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In familial cortical myoclonic tremor with epilepsy, photic stimulation can trigger visual-related symptoms and induce a photoparoxysmal response on electroencephalography. This is known as photosensitivity. To explore the mechanism of prominent visual-related symptoms and photosensitivity in patients with genetically confirmed familial cortical myoclonic tremor with epilepsy type 1, resting-state functional magnetic resonance imaging data and electroencephalography data were collected from 31 patients carrying the heterozygous pathogenic intronic pentanucleotide (TTTCA)n insertion in the sterile alpha motif domain-containing 12 gene and from 52 age- and sex-matched healthy controls. Results: (1) Both regional homogeneity and degree centrality values in the bilateral calcarine sulcus were significantly increased in patients compared with HCs. (2) When the calcarine sulcus area with increased regional homogeneity was taken as a seed, increased functional connectivity values were observed in the right precentral gyrus, while decreased functional connectivity values were observed in the right superior frontal gyrus and right inferior parietal lobule. (3) independent component analysis showed increased connectivity in the left calcarine sulcus inside the medial visual network. (4) Correlation analysis revealed significant positive correlation between regional homogeneity values and frequency of seizure, and photoparoxysmal response grades were positively correlated with the severity of cortical tremor and duration of epilepsy. The findings provide strong evidence for the interpretation of visual-related symptoms and photosensitivity in familial cortical myoclonic tremor with epilepsy and may also relate to other epilepsy syndromes with photosensitivity. We speculate the significant functional change in primary visual cortex probably an imaging biomarker for the disease.

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.

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.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.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.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.

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.

Primary familial brain calcification is a monogenic disease characterized by bilateral calcifications in the basal ganglia and other brain regions, and commonly presents motor, psychiatric, and cognitive symptoms. Currently, four autosomal dominant (SLC20A2, PDGFRB, PDGFB, XPR1) and one autosomal recessive (MYORG) causative genes have been identified. Compared with patients with autosomal dominant primary familial brain calcification, patients with the recessive form of the disease present with more severe clinical and imaging phenotypes, and deserve more clinical and research attention. Biallelic mutations in MYORG cannot explain all autosomal recessive primary familial brain calcification cases, indicating the existence of novel autosomal recessive genes. Using homozygosity mapping and whole genome sequencing, we detected a homozygous frameshift mutation (c.140delT, p.L48*) in the JAM2 gene in a consanguineous family with two affected siblings diagnosed with primary familial brain calcification. Further genetic screening in a cohort of 398 probands detected a homozygous start codon mutation (c.1A>G, p.M1?) and compound heterozygous mutations [c.504G>C, p.W168C and c.(67+1_68-1)_(394+1_395-1), p.Y23_V131delinsL], respectively, in two unrelated families. The clinical phenotypes of the four patients included parkinsonism (3/4), dysarthria (3/4), seizures (1/4), and probable asymptomatic (1/4), with diverse onset ages. All patients presented with severe calcifications in the cortex in addition to extensive calcifications in multiple brain areas (lenticular nuclei, caudate nuclei, thalamus, cerebellar hemispheres, ± brainstem; total calcification scores: 43–77). JAM2 encodes junctional adhesion molecule 2, which is highly expressed in neurovascular unit-related cell types (endothelial cells and astrocytes) and is predominantly localized on the plasma membrane. It may be important in cell-cell adhesion and maintaining homeostasis in the CNS. In Chinese hamster ovary cells, truncated His-tagged JAM2 proteins were detected by western blot following transfection of p.Y23_V131delinsL mutant plasmid, while no protein was detected following transfection of p.L48* or p.1M? mutant plasmids. In immunofluorescence experiments, the p.W168C mutant JAM2 protein failed to translocate to the plasma membrane. We speculated that mutant JAM2 protein resulted in impaired cell-cell adhesion functions and reduced integrity of the neurovascular unit. This is similar to the mechanisms of other causative genes for primary familial brain calcification or brain calcification syndromes (e.g. PDGFRB, PDGFB, MYORG, JAM3, and OCLN), all of which are highly expressed and functionally important in the neurovascular unit. Our study identifies a novel causative gene for primary familial brain calcification, whose vital function and high expression in the neurovascular unit further supports impairment of the neurovascular unit as the root of primary familial brain calcification pathogenesis.

Background Mutations in the SYNJ1 have been associated with early onset of atypical Parkinson's disease (PARK20). Patients with PARK20 exhibit a wide phenotypic variability. Here, we report the clinical and genetic findings in two affected siblings with a novel homozygous SYNJ1 mutation. Methods A consanguineous family with two affected siblings with Parkinson's disease was recruited. Both siblings underwent detailed neurological examinations. Whole genome sequencing was performed in the proband. Results Both affected siblings presented with pure parkinsonism with no other atypical symptoms and a slow disease progression. The proband had an excellent response to levodopa. Performing the levodopa challenge test in the proband's older brother resulted in improvements in the parkinsonism signs. Genetic analysis identified a homozygous missense mutation in SYNJ1 (c.2495A > G, p.Y832C) in both of siblings. In silico analyses revealed that the mutation was deleterious. Conclusions Screening for SNYJ1 should be considered in patients with typical levodopa-responsive Parkinson's disease.

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.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.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.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.

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.

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.

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.

BACKGROUND Very recently, the MYORG gene was identified as a novel causative gene for autosomal-recessive primary familial brain calcification. OBJECTIVE To investigate the clinical, genetic, and neuroradiological characteristics of primary familial brain calcification patients with biallelic MYORG mutations in China. METHODS We collected clinical and neuroradiological data of 169 Chinese patients with primary familial brain calcification, including 151 sporadic patients and 18 patients from 13 families compatible with an autosomal-recessive mode of inheritance. Mutational analysis of MYORG was performed in the cohort. RESULTS We identified four, including three novel, MYORG mutations segregating in four families with 5 patients: one nonsense mutation (c.1431C>A, p.Y477*), one missense mutation (c.687G>T, p.W229C), and two nonframeshift indels (c.348_349insCTGGCCTTCCGC, p.116_117insLAFR; c. 428_442delTGCACTTCTTCATCC, p.143_147delLHFFI). The 12-base-pair insertion, c.348_349insCTGGCCTTCCGC, was found in either homozygous or heterozygous state in 2 probands of our cohort and another Chinese primary familial brain calcification patient previously reported on in the literature. Haplotype analysis of our patients harboring the insertion indicated a founder effect in the ethnic Han Chinese population. To date, biallelic MYORG mutations have been reported in 17 patients (including our cohort). Most patients were symptomatic (13 of 17; 76.5%), and the most recurrent symptoms were movement disorders (10 of 17; 58.8%), cognitive decline (7 of 17; 41.2%), and cerebellar symptoms (6 of 17; 35.3%). All patients had calcifications on comprehensive cranial CT, most frequently located in the basal ganglia (17 of 17; 100%), cerebellum (17 of 17; 100%), subcortical white matter (14 of 17; 82.4%), and thalamus (13 of 17; 76.5%). CONCLUSIONS We confirmed MYORG as a novel causative gene for primary familial brain calcification and further expanded the mutational and phenotypic spectrum of MYORG-related primary familial brain calcification. © 2018 International Parkinson and Movement Disorder Society.

Finger tapping test is an important neuropsychological test to evaluate human motor function. Most recent researches simplified the finger tapping motion as a scissors-like motion, though the rotation axis of the thumb was different from that of the forefinger. In this paper, we proposed a three-dimensional (3-D) finger tapping measurement system to obtain 3-D pattern features in finger tapping test for patients with Parkinson’s disease (PD). The proposed system collected the motion of the thumb and the forefinger by nine-degrees-freedom sensors and calculated 3-D motion of finger tapping by an orientation estimation method and a 3-D finger-tapping kinematic model. We further extracted 3-D pattern features, i.e. motor coordination and relative thumb motion, from 3-D Finger Tapping motion. Moreover, we used the proposed system to collect the finger-tapping motion of 43 PD patients and 30 healthy controls in horizontal tasks and vertical tasks. The results indicated that 3-D pattern features showed a better performance than one-dimensional features in the identification of mild PD patients.Clinical Relevance— These three-dimensional pattern features could be used to evaluate finger tapping motion in a novel way, which could be used to better identify mild Parkinson’s disease patients. Furthermore, the results showed that a combination of horizontal tasks and vertical tasks might be a better way to identify mild Parkinson’s disease patients.

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. This study aimed to investigate the relationship between vestibular dysfunction and postural abnormalities in PD patients with LTF. 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. 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. Vestibular dysfunction may be an independent risk factor for LTF in PD patients.

Dysphagia is relatively common in patients with Parkinson disease (PD) and can have a negative impact on their quality of life; therefore, it is imperative that its prevalence in PD patients is studied. The aim of this study was to explore the prevalence and clinical correlation of dysphagia in Chinese PD patients. We recruited 116 Chinese PD patients. A videofluoroscopic study of swallowing (VFSS) was used to identify dysphagia. Assessments, including water drinking test, relative motor symptoms, non-motor symptoms (NMS) and quality of life, were performed to analyze the risks of dysphagia. The prevalence of dysphagia was 87.1%. The comparison of demographic and clinical features between patients with and without dysphagia included sex, education level, disease course, Mini-mental State Examination (MMSE), Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Question 6, 7 of the Unified Parkinson Disease Rating Scale (UPDRS Part II), Hoehn-Yahr stage (H&Y), water drinking test, 39-item Parkinson Disease Questionnaire (PDQ-39) and Non-Motor Symptoms Quest (NMSQ). We found significant correlations between dysphagia and age. Using age, disease course, and H&Y stage as the independent variable in our regression analysis for assessing the risk factors of dysphagia in PD patients, age and H&Y stage displayed a strong correlation as the risk factors. The risk of dysphagia in elderly PD patients is 1.078 times greater than that of younger PD patients. Also, the risk of dysphagia in PD patients of a greater H&Y staging is 3.260 times greater than that of lower staging PD patients. Our results suggest that dysphagia is common in Chinese PD patients. Older patients or those in higher H&Y stages are more likely to experience dysphagia. There is no correlation between dysphagia and PD duration.

To explore the genetic basis of a patient with early-onset Parkinson disease from a consanguineous family.Homozygosity mapping and Sanger sequencing of cDNA were used to identify the causative mutation.A homozygous missense variation (c.56CG, p.Thr19Arg) in the PARK7 gene was identified in the patient. In silico analysis suggested the c.56CG variation to be pathogenic.Homozygous c.56CG variation of the PARK7 gene was the disease-causing variation in this family.

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 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 (TTTCA)To identify the cause of familial cortical myoclonic tremor with epilepsy pedigrees without (TTTCA)Repeat-primed polymerase chain reaction, long-range polymerase chain reaction, and Sanger sequencing were performed to identify the existence of a novel (TTTGA)We identified a novel expanded intronic (TTTGA)The targeted long-read sequencing helped us to elucidate the accurate structures of the (TTTGA)

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.

To explore the genetic basis for a Chinese pedigree where three siblings were affected with Parkinson's disease.Multiple ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS) were employed to detect the causative mutation. Sanger sequencing of cDNA was also used for verify the effect of mutation on the transcription of RNA.Heterozygous deletion of exon 3 of the PARK2 gene was detected by MLPA, while a heterozygous splice site variant c.619-3GC was detected by NGS. Both mutations were shown to result in aberrant transcripts of the PARK2 gene (loss of exons 3 and 6, respectively) by Sanger sequencing of cDNA. Both mutations have co-segregated with the disease in the pedigree.Compound heterozygous mutations of the PARK2 gene probably underlie the disease in this pedigree. Identification of the splice site variant c.619-3GC has expanded the mutation spectrum of the PARK2 gene.

Purpose To investigate the differences in spontaneous brain activity between Parkinson's disease (PD) patients with rapid eye movement sleep behavior disorder (RBD), PD patients without RBD, and normal controls, which may shed new light on the neural mechanism of RBD. Materials and Methods Eighteen PD patients with RBD, 16 patients without RBD, and 19 age- and gender-matched normal controls underwent clinical assessment and functional magnetic resonance imaging (fMRI) with a 3.0T scanner. Resting-state fMRI scans were collected using an echo planar imaging sequence. Amplitude of low-frequency fluctuations (ALFF) were calculated to measure spontaneous brain activity in each subject. Results Compared with PD patients without RBD, patients with RBD exhibited significantly decreased ALFF values (P < 0.001, cluster level) in primary motor cortex extending to premotor cortex. Compared with normal controls, PD patients exhibited decreased ALFF values (P < 0.001, cluster level) in caudate and putamen (P < 0.001, cluster level), and increased ALFF values (P = 0.03, cluster level) in prefrontal cortex. Conclusion The altered spontaneous brain activity in motor cortex may contribute to the pathogenesis of RBD in PD patients, which further supports the idea that the pathophysiology of RBD involves not only midbrain dysfunction but also cerebral cortex abnormalities. Our findings provide additional insight into the neural mechanism of RBD and may drive future research to develop better treatment. Level of Evidence: 3 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;46:697–703

Objective Familial cortical myoclonic tremor with epilepsy is a rare epilepsy syndrome. Herein, we report on nine Chinese familial cortical myoclonic tremor with epilepsy pedigrees to delineate its clinical and neurophysiological features. Methods Detailed clinical and neurophysiological data were obtained. Somatosensory evoked potential amplitudes and clinical profile were analyzed using multilevel statistical models. Age-at-onset anticipation was analyzed using Kaplan-Meier survival analysis. Results Fifty-five patients were interviewed directly, whose mean age at onset of cortical tremor and generalized tonic-clonic seizures were 31.0 ± 8.3 and 36.0 ± 7.9 years. Giant somatosensory evoked potential was detected in 87.5% (28 of 32) of patients, and long-latency cortical reflex was detected in 93.5% (29 of 31). Cortical tremor severity was significantly higher in patients with longer disease duration of cortical tremor (P = 0.0061). Somatosensory evoked potential amplitudes were significant higher in patients with higher level of cortical tremor severity (P = 0.0003) and those using antiepileptic drugs (P = 0.0150). Age-at-onset anticipation of cortical tremor with paternal transmission was found with statistical significance (P = 0.022). Conclusion We provided the clinical and neurophysiological features of familial cortical myoclonic tremor with epilepsy patients. This study is reported for the presentation of this rare disease in a Chinese population with the largest single report on familial cortical myoclonic tremor with epilepsy worldwide. Age-at-onset anticipation of cortical tremor with paternal transmission was statistically significant, which further confirmed a possibility of unstable expanding repeat in the genetic mechanism of familial cortical myoclonic tremor with epilepsy. © 2016 International Parkinson and Movement Disorder Society

Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant epilepsy syndrome with considerable clinical and genetic heterogeneity. The most important clinical manifestations include adult onset, cortical myoclonic tremor, with or without epileptic seizures. Of the four loci reported, which included 8q24 (FCMTE1), 2p11.1-q12.2 (FCMTE2), 5p15.31-p15.1 (FCMTE3), and 3q26.32-3q28 (FCMTE4), only one probably causative mutation was found co-segregated in two FCMTE2 pedigrees in the α2-adrenergic receptor subtype B (ADRA2B) gene. In this review we discuss studies that focused on the molecular genetics of FCMTE, its neuropathology, clinical, neurophysiological and neuroimaging features, which may offer useful clues for the search for causative FCMTE genes. Next-generation sequencing has identified many causative genes in monogenic diseases. However, most next-generation sequencing applications focus on detecting single nucleotide variants or small insertions/deletions, which do not completely resolve the challenge of identifying causative genes in FCMTE. Recent progress in exploring FCMTE has revealed that special mutations such as copy number variants, exon rearrangements and large trinucleotide repeat expansion (or polynucleotide repeat expansion) should be considered. Clues from neuropathological, clinical, neurophysiological and neuroimaging studies indicate that the candidate causative genes should be expressed in the cerebellum, especially in Purkinje cells, and be associated with calcium signaling and GABA receptors. We propose that the developing novel algorithms of next-generation sequencing data, which could detect structure variants and candidate causative gene selection when combined with special mutations detection analysis represent possible future direction of a rational search for causative genes in FCMTE.

Background Recently, the LRP10 gene has been identified as a novel genetic cause in individuals affected by Parkinson's disease (PD), Parkinson's disease dementia, or dementia with Lewy bodies. Objective We investigated the involvement of LRP10 mutations in Chinese patients with familial PD and reviewed previous studies of LRP10 mutations in patients with PD. Methods A mutation analysis of the LRP10 gene was performed in a cohort of 205 unrelated Chinese patients with familial PD. Burden analysis was conducted using data from the Genome Aggregation Database and 5 genetic studies of LRP10 in patients with PD (including our cohort). Results A total of 3 novel potentially pathogenic variants, c.32T>A (p.L11H), c.1184G>A (p.R395H), and c.1333G>A (p.A445T), were detected in 3 probands of our cohort. However, burden analysis argued against an overrepresentation of variant alleles in patients with PD. Conclusions Genetic screening of the LRP10 gene in our cohort may provide independent, albeit limited, evidence for the pathogenicity of LRP10 in familial PD. Burden analysis using data from current studies failed to support the association between LRP10 and PD in general. Thus, more robust replication studies are warranted to determine the involvement of LRP10 in the pathogenesis of PD. © 2019 International Parkinson and Movement Disorder Society.

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.

Background Depression is a relatively common and serious nonmotor symptom of Parkinson's disease (PD), which reduces the quality of patients' life. Although disturbances in some related brain networks have been reported, the pathophysiology of depression in PD is still unclear. Here, we aim to investigate whole-brain functional connectivity patterns in depressed PD patients. Methods We recruited 17 PD patients diagnosed with major depressive disorder, 17 PD patients without depression, and 17 healthy control subjects. Resting-state functional MRI and eigenvector centrality mapping were used to identify functional connectivity alterations among these groups. Results Results showed that depressed PD patients had decreased functional connectivity in the left dorsolateral prefrontal cortex and right superior temporal gyrus and increased functional connectivity in the right posterior cingulate cortex, compared to nondepressed patients. In addition, there was a significant negative correlation between functional connectivity and depression scores in the posterior cingulate cortex. Conclusions This study suggests that functional connectivity changes in certain nodes of brain networks might contribute to depression in patients with PD. © 2015 International Parkinson and Movement Disorder Society

Familial cortical myoclonic tremor with epilepsy (FCMTE) is an autosomal dominant epilepsy syndrome. Four loci, including 8q24 (FCMTE1), 2p11.1-q12.2 (FCMTE2), 5p15.31-p15.1 (FCMTE3), and 3q26.32-3q28 (FCMTE4) were previously reported. Herein, we report a new FCMTE1 pedigree from Chinese population with its clinical and genetic study results. Whole genome scan was performed to identify the causative gene region and copy number variants. Whole-exome sequencing was used to identify the causative gene. There were twelve affected members alive in this FCMTE1 pedigree. Nine affected members had both cortical myoclonic tremor and epilepsy, while three affected members had only cortical myoclonic tremor. Electrophysiologic examinations manifested giant somatosensory evoked potentials and long-latency cortical reflex in some affected members. Whole genome scan identified a 20.4 Mb causative gene region at 8q22.3-q24.13. No copy number variants were identified as the causative mutation. Whole-exome sequencing identified a co-segregated mutation (c.206A>T; p.Y69F) in the SLC30A8 gene. However, the evidence supporting this gene as the causative gene of FCMTE1 is not enough. We report the first Chinese FCMTE1 pedigree. No copy number variants, point mutation or small insertion/deletion were detected in the identified region that showed an association with FCMTE1. Further studies could focus on other possible genetic mechanisms while the association between the SLC30A8 and FCMTE1 needs further evidence.

Charcot–Marie–Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is the most common inherited peripheral nerve disorder. Missense mutations, such as K141N, in the small heat shock protein HSPB8 are known to cause distal hereditary motor neuropathy 2A (dHMN2A) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). However, of critical clinical significance, very few specific therapies for this disease exist. In the present study, we investigated the impact of mutant K141N HSPB8 on mitochondrial distribution and function in a cellular model of CMT2L. Our results indicate that K141N HSPB8 induced mitochondrial aggregation and caused increased oxidative stress injury. As an extraction from Chinese celery Apium graveolens Linn seeds, L-3-n-Butylphthalide (NBP), has been reported to exert many neuroprotective effects, we interrogated whether NBP could elicit a protective effect on the cell injury typically caused by HSPB8 K141N mutations. We found NBP could reverse the pathological processes induced by HSPB8 K141N mutation via an antioxidant effect, modulation of the Bax/Bcl-2 mitochondrial apoptotic and Nrf2 pathways. We propose a novel function of HSPB8, highlighting the consequence of the K141N pathogenic mutation. Furthermore, we suggest NBP may have promising therapeutic potential in the treatment of CMT2L.

To investigate the differences in spontaneous brain activity between Parkinson's disease (PD) patients with rapid eye movement sleep behavior disorder (RBD), PD patients without RBD, and normal controls, which may shed new light on the neural mechanism of RBD.Eighteen PD patients with RBD, 16 patients without RBD, and 19 age- and gender-matched normal controls underwent clinical assessment and functional magnetic resonance imaging (fMRI) with a 3.0T scanner. Resting-state fMRI scans were collected using an echo planar imaging sequence. Amplitude of low-frequency fluctuations (ALFF) were calculated to measure spontaneous brain activity in each subject.Compared with PD patients without RBD, patients with RBD exhibited significantly decreased ALFF values (P0.001, cluster level) in primary motor cortex extending to premotor cortex. Compared with normal controls, PD patients exhibited decreased ALFF values (P0.001, cluster level) in caudate and putamen (P0.001, cluster level), and increased ALFF values (P = 0.03, cluster level) in prefrontal cortex.The altered spontaneous brain activity in motor cortex may contribute to the pathogenesis of RBD in PD patients, which further supports the idea that the pathophysiology of RBD involves not only midbrain dysfunction but also cerebral cortex abnormalities. Our findings provide additional insight into the neural mechanism of RBD and may drive future research to develop better treatment.3 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2017;46:697-703.

Recently, Funayama et al. identified CHCHD2 as a novel causative gene of Parkinson disease (PD). However, the relationship between CHCHD2 and essential tremor (ET) patients was still unknown. Genetic analysis of CHCHD2 gene was conducted in 60 probands of ET families with autosomal dominant inheritance and 90 healthy controls in Chinese population. No pathogenic CHCHD2 mutation was found in ET patients. However, we identified one rare variant, c.5C>T, a reported risk variant for sporadic PD in Japanese populations, and examined the frequency of three common variants. Our results suggested that CHCHD2 mutations may be rare in Chinese familial ET patients.

Postural deformities in the coronal plane were frequent and disabling complications of PD, which reduces the quality of life of patients. This study aimed to garner greater attention to the Parkinson disease (PD)-related postural trunk deviations in the coronal plane by exploring a method for diagnosis because of the lack of any uniform diagnostic criteria and epidemiological studies. It also aimed to provide correlation data in the Chinese PD patients. In this cross-sectional study, 503 consecutive outpatients with PD were enrolled who underwent standardized clinical evaluation. The study recruited 83 PD patients diagnosed with Pisa syndrome (PS). Scoliosis and coronal imbalance were diagnosed accurately by radiographic data. The PD patients were compared based on the Cobb angle and coronal balance for several demographic and clinical variables. PD patients with PS had a prevalence of 16.5%. The prevalence of coronal imbalance and scoliosis was 10.34 and 7.75%, respectively. PD patients with PS were older and had a more severe disease, significantly longer disease duration and treatment duration, and reduced quality of life. The most important finding was that the different morphology of the spinal level had an effect on the severity of coronal balance or Cobb angle. The present study indicated that the postural deformities in the coronal plane were related to the morphology of the spinal level, especially the position of the Cobb angle. To benefit the PD patients with PS, the full-length standing spine radiographs should be performed as early as possible.

Familial cortical myoclonic tremor with epilepsy is a rare epilepsy syndrome. Herein, we report on nine Chinese familial cortical myoclonic tremor with epilepsy pedigrees to delineate its clinical and neurophysiological features.Detailed clinical and neurophysiological data were obtained. Somatosensory evoked potential amplitudes and clinical profile were analyzed using multilevel statistical models. Age-at-onset anticipation was analyzed using Kaplan-Meier survival analysis.Fifty-five patients were interviewed directly, whose mean age at onset of cortical tremor and generalized tonic-clonic seizures were 31.0 ± 8.3 and 36.0 ± 7.9 years. Giant somatosensory evoked potential was detected in 87.5% (28 of 32) of patients, and long-latency cortical reflex was detected in 93.5% (29 of 31). Cortical tremor severity was significantly higher in patients with longer disease duration of cortical tremor (P = 0.0061). Somatosensory evoked potential amplitudes were significant higher in patients with higher level of cortical tremor severity (P = 0.0003) and those using antiepileptic drugs (P = 0.0150). Age-at-onset anticipation of cortical tremor with paternal transmission was found with statistical significance (P = 0.022).We provided the clinical and neurophysiological features of familial cortical myoclonic tremor with epilepsy patients. This study is reported for the presentation of this rare disease in a Chinese population with the largest single report on familial cortical myoclonic tremor with epilepsy worldwide. Age-at-onset anticipation of cortical tremor with paternal transmission was statistically significant, which further confirmed a possibility of unstable expanding repeat in the genetic mechanism of familial cortical myoclonic tremor with epilepsy. © 2016 International Parkinson and Movement Disorder Society.

To analyze the clinical and genetic features of a family with Parkinson's disease caused by expansion of CAG triplet repeat in the ATXN2 gene.The CAG/CAA repeat in the ATXN2 gene was analyzed by polymerase chain reaction (PCR) and Sanger sequencing.Molecular testing has documented a pathological heterozygous expansion of the CAG repeat from 33 to 35 in 6 patients and other 8 family members. Two patients had pure CAG triplet repeat expansion in their ATXN2 gene, while others had CAA interruption.Expanded CAG/CAA repeat in the ATXN2 gene is the causative mutation of the disease in this family.The 8 members with expanded CAG/CAA repeat may be asymptomatic patients. It is supposed that the number and configuration of the ATXN2 CAG/CAA repeat expansion may play an important role in the phenotypic variability of Parkinson's disease.

Depression is a relatively common and serious nonmotor symptom of Parkinson's disease (PD), which reduces the quality of patients' life. Although disturbances in some related brain networks have been reported, the pathophysiology of depression in PD is still unclear. Here, we aim to investigate whole-brain functional connectivity patterns in depressed PD patients.We recruited 17 PD patients diagnosed with major depressive disorder, 17 PD patients without depression, and 17 healthy control subjects. Resting-state functional MRI and eigenvector centrality mapping were used to identify functional connectivity alterations among these groups.Results showed that depressed PD patients had decreased functional connectivity in the left dorsolateral prefrontal cortex and right superior temporal gyrus and increased functional connectivity in the right posterior cingulate cortex, compared to nondepressed patients. In addition, there was a significant negative correlation between functional connectivity and depression scores in the posterior cingulate cortex.This study suggests that functional connectivity changes in certain nodes of brain networks might contribute to depression in patients with PD.

Hereditary spastic paraplegia (HSP or SPG) is a group of genetically and clinically heterogeneous neurodegenerative disorders. At least 52 different gene loci have been identified so far, involving autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), and maternal inheritance. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes are responsible for about 50% of pure AD-HSP patients. In this study, SPAST and ATL1 mutations were screened in 36 unrelated HSP patients (17 probands with AD family history and 19 sporadic HSP patients) by direct sequencing and multiplex ligation dependent probe amplification (MLPA). We identified 3 micro-mutations and 2 exon deletions in SPAST gene and 2 micro-mutations in ATL1 gene. Four of five micro-mutations were novel and del. ex. 13–15 in SPAST was not reported previously. In this cohort of Chinese patients with spastic paraplegia, SPAST and ATL1 mutations were found in 5 of 17 HSP probands with AD family history and in 2 of 19 sporadic HSP patients. Four novel micro-mutations and one novel exon deletion were identified, which broadened the mutational spectrum of the genes.

Dural arteriovenous fistula (DAVF) is a rare type of cerebral arteriovenous malformation. The occurrence of parkinsonism together with progressive cognitive dysfunction caused by DAVF has been rarely reported. The probable underlying pathophysiology could be due to venous hypertension caused by DAVF which leads to basal ganglia and cortical dysfunction. Here, two DAVF cases were reported presenting with parkinsonism and progressive cognitive dysfunction. A 54-year-old man (case 1) and a 75-year-old man (case 2) presented with bradykinesia, gait disturbances and cognitive dysfunction who were initially misdiagnosed as having Parkinson's disease. Case 1 exhibited a characteristic type of subcortical calcification on CT scan, while case 2 had specific resting tremor and intracranial hypertension. Both cases showed transient response to the dopaminergic treatment. After 3D time-of-flight (TOF) magnetic resonance arteriography (MRA) or digital subtraction arteriography (DSA), they were diagnosed as having DAVF. This report suggests the possibility of DAVF in patients presenting with parkinsonism and progressive cognitive dysfunction, which requires further attention to be paid, especially in those with transient response to levodopa. Early 3D TOF MRA or DSA is recommended for the diagnosis of DAVF.