A novel homozygous CLN6 Tyr142Cys variant in a nonconsanguineous family with Kufs disease.

BACKGROUND: Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it's rare and challenging to diagnose. CASE DESCRIPTION: The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic-clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband's younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G. CONCLUSION: Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene.

Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript.

Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family. Methods: A comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient's condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro. Results: The patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154-6 C > G in the WDR62 intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons. Conclusion: This study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2.

Removal of Ocular and Muscular Artifacts From Multi-Channel EEG Using Improved Spatial-Frequency Filtering.

Over recent decades, electroencephalogram (EEG) has become an essential tool in the field of clinical analysis and neurological disease research. However, EEG recordings are notably vulnerable to artifacts during acquisition, especially in clinical settings, which can significantly impede the accurate interpretation of neuronal activity. Blind source separation is currently the most popular method for EEG denoising, but most of the sources it separates often contain both artifacts and brain activity, which may lead to substantial information loss if handled improperly. In this paper, we introduce a dual-threshold denoising method combining spatial filtering with frequency-domain filtering to automatically eliminate electrooculogram (EOG) and electromyogram (EMG) artifacts from multi-channel EEG. The proposed method employs a fusion of second-order blind identification (SOBI) and canonical correlation analysis (CCA) to enhance source separation quality, followed by adaptive threshold to localize the artifact sources, and strict fixed threshold to remove strong artifact sources. Stationary wavelet transform (SWT) is utilized to decompose the weak artifact sources, with subsequent adjustment of wavelet coefficients in respective frequency bands tailored to the distinct characteristics of each artifact. The results of synthetic and real datasets show that our proposed method maximally retains the time-domain and frequency-domain information in the EEG during denoising. Compared with existing techniques, the proposed method achieves better denoising performance, which establishes a reliable foundation for subsequent clinical analyses.

Short-Term Efficacy of Cerebello-spinal tDCS and Body Weight-Supported Treadmill Training in the Hypertrophic Olivary Degeneration: a Rare Case Report.

The present case study reported a patient diagnosed with hypertrophic olivary degeneration, a rare condition characterized by a trans-neuronal degeneration and signal enhancement in T2-weighted images on magnetic resonance imaging, usually caused by cerebral hemorrhage, cerebral infarction, and trauma. Furthermore, the relevant literature review was performed. The existing pharmacological treatment has limited clinical benefits on the patient. Since spontaneous remission hardly occurs in the disease, there are no other effective treatments. In this case, the patient was a 55-year-old Chinese male who presented progressive gait difficulty for several months due to both-sided ataxia. Neurological examination revealed upper extremity and lower limb bilateral spasticity, ataxia, slurred speech, and dysmetria. Therefore, our study treated the patient through the inventive application of cerebello-spinal transcranial direct current stimulation and body weight-supported treadmill training. After a 4-week treatment, the patient could walk independently, without aid, speeding up by 7%, as well as the ataxia symptoms, and balance has improved significantly. It was demonstrated in this case report that the combination of cerebello-spinal tDCS and body weight-supported treadmill training can be an effective treatment for patients with Hypertrophic olivary degeneration.

Transcranial Alternating Current Stimulation in a Patient with Ataxia-Ocular Apraxia 2: a Case Report.

Ataxia-ocular apraxia 2 (AOA2) is a rare neurodegenerative autosomal recessive disorder with no effective treatment. In this study, we present the case of a patient diagnosed with AOA2, who experienced walking instability and uncoordinated movement. The patient underwent transcranial alternating current stimulation (tACS) treatment for 4 weeks with follow-up after 1 month. The effectiveness of the treatment was evaluated using the International Cooperative Ataxia Rating Scale (ICARS), the Scale for the Assessment and Rating of Ataxia (SARA), the 9-Hole Peg Test (9HPT), and functional near-infrared spectroscopy (fNIRS). Following treatment, the patient's ataxia symptoms showed significant improvement and continued to be alleviated during the follow-up period, suggesting a lasting effect of tACS treatment. Our findings from this case study provide compelling evidence for the potential of tACS as a treatment option for AOA2.

Vision-based estimation of MDS-UPDRS scores for quantifying Parkinson's disease tremor severity.

Parkinson's disease (PD) is a common neurodegenerative movement disorder among older individuals. As one of the typical symptoms of PD, tremor is a critical reference in the PD assessment. A widely accepted clinical approach to assessing tremors in PD is based on part III of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). However, expert assessment of tremor is a time-consuming and laborious process that poses considerable challenges to the medical evaluation of PD. In this paper, we proposed a novel model, Global Temporal-difference Shift Network (GTSN), to estimate the MDS-UPDRS score of PD tremors based on video. The PD tremor videos were scored according to the majority vote of multiple raters. We used Eulerian Video Magnification (EVM) pre-processing to enhance the representations of subtle PD tremors in the videos. To make the model better focus on the tremors in the video, we proposed a special temporal difference module, which stacks the current optical flow to the result of inter-frame difference. The prediction scores were obtained from the Residual Networks (ResNet) embedded with a novel module, the Global Shift Module (GSM), which allowed the features of the current segment to include the global segment features. We carried out independent experiments using PD tremor videos of different body parts based on the scoring content of the MDS-UPDRS. On a fairly large dataset, our method achieved an accuracy of 90.6% for hands with rest tremors, 85.9% for tremors in the leg, and 89.0% for the jaw. An accuracy of 84.9% was obtained for postural tremors. Our study demonstrated the effectiveness of computer-assisted assessment for PD tremors based on video analysis. The latest version of the code is available at https://github.com/199507284711/PD-GTSN.

Levodopa-Induced Ocular Dyskinesia in an Early-Onset Parkinson Disease Patient With GBA Mutation.

OBJECTIVES: The aim of this study was to report a case of levodopa-induced ocular dyskinesia in an early-onset Parkinson disease patient and to investigate the pathogenic gene. METHODS: We report the case of a 49-year-old male patient with a 13-year history of Parkinson disease. Involuntary eye movements were noticed after treatment with amantadine for limb dyskinesias. Levodopa-induced ocular dyskinesias involving repetitive, transient, and stereotyped rightward deviations of gaze appeared after intake of an antiparkinsonian drug. Limb dyskinesias also occurred simultaneously. We used a next-generation sequencing targeted gene panel and found a heterozygous missense mutation (p.R535H) in GBA. Direct Sanger sequencing verified the missense mutation. CONCLUSIONS: We report the case of an uncommon early-onset PD patient carrying a GBA mutation presenting ocular dyskinesia. Genetic screening may provide a better mechanistic insight into dyskinesias.

Six Visual Rating Scales as A Biomarker for Monitoring Atrophied Brain Volume in Parkinson's Disease.

The focus of our investigation was to determine the feasibility of using six visual rating scales as whole-brain imaging markers for monitoring atrophied brain volume in Parkinson's disease (PD). This was a prospective cross-sectional single-center observational study. A total of 98 PD patients were enrolled and underwent an MRI scan and a battery of neuropsychological evaluations. The brain volume was calculated using the online resource MRICloud. Brain atrophy was rated based on six visual rating scales. Correlation analysis was performed between visual rating scores and brain volume and clinical features. We found a significant negative correlation between the total scores of visual rating scores and quantitative brain volume, indicating that six visual rating scales reliably reflect whole brain atrophy in PD. Multiple linear regression-based analyses indicated severer non-motor symptoms were significantly associated with higher scores on the visual rating scales. Furthermore, we performed sample size calculations to evaluate the superiority of visual rating scales; the result show that using total scores of visual rating scales as an outcome measure, sample sizes for differentiating cognition injury require significantly fewer subjects (n = 177) compared with using total brain volume (n = 2524). Our data support the use of the total visual rating scores rather than quantitative brain volume as a biomarker for monitoring cerebral atrophy.

Combination of autoimmune pancreatitis and peripheral neuropathy on an IgG4-related disease patient with 4 years following-up.

Type1 autoimmune pancreatitis (AIP) is the first recognized and the most common manifestation of IgG4-related disease. However, AIP patient presented with neuropathy in the extremities have not been reported previously. We reported a rare combination of autoimmune pancreatitis and peripheral neuropathy on an IgG4-related disease patient based on histological features to expand the clinical spectrum of IgG4-related disease.

Clinical and genetic features of somatic mosaicism in facioscapulohumeral dystrophy.

PURPOSE: To analyse the clinical spectrum, genetic features, specific D4Z4 hypomethylation status and genotype-phenotype correlations for somatic mosaicism in facioscapulohumeral dystrophy (FSHD). METHODS: This was a prospective, hospital-based, case-control, observational study of 35 participants with FSHD with somatic mosaicism recruited over 10 years, with 17 penetrant patients and 18 non-penetrant mutation carriers. This study also included a univariate comparison of 17 paired mosaic and non-mosaic patients with FSHD. RESULTS: Mosaic participants with FSHD varied in age of diagnosis (median 45; range 15-65 years), muscle strength (FSHD clinical score median 0; range 0-10 points), clinical severity (age-corrected clinical severity score (ACSS) median 0; range 0-467 points), D4Z4 repeats (median 3; range 2-5 units), mosaic proportion (median 55%; range 27%-72%) and D4Z4 methylation extent (median 49.82%; range 27.17%-64.51%). The genotypic severity scale and D4Z4 methylation extent were significantly associated with ACSS (p1=0.003; p2=0.002). Among the matched pairs, the 17 mosaic patients had shorter D4Z4 repeats, lower FSHD clinical scores and lower ACSS than non-mosaic patients. Additionally, 34 of 35 (97%) participants carried two mosaic arrays, while a single patient had three mosaic arrays (3%). Two cases also carried four-type non-mosaic arrays on chromosome 10 (translocation configuration). CONCLUSIONS: Broadly, this large mosaic FSHD cohort exhibited significant clinical heterogeneity and relatively slight disease severity. Both genotypic severity scale and D4Z4 hypomethylation status served as modifiers of clinical phenotypes. Consistent with previous reports, mitotic interchromosomal/intrachromosomal gene conversion without crossover was here identified as a major genetic mechanism underlying mosaic FSHD.

Clinical and genetic characterization of limb girdle muscular dystrophy R7 telethonin-related patients from three unrelated Chinese families.

Limb girdle muscular dystrophy LGMD R7 telethonin-related is a rare autosomal recessive muscle disorder characterized by proximal muscle weakness of pelvic and shoulder girdles. Mutation in TCAP is responsible for LGMD R7, and the disease has a wide geographic distribution in diverse populations, but genotype-phenotype relationships remain unclear. We collected 5 LGMD R7 patients from three unrelated Chinese families. The average onset age was 16 ± 1.41; the initial symptoms included progressive proximal muscle weakness in limbs, difficulty in fast running, and asymmetric muscle atrophy in calves. Muscle MR imaging showed varying severity of fatty infiltration in the pelvic girdle, thigh, and calf muscles, and the severity of muscle infiltration was related to the length of the disease course. Muscle histopathology revealed aberrantly sized muscle fibers, internal nuclei, split fibers, rimmed vacuoles, monocyte invasion, and necrotic fibers. Sequencing identified one novel and one previously reported TCAP mutation. Our study extends the known distribution of this rare muscular dystrophy and presents the first detailed clinical and genetic characterizations of LGMD R7 cases from the Chinese population. Our work expands the mutation spectrum known for LGMD R7 and emphasizes the need for clinicians to consider TCAP mutations when evaluating patients with symptoms of limb girdle muscular dystrophy.

Analysis of Exon Dosage Using Multiplex Ligation-Dependent Probe Amplification in Chinese Patients with Early-Onset Parkinson's Disease.

INTRODUCTION: Several studies have identified a number of genes associated with Parkinson's disease (PD). Genomic rearrangements (exon dosage variations) in these genes have emerged as significant, causing mutations. However, exon dosage variations in several PD genes were rarely investigated in Chinese patients. OBJECTIVE: This study was aimed at determining the prevalence of PD-causing genes' exon rearrangements in Chinese sporadic early-onset PD (EOPD) patients. METHODS: A total of 150 Chinese sporadic EOPD patients and 100 healthy controls were enrolled. Multiplex ligation-dependent probe amplification (MLPA) was used to detect exon dosage in PD genes, including SNCA, PARKIN, UCHL1, PINK1, DJ1, LRRK2, and ATP13A2. Positive results were verified by real-time quantitative polymerase chain reaction. And exon sequencing was employed to screen for subtle mutations. Novel exon dosage variations were screened in families and controls. RESULTS: PARKIN exon rearrangements were detected in 10 (6.7%) patients, including a novel heterozygous duplication of PARKIN exons 1-4. Clinical investigation showed that the percentage of individuals with PARKIN exon rearrangements was higher in the younger patients. Notably, the MLPA screening detected a heterozygous deletion of UCHL1 exon 1 in a patient. MLPA analysis in the family detected the deletion in an asymptomatic sister, indicating incomplete penetrance. CONCLUSION: Exon copy number variations (CNVs) in the PARKIN gene are relatively common among Chinese sporadic EOPD patients, whereas exon CNVs in other known PD genes can also be detected. Our findings demonstrate that it is important to perform exon dosage analysis for several known PD genes to obtain a better mechanistic insight into PD pathogenesis.

A "Triple Trouble" Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a "complex disease plus" patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy. METHODS: Standard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification (MLPA), whole exome sequencing (WES), and targeted methylation sequencing. RESULTS: The patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient's mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES. CONCLUSIONS: The present study described a "tripe trouble" with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.