSP, lower outer temporal macular thickness was also positively correlated with decreased dopamine transporter binding in the caudate. CONCLUSION: The pRNFL and macular thinning may be candidate markers for monitoring disease severity. Additionally, macular thinning may be an in vivo indicator of nigrostriatal dopaminergic cell degeneration in PSP patients.

Nature-inspired preparation of self-adhesive, frost-resistant, and ion-conductive hydrogels for flexible strain sensors.

A nature-inspired strategy has been developed to prepare polyvinyl alcohol (PVA)/catechol-modified quaternized chitosan (QCS-C)/MXene hydrogels with good self-adhesion, frost-resistance, and high ion-conductivity. The PVA/QCS-C/MXene hydrogel shows an ionic conductivity of 8.82 S m-1 and a gauge factor of 33.53 at low strain (0-10%), and remains flexible and conductive at -47 °C. The PVA/QCS-C15/MXene hydrogel displays promising potential as an ionically conductive hydrogel sensor for applications in flexible electronic devices.

Mills' syndrome is a unique entity of upper motor neuron disease with N-shaped progression: Three case reports.

BACKGROUND: Mills' syndrome is an extremely rare degenerative motor neuron disorder first described by Mills in 1900, but its nosological status is still not clear. We aimed to analyze the clinical features of Mills' syndrome. CASE SUMMARY: Herein, we present 3 cases with similar features as those described in Mills' original paper and review the related literature. Our patients showed middle- and older-age onset, with only upper motor neuron symptoms evident throughout the course of the disease. Spastic hemiplegia began in the lower extremity with a unique progressive pattern. CONCLUSION: We consider that Mills' syndrome is a unique entity of motor neuron disorder with an N-shaped progression. Clinicians should maintain a high index of suspicion for the diagnosis of Mills' syndrome when the onset involves lower extremity paralysis without evidence of lower motor neuron or sensory involvement.

White matter alterations in familial cortical myoclonic tremor with epilepsy type 1.

OBJECTIVE: Although previous imaging studies have reported cerebellar gray matter loss in patients with familial cortical myoclonic tremor with epilepsy (FCMTE), the corresponding white matter alterations remain unknown. We investigated white matter structural changes in FCMTE1 and compared them with clinical and electrophysiological features. METHODS: We enrolled 36 patients carrying heterozygous pathogenic intronic pentanucleotide insertions in the SAMD12 gene and 52 age- and sex-matched healthy controls. Diffusion tensor imaging-derived metrics, including fractional anisotropy, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated along with white matter voxel-based morphometry (VBM) analysis. We also examined correlations between magnetic resonance metrics and clinical and electrophysiological features. RESULTS: We detected widespread white matter reductions in MD, RD, and AD values in FCMTE1 patients, including in the commissural, projection, and association fibers. VBM analysis revealed that increases in white matter volume predominantly occurred in the right cerebellum and sagittal stratum. MD, RD, AD, and VBM analysis clearly indicated changes in the sagittal stratum. We found a positive correlation between VBM values in the right cerebellum and somatosensory-evoked potential P25-N33 amplitude. Decreased MD and AD values in the right sagittal stratum were detected in patients with versus without photophobia. SIGNIFICANCE: FCMTE is a network disorder involving a wide range of cortical and subcortical structures, including the cerebellum, thalamus, thalamocortical connections, and corticocortical connections. The right sagittal stratum is closely related with visual symptoms, especially photophobia. Our findings indicate that cerebellum and cortical hyperexcitability are closely linked, and emphasize the important role of the cerebellum in the pathophysiological mechanisms of cortical tremor.

The role of NOTCH2NLC in Parkinson's disease: A clinical, neuroimaging, and pathological study.

BACKGROUND AND PURPOSE: Recently, the pathogenic and intermediate GGC repeat expansion in NOTCH2NLC was detected in Parkinson's disease (PD). However, detailed clinical, neuroimaging, and pathological information of clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC remains scarce. Thus, we aimed to elucidate the clinical, neuroimaging, and pathological characteristics of PD patients carrying the pathogenic GGC repeat expansion in NOTCH2NLC. METHODS: The NOTCH2NLC GGC repeat expansion was screened in 941 sporadic PD patients and 244 unrelated probands. Comprehensive assessments were performed in three PD patients with pathogenic GGC repeat expansion in NOTCH2NLC. The repeat expansion length was estimated using CRISPR/Cas9-based targeted long-read sequencing. RESULTS: The three patients (two PD patients from Family 1 and one sporadic PD) carrying the pathogenic NOTCH2NLC expansion were reconfirmed with a diagnosis of clinically established PD. Although they lacked the typical neuronal intranuclear inclusion disease (NIID) magnetic resonance imaging (MRI) feature, the typical PD pattern of striatal dopamine transporter loss was detected. Notably, all three patients presented with systemic areflexia, and other secondary causes of polyneuropathy were excluded. Skin biopsy showed intranuclear inclusions and an absence of phosphorylated alpha-synuclein deposition in the skin nerve fibers of all three patients. CONCLUSIONS: Although these clinically diagnosed PD patients with pathogenic GGC repeat expansion in NOTCH2NLC were hardly distinguishable from idiopathic PD based on clinical course and neuroimaging features, the pathological findings indicated that their phenotype was a PD phenocopy of NIID. Systemic areflexia may be an important and unique clinical clue suggesting further genetic testing and skin biopsy examination to confirm the diagnosis of NIID in patients presenting with a PD phenocopy.

Neuronal intranuclear inclusion disease tremor-dominant subtype: A mimicker of essential tremor.

BACKGROUND AND PURPOSE: The GGC repeat expansion in the NOTCH2NLC gene has been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). Recently, this repeat expansion was also reported to be associated with essential tremor (ET). However, some patients with this repeat expansion, initially diagnosed with ET, were eventually diagnosed with NIID. Therefore, controversy remains regarding the clinical diagnosis of these expansion-positive patients presenting with tremor-dominant symptoms. This study aimed to clarify the clinical phenotype in tremor-dominant patients who have the GGC repeat expansion in the NOTCH2NLC gene. METHODS: We screened for pathogenic GGC repeat expansions in 602 patients initially diagnosed with ET and systematically re-evaluated the clinical features of the expansion-positive probands and their family members. RESULTS: Pathogenic GGC repeat expansion in the NOTCH2NLC gene was detected in 10 probands (1.66%). Seven of these probands were re-evaluated and found to have systemic areflexia, cognitive impairment, and abnormal nerve conduction, which prompted a change of diagnosis from ET to NIID. Three of the probands had typical hyperintensity in the corticomedullary junction on diffusion-weighted imaging. Intranuclear inclusions were detected in all four probands who underwent skin biopsy. CONCLUSIONS: The NIID tremor-dominant subtype can be easily misdiagnosed as ET. We should take NIID into account for differential diagnosis of ET. Systemic areflexia could be an important clinical clue suggesting that cranial magnetic resonance imaging examination, or even further genetic testing and skin biopsy examination, should be used to confirm the diagnosis of NIID.

Cardiovascular autonomic dysfunction is associated with executive dysfunction and poorer quality of life in progressive supranuclear palsy-Richardson's syndrome.

BACKGROUND: Autonomic dysfunction in progressive supranuclear palsy (PSP) is not uncommon but is easily neglected. OBJECTIVE: We evaluated blood pressure (BP) profiles in PSP patients and aimed to determine the associations between BP variability and cognition and quality of life. METHODS: Consecutive patients diagnosed with PSP were enrolled in this cross-sectional study. All patients underwent 24-hour ambulatory blood pressure monitoring, office blood pressure measurements, and comprehensive clinical assessments. RESULTS: We enrolled 31 PSP patients. Ten (32.3%) patients presented with reverse dipping, 10 (32.3%) presented with reduced dipping, and 11 (35.5%) presented with normal dipping. Additionally, 19 (61.3%) patients had supine hypertension, and no patients had orthostatic hypotension. In the entire PSP cohort, the Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) score, Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT) score, and daytime systolic BP (SBP) standard deviation explained 61.5% (adjusted R2) of the variance in Parkinson's Disease Questionnaire-39 (PDQ-39) scores. In the PSP with Richardson's syndrome group, the daytime SBP coefficient of variation and Mini-Mental State Examination score accounted for 33.9% of the variance in Frontal Assessment Battery scores. The MDS-UPDRS III score, 24-hour SBP coefficient of variation, and SCOPA-AUT score explained 77.6% of the variance in PDQ-39 scores. CONCLUSIONS: Greater BP variability was associated with executive dysfunction and poorer quality of life in patients with PSP. A high prevalence of abnormal dipping patterns indicated circadian disruption in patients with PSP.

Graphene oxide-reinforced poly (ether-ether-ketone)/silica composites with improved mechanical performance and surface bioactivity.

The control of interfacial interaction between polymers and fillers is essential for the fabrication of high-performance polymer composites. In this work, poly(ether-ether-ketone)/silica (PEEK/SiO2) and PEEK/SiO2/graphene oxide (GO) composite were prepared by ball milling-ultrasonic dispersion combined with melt extrusion injection molding. GO nanosheets were introduced as the interfacial enhancer to improve interfacial binding between SiO2 and PEEK. Mechanical tests showed that the incorporation of SiO2 and GO greatly optimized the modulus, strength, and fracture toughness of the composites. The tensile strength and Young's modulus of the PEEK/SiO2 composites increases with the increase of SiO2 content. The maximum tensile strength and Young's modulus of the PEEK/SiO2 composites are approximate 95.9 ± 0.6 MPa and 4.007 ± 0.005 GPa at 30 wt% of SiO2, an increase of 6.4% and 21.2% than that of pure PEEK. The maximum tensile strength and Young's modulus of the PEEK/SiO2/GO composite are further improved to approximate 101.5 ± 0.7 MPa and 4.62 ± 0.08 GPa at a GO content of 1.5% wt, which is 12.6% and 39.4% higher than that of pure PEEK. In addition, SEM images show that numerous HA formed on the surface of the PEEK/SiO2/GO composite after immersion in SBF for 7 days, and the HA layer becomes gradually thicker after 14 days, implying the good osteogenic activity of PEEK/SiO2/GO composites. Therefore, these results suggest that the use of GO as a novel filler surface modifier for the preparation of high-performance composites may become a novel interfacial design strategy for the development of high-performance composites.

The link between lateral trunk flexion in Parkinson's disease and vestibular dysfunction: a clinical study.

INTRODUCTION: Lateral trunk flexion (LTF) is a common postural deformity in Parkinson's disease (PD). Postural control is known to depend on visual, vestibular, and somatosensory information. OBJECTIVES: This study aimed to investigate the relationship between vestibular dysfunction and postural abnormalities in PD patients with LTF. METHODS: We enrolled a total of 19 PD patients with LTF (PD-LTF+) and 19 age- and sex-matched PD patients without LTF (PD-LTF-). All patients underwent vestibular tests, including spontaneous nystagmus, gaze-evoked nystagmus, ocular movements, optokinetic eye test, fast positioning maneuvers, and the bithermal caloric test. RESULTS: Most of the PD-LTF + patients had abnormal vestibular function (11/19), while there were fewer vestibular function injuries in the control group (3/19). In PD-LTF + group, there were 5 patients (5/11, 45.5%) of peripheral vestibular dysfunction, 2 patients (2/11, 18.2%) of central vestibular damage, and 4 patients (4/11, 36.4%) of mixed injuries. The peripheral vestibular deficiencies could be either bilateral (4/9, 44.4%) or unilateral (5/9, 55.6%). The unilateral vestibular dysfunction was ipsilateral to the leaning side in 2 patients and contralateral to the leaning side in the other 3 patients. CONCLUSION: Vestibular dysfunction may be an independent risk factor for LTF in PD patients.

Altered Cerebello-Motor Network in Familial Cortical Myoclonic Tremor With Epilepsy Type 1.

BACKGROUND: Intronic pentanucleotide insertion in the sterile alpha motif domain-containing 12 gene was recently identified as the genetic cause of familial cortical myoclonic tremor with epilepsy type 1. OBJECTIVES: We thereafter conducted a multimodal MRI research to further understand familial cortical myoclonic tremor with epilepsy type 1. METHODS: We enrolled 31 patients carrying heterozygous pathogenic intronic pentanucleotide insertion in the sterile alpha motif domain-containing 12 gene and 31 age- and sex-matched healthy controls. We compared multimodal MRI metrics, including voxel-based morphometry, fractional anisotropy of diffuse tensor imaging, frequency-dependent percent amplitude fluctuation, and seed-based functional connectivity of resting-state functional MRI. RESULTS: Significant decreased gray matter volume was found in the cerebellum. Percent amplitude fluctuation analysis showed significant interaction effect of "Frequency by Group" in three regions, including the vermis VIII, left cerebellar lobule VIII, and left precentral gyrus. Specifically, the lowest-frequency band exhibited significant increased percent amplitude fluctuation in patients in the two cerebellar subregions, whereas the highest-frequency band exhibited decreased percent amplitude fluctuation in the precentral gyrus in patients. Discriminative analysis by support vector machine showed a mean accuracy of 82% (P = 1.0-5 ). An increased functional connectivity between vermis VIII and the left precentral gyrus was found in patients with familial cortical myoclonic tremor with epilepsy type 1. A positive correlation between the percent amplitude fluctuation in the left cerebellar lobule VIII and duration of cortical tremor was also found. CONCLUSION: The cerebellum showed both structural and functional damages. The distinct change of spontaneous brain activity, that is, increased ultra-low-frequency amplitude in the cerebellum and the decreased higher-frequency amplitude in the motor cortex, might be a pathophysiological feature of familial cortical myoclonic tremor with epilepsy type 1. © 2020 International Parkinson and Movement Disorder Society.

MYORG Mutation Heterozygosity Is Associated With Brain Calcification.

BACKGROUND: Biallelic mutations in the MYORG gene were first identified as the cause of recessively inherited primary familial brain calcification. Interestingly, some heterozygous carriers also exhibited brain calcifications. OBJECTIVES: To further investigate the role of single heterozygous MYORG mutations in the development of brain calcifications. METHODS: A nation-wide cohort of Chinese primary familial brain calcification probands was enrolled from March 2016 through September 2019. Mutational analysis of MYORG was performed in 435 primary familial brain calcification probands who were negative for mutations in the other four known primary familial brain calcification-causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1). RESULTS: Biallelic MYORG mutations were identified in 14 primary familial brain calcification patients from 10 unrelated families. Interestingly, 12 heterozygous carriers from seven of these families also exhibited mild-to-moderate brain calcifications. Moreover, single heterozygous mutations were detected in an additional 9 probands and in 7 of their family members affected with brain calcifications. In our cohort, clinical and imaging penetrance of individuals with biallelic mutations were 100%, whereas among individuals with heterozygous mutations, penetrance of imaging phenotype was reduced to 73.7% (28 of 38) and clinical penetrance was much lower. Most (34 of 38) remained asymptomatic whereas 4 carriers had symptoms of uncertain clinical significance (nonspecific depression, epilepsy and late-onset parkinsonism). Compared with individuals with biallelic MYORG mutations, individuals with heterozygous mutations had brain calcifications with much lower calcification scores (P < 2e-16). CONCLUSIONS: Presence of brain calcifications in individuals with heterozygous MYORG mutations suggested a semidominant inheritance pattern with incomplete penetrance. This finding further expanded the genotype-phenotype correlations of MYORG-related primary familial brain calcification. © 2020 International Parkinson and Movement Disorder Society.

Intronic (TTTGA)n insertion in SAMD12 also causes familial cortical myoclonic tremor with epilepsy.

BACKGROUND: Intronic (TTTCA)n insertions in the SAMD12, TNRC6A, and RAPGEF2 genes have been identified as causes of familial cortical myoclonic tremor with epilepsy. OBJECTIVE: To identify the cause of familial cortical myoclonic tremor with epilepsy pedigrees without (TTTCA)n insertions in SAMD12, TNRC6A, and RAPGEF2. METHODS: Repeat-primed polymerase chain reaction, long-range polymerase chain reaction, and Sanger sequencing were performed to identify the existence of a novel (TTTGA)n insertion. Targeted long-read sequencing was performed to confirm the accurate structure of the (TTTGA)n insertion. RESULTS: We identified a novel expanded intronic (TTTGA)n insertion at the same site as the previously reported (TTTCA)n insertion in SAMD12. This insertion cosegregated with familial cortical myoclonic tremor with epilepsy in 1 Chinese pedigree with no (TTTCA)n insertion. In the targeted long-read sequencing of 2 patients and 1 asymptomatic carrier in this pedigree, with 1 previously reported (TTTCA)n -insertion-carrying patient as a positive control, a respective total of 302, 159, 207, and 50 on-target subreads (predicated accuracy: ≥90%) spanning the target repeat expansion region were generated. These sequencing data revealed the accurate repeat expansion structures as (TTTTA)114-123 (TTTGA)108-116 in the pedigree and (TTTTA)38 (TTTCA)479 in (TTTCA)n -insertion-carrying patient. CONCLUSION: The targeted long-read sequencing helped us to elucidate the accurate structures of the (TTTGA)n and (TTTCA)n insertions. Our finding offers a novel possible cause for familial cortical myoclonic tremor with epilepsy and might shed light on the identification of genetic causes of this disease in pedigrees with no detected (TTTCA)n insertion in the reported causative genes. © 2019 International Parkinson and Movement Disorder Society.

Alteration of Brain Functional Connectivity in Parkinson's Disease Patients with Dysphagia.

Dysphagia is a common non-primary symptom of patients with Parkinson's disease. The aim of this study is to investigate the underlying alterations of brain functional connectivity in Parkinson's disease patients with dysphagia by resting-state functional magnetic resonance imaging. We recruited 13 Parkinson's disease patients with dysphagia and ten patients without dysphagia, diagnosed by videofluoroscopic study of swallowing. Another 13 age and sex-matched healthy subjects were recruited. Eigenvector centrality mapping was computed to identify functional connectivity alterations among these groups. Parkinson's disease patients with dysphagia had significantly increased functional connectivity in the cerebellum, left premotor cortex, the supplementary motor area, the primary motor cortex, right temporal pole of superior temporal gyrus, inferior frontal gyrus, anterior cingulate cortex and insula, compared with patients without dysphagia. This study suggests that functional connectivity changes in swallowing-related cortexes might contribute to the occurrence of dysphagia in Parkinson's disease patients.

Underestimated disease prevalence and severe phenotypes in patients with biallelic variants: A cohort study of primary familial brain calcification from China.

BACKGROUND: Primary familial brain calcification (PFBC) is a rare calcifying disorder of the brain with extensive clinical and genetic heterogeneity. Its prevalence is underestimated due to clinical selection bias (compared with symptomatic PFBC patients, asymptomatic ones are less likely to undergo genetic testing). METHODS: A total of 273 PFBC probands were enrolled in a multicenter retrospective cohort study by two different approaches. In Group I (nonsystematic approach), 37 probands diagnosed at our clinic were enrolled. In Group II (systematic approach), 236 probands were enrolled by searching the medical imaging databases of 50 other hospitals using specific keywords. Genetic testing of four genes known to be causative of autosomal dominant PFBC was performed in all probands using cDNA. All identified variants were further confirmed using genomic DNA and classified according to ACMG-AMP recommendations. RESULTS: Thirty-two variants including 22 novel variants were detected in 37 probands. Among these probands, 83.8% (31/37) were asymptomatic. Two probands with homozygous pathogenic SLC20A2 variants presented more severe brain calcification and symptoms. Based on the variant detection rate of probands in Group II, we extrapolated an overall minimal prevalence of PFBC of 6.6 per 1,000, much higher than previously reported (2.1 per 1000). CONCLUSIONS: We identified a higher proportion of genetically confirmed PFBC probands who were asymptomatic. These patients would be overlooked due to clinical selection bias, leading to underestimation of the disease prevalence. Considering that PFBC patients with biallelic variants had more severe phenotypes, this specific condition should be focused on in genetic counseling.

Intronic pentanucleotide TTTCA repeat insertion in the SAMD12 gene causes familial cortical myoclonic tremor with epilepsy type 1.

Familial cortical myoclonic tremor with epilepsy is an autosomal dominant neurodegenerative disease, characterized by cortical tremor and epileptic seizures. Although four subtypes (types 1-4) mapped on different chromosomes (8q24, 2p11.1-q12.2, 5p15.31-p15.1 and 3q26.32-3q28) have been reported, the causative gene has not yet been identified. Here, we report the genetic study in a cohort of 20 Chinese pedigrees with familial cortical myoclonic tremor with epilepsy. Linkage and haplotype analysis in 11 pedigrees revealed maximum two-point logarithm of the odds (LOD) scores from 1.64 to 3.77 (LOD scores in five pedigrees were >3.0) in chromosomal region 8q24 and narrowed the candidate region to an interval of 4.9 Mb. Using whole-genome sequencing, long-range polymerase chain reaction and repeat-primed polymerase chain reaction, we identified an intronic pentanucleotide (TTTCA)n insertion in the SAMD12 gene as the cause, which co-segregated with the disease among the 11 pedigrees mapped on 8q24 and additional seven unmapped pedigrees. Only two pedigrees did not contain the (TTTCA)n insertion. Repeat-primed polymerase chain reaction revealed that the sizes of (TTTCA)n insertion in all affected members were larger than 105 repeats. The same pentanucleotide insertion (ATTTCATTTC)58 has been reported to form RNA foci resulting in neurotoxicity in spinocerebellar ataxia type 37, which suggests the similar pathogenic process in familial cortical myoclonic tremor with epilepsy type 1.