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.

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.

A de novo variant of POLR3B causes demyelinating Charcot-Marie-Tooth disease in a Chinese patient: a case report.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, which are subdivided into demyelinating and axonal forms. Biallelic mutations in POLR3B are the well-established cause of hypomyelinating leukodystrophy, which is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. To date, only one study has reported the demyelinating peripheral neuropathy phenotype caused by heterozygous POLR3B variants. CASE PRESENTATION: A 19-year-old male patient was referred to our hospital for progressive muscle weakness of the lower extremities. Physical examination showed muscle atrophy, sensory loss and deformities of the extremities. Nerve conduction studies and electromyography tests revealed sensorimotor demyelinating polyneuropathy with secondary axonal loss. Trio whole-exome sequencing revealed a de novo variant in POLR3B (c.3137G > A). CONCLUSIONS: In this study, we report the case of a Chinese patient with a de novo variant in POLR3B (c.3137G > A), who manifested demyelinating CMT phenotype without additional neurological or extra-neurological involvement. This work is the second report on POLR3B-related CMT.

Cortical Excitability in Temporal Lobe Epilepsy with Bilateral Tonic-Clonic Seizures.

OBJECTIVE: We investigated motor cortical excitability (CE) in unilateral temporal lobe epilepsy (TLE) and its relationship to bilateral tonic-clonic seizure (BTCS) using paired-pulse transcranial magnetic stimulation (TMS). METHODS: In this cross-sectional study, we enrolled 46 unilateral TLE patients and 16 age-and sex-matched healthy controls. Resting motor thresholds (RMT); short-interval intracortical inhibition (SICI, GABAA receptor-mediated); facilitation (ICF, glutamatergic-mediated) with interstimulus intervals (ISIs) of 2, 5, 10, and 15 ms; and long-interval intracortical inhibition (LICI, GABAB receptor-mediated) with ISIs of 200-400 ms were measured via paired-pulse TMS. Comparisons were made between controls and patients with TLE, and then among the TLE subgroups (no BTCS, infrequent BTCS and frequent BTCS subgroup). RESULTS: Compared with controls, TLE patients had higher RMT, lower SICI and higher LICI in both hemispheres, and higher ICF in the ipsilateral hemisphere. In patients with frequent BTCS, cortical hyperexcitability in the ipsilateral hemisphere was found in a parameter-dependent manner (SICI decreased at a stimulation interval of 5 ms, and ICF increased at a stimulation interval of 15 ms) compared with patients with infrequent or no BTCS. CONCLUSIONS: Our results demonstrate that motor cortical hyper-excitability in the ipsilateral hemisphere underlies the epileptogenic network of patients with active BTCS, which is more extensive than those with infrequent or no BTCS.

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.

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.

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.

Clinical and neurophysiological features of familial cortical myoclonic tremor with epilepsy.

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.

Transcorneal electrical stimulation promotes survival of retinal ganglion cells after optic nerve transection in rats accompanied by reduced microglial activation and TNF-α expression.

Microglial activation plays a crucial role in the pathological processes of various retinal and optic nerve diseases. TNF-α is a pro-inflammatory cytokine that is rapidly upregulated and promotes retinal ganglion cells (RGCs) death after optic nerve injury. However, the cellular source of TNF-α after optic nerve injury remains unclear. Thus, we aimed to determine the changes of retinal microglial activation in a rat model of optic nerve transection (ONT) after transcorneal electrical stimulation (TES). Furthermore, we assessed TNF-α expression after ONT and evaluated the effects of TES on TNF-α production. Rats were divided into 2 control groups receiving a sham surgery procedure, 2 ONT+Sham TES groups, and 2 ONT+TES groups. The rats were sacrificed on day 7 or 14 after ONT. RGCs were retrogradely labelled by Fluorogold (FG) 7 days before ONT, one TES group and corresponding controls were stimulated on day 0, 4, and the second were stimulated on day 0, 4, 7, 10. Whole-mount immunohistofluorescence, quantification of RGCs and microglia, and western blot analysis were performed on day 7 and 14 after ONT. TES significantly increased RGCs survival on day 7 and 14 after ONT, which was accompanied by reduced microglia on day 7, but not 14. TNF-α was co-localized with ameboid microglia and significantly increased on day 7 and 14 after ONT. TES significantly reduced TNF-α production on day 7 and 14 after ONT. Our study demonstrated that TES promotes RGCs survival after ONT accompanied by reduced microglial activation and microglia-derived TNF-α production.

[The significance of quantitative temperature sense thresholds in diagnosis of small fibrous sensory neuropathy in patients with type 2 diabetes].

OBJECTIVE: To evaluate the small fiber function in patients with type 2 diabetes mellitus of the early stage by measuring the sensory threshold with the quantitative temperature testing technology. METHODS: Twenty cases of patients with type 2 diabetes with no neurological deficit (DM group) and twenty age and sex-matched healthy controls underwent the detecting of cold sensory threshold (CST), warm sensory threshold (WST), cold pain threshold (CPT), heat pain threshold (HPT) in both inside of their hands. RESULTS: There was no significant difference in CST, WST, CPT and HPT between left and right inside of hand of the same sample among all the testers. But the four kinds of threshold showed significant difference in the right inside of hand between patients and healthy people ( P < 0.05). In addition, the CST and WST differed significantly in the left inside of hand between the patients and healthy controls while the CPT and HPT showed no significant difference in the left inside of hand between them. Patients group and control group with CST and WST on the left side of the comparison difference was statistically significant (P < 0.05). CONCLUSION: Quantitative analysis of temperature sense threshold can not only reflect increase of the pain threshold value, also can reflect its decrease, i. e. hyperalgesia, which may help to diagnose small fibrous peripheral neuropathy recognition, especially in early diabetic peripheral neuropathy.

Fine mapping and whole-exome sequencing of a familial cortical myoclonic tremor with epilepsy family.

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.

[Event-related potentials P300 with memory function and psychopathology in first-episode paranoid schizophrenia].

OBJECTIVE: To investigate the variability of event-related potentials P(300) and the relationship with memory function/psychopathology in patients with first-episode paranoid schizophrenia. METHODS: Thirty patients with first-episode paranoid schizophrenia (patient group) and twenty health subjects (control group) were enrolled in the study. The auditory event-related potentials P300 at the scalp electrodes Cz, Pz and Wechsler Memory Scale (WMS) were examined in both groups, Positive And Negative Syndrome Scale (PANSS) was evaluated in patient group. RESULTS: In comparison with control group, patients had longer latency of P300 [(390.6 ± 47.6)ms at Cz and (393.3 ± 50.1)ms at Pz] (P<0.01), lower amplitude of P300 [(7.7 ± 3.4) µV at Cz and (8.5 ± 3.9)µV at Pz] (P<0.05-0.01). The memory quotient (88.1 ± 10.0) scores and short-term memory, immediate memory in patient group were damaged significantly (P<0.05-0.01). In patient group, the latency of P300 was correlated positively with PANSS scores and negatively with WMS scores (P<0.05-0.01). CONCLUSION: First-episode paranoid schizophrenia has memory deficit, which can be evaluated comprehensively by P300 and WMS. The longer latency of P300 might be associated with the increased severity of first-episode paranoid schizophrenia.

Clinical features and Cu/Zn superoxide dismutase gene mutations in two mainland Chinese families with amyotrophic lateral sclerosis.

Clinical information of two families with amyotrophic lateral sclerosis (ALS) was studied and a mutation analysis of the SOD1 gene was performed using direct DNA sequencing. Two previously reported mutations of the SOD1 gene, G20T (Cys6Phe substitution), and G255C (Leu84Phe substitution), were identified and cosegregated with the disease in the two families. Patients with a Cys6Phe mutation demonstrated rapid disease progression with severe clinical phenotypes, and the patients with a Leu84Phe mutation had a variety of different clinical phenotypes. This is the third report of SOD1 gene mutations in Mainland Chinese patients with different ALS phenotypes. This supports the hypothesis that the clinical course of ALS may vary depending on the specific genetic mutation.

Clinical manifestations and management of acute thallium poisoning.

Clinical information regarding 3 patients diagnosed with acute thallium poisoning was collected and retrospectively analyzed. All 3 patients presented with severe burning pain in the lower limbs and the abdomen. Diffuse alopecia, hepatic dysfunction and Mees' lines in the digits of each limb were observed between 2 and 3 weeks after onset. A physical examination demonstrated paresthesia of all 4 limbs, but normal deep tendon reflexes. Blood and urine thallium concentrations were significantly elevated. Treatment was initiated using hemoperfusion, hemodialysis, potassium supplementation, oral laxatives and B complex supplementation. Clinical symptoms improved as blood and urine thallium concentrations decreased, although a residual sensory neuropathy remained. This study demonstrated that the primary clinical manifestations of acute thallium poisoning include gastrointestinal symptoms, polyneuropathy and dermatological changes. Hemoperfusion and hemodialysis may be effective treatments for acute thallium poisoning.

[Clinical and genetic analysis of a pedigree of myotonic dystrophy disease].

OBJECTIVE: To investigate the clinical manifestations and to make genetic analysis in a pedigree with myotonic dystrophy disease. METHODS: The proband and available family members were identified by neurological examination. The clinical manifestation of 8 patients (including the proband) was analyzed; the electromyographic data of 5 patients were compared with 6 other family members. Blood samples were obtained from the 7 patients of the family (excepting II6). DM(1) and DM(2) gene were amplified by PCR, tested by agarose electrophoresis, then analyzed by genetic analyzer. RESULTS: Myotonia and muscle weakness were the main manifestations associated with heart block (7/8) and cataract(6/7). Electromyologram showed myopathic abnormalities not only in patients but also in other members of the family (5/6). The CTG repeats in DM1 and CCTG repeats in DM2 were all in normal range. CONCLUSION: There likely to be new mutants in this DM pedigree and further study is needed.

[Study of the neuropsychology and aural event related evoked potential on patients with the infarction in basal ganglia region].

AIM: To learn the condition of the memory and the visual space of the patient who has suffered from the infarction in basal ganglia region, and to analyze its impact on and the characteristics of the patients' cognition. METHODS: By testing respectively on 21 subjects who were initially infarcted in basal ganglia with single focus on one side, and 21 healthy volunteers with corresponding age, gender and educational background with Rey-Osterrieth Complex Figure Scale (Rey), Clinical Memory Scale (CMS), Hospital Anxiety-Depression Scale (HAD), National Institute of Health Stroke Scale (NIHSS), Oxford Handicap Scale (OHS), Barthel Index (BI), and Aural Event Related Evoked Potential (AERP) as well. RESULTS: Compared with the control group, the patient group got higher scores of anxiety and depression in HAD), which showed absolutely statistical significance; they demonstrated longer reaction time in AERP, which also showed statistical significance; and in CMS. they displayed inferior performance in the free picture recall and the memory quotient (MQ), which again had statistical significance. However, compared with the control group, the patient group got scores with no significance in copy, immediate recall and delayed recall in Rey. CONCLUSION: The infarction in basal ganglia region with single focus on one side may impact on the patient's executive function, memory function and emotion. But no impact is showed on patient's visual space function.