Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE-S003) in Parkinson's disease.

BACKGROUND: Intranasal transplantation of ANGE-S003 human neural stem cells showed therapeutic effects and were safe in preclinical models of Parkinson's disease (PD). We investigated the safety and tolerability of this treatment in patients with PD and whether these effects would be apparent in a clinical trial. METHODS: This was a 12-month, single-centre, open-label, dose-escalation phase 1 study of 18 patients with advanced PD assigned to four-time intranasal transplantation of 1 of 3 doses: 1.5 million, 5 million or 15 million of ANGE-S003 human neural stem cells to evaluate their safety and efficacy. RESULTS: 7 patients experienced a total of 14 adverse events in the 12 months of follow-up after treatment. There were no serious adverse events related to ANGE-S003. Safety testing disclosed no safety concerns. Brain MRI revealed no mass formation. In 16 patients who had 12-month Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) data, significant improvement of MDS-UPDRS total score was observed at all time points (p<0.001), starting with month 3 and sustained till month 12. The most substantial improvement was seen at month 6 with a mean reduction of 19.9 points (95% CI, 9.6 to 30.3; p<0.001). There was no association between improvement in clinical outcome measures and cell dose levels. CONCLUSIONS: Treatment with ANGE-S003 is feasible, generally safe and well tolerated, associated with functional improvement in clinical outcomes with peak efficacy achieved at month 6. Intranasal transplantation of neural stem cells represents a new avenue for the treatment of PD, and a larger, longer-term, randomised, controlled phase 2 trial is warranted for further investigation.

Identification of TH Variants in Chinese Dopa-Responsive Dystonia Patients and Long-Term Outcomes.

Background: Dopa-responsive dystonia (DRD) is a movement disorder that is highly clinically and genetically heterogeneous. Our study summarizes clinical characteristics and long-term outcomes in patients with dopa-responsive dystonia with the aim of obtaining further knowledge on this disorder. Methods: Patients who met DRD genetic diagnostic criteria through whole-exome sequencing and took levodopa for over 3 years were included in our study. Detailed information was collected on these patients, including family history, age at onset, age and dosage at starting levodopa, current medication and dosage, levodopa duration, diurnal fluctuation, and other clinical features. The Burke-Fahn-Marsden Dystonia Rating Scale-Motor (BFMDRS-M) score was used to evaluate patients' dystonia and variation after levodopa. According to the long-term outcomes, patients were further graded as good (dystonia improved by more than 50% after levodopa, and no further motor symptoms appeared) and poor (dystonia improved by <50% after levodopa, or new motor symptoms appeared). Results: A total of 20 DRD patients were included (11 with GCH1 variants, 9 with TH variants). During long-term levodopa treatment, three patients with TH variants (3/20, 15%) developed motor symptoms, including body jerks and paroxysmal symptoms, and responded well to increasing levodopa doses. The patient with homozygous mutation c.1481C>T/p. Thr494Met harbored more serious symptoms and poor response to levodopa and showed decreased cardiac uptake in MIBG. Conclusions: Most DRD patients showed satisfactory treatment outcomes after long-term levodopa, whereas few patients with TH variants presented motor symptoms, which is considered to be related to dopamine insufficiency. For patients with motor symptoms after long-term levodopa, increasing the dose slowly might be helpful to relieve symptoms.

MELAS/LS Overlap Syndrome Associated With Mitochondrial DNA Mutations: Clinical, Genetic, and Radiological Studies.

Introduction: Mitochondrial diseases are characterized by considerable clinical and genetic heterogeneity. Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS) and Leigh syndrome (LS) are both established mitochondrial syndromes; sometimes they can overlap. Methods: A retrospective observational cohort study was done to analyze the clinical manifestations, biochemical findings, neuroimaging and genetic data, and disease outcomes of 14 patients with identified MELAS/LS overlap syndrome. Results: A total of 14 patients, 9 males and 5 females, were enrolled. The median age at onset was 14 years, while the average age was 12.6 years. As for clinical features in concordance with MELAS, the top three most common symptoms were seizures, cognitive impairment, and stroke-like episodes (SLE). Brain atrophy was present in seven patients. As for the clinical hallmarks of LS, the top three most common symptoms were ataxia, spastic paraplegia, and bulbar palsy. Patients presented with individual syndrome or overlap syndromes with similar frequency, and the prognosis did not seem to be related to the initial presentation. Thirteen patients were identified with MTND mutations, among which m.13513G>A mutation in the MT-ND5 gene was the most common. Only one patient with m.8344A>G mutation of MTTK gene was found. Discussion: Our study demonstrated that MTND genes are important mutation hot spots in MELAS/LS overlap syndrome. The follow-up is very important for the final diagnosis of overlap syndrome.

Dissociative Tremor Response with Pallidal Deep Brain Stimulation in Parkinson's Disease.

Background: Pallidal and subthalamic targets are commonly used for deep brain stimulation in Parkinson's disease (PD), with similar efficacy for resting tremor control. However, neuromodulatory effects on kinetic and postural tremor in PD is less clear. Case Report: We present a 67-year-old PD patient with marked dissociative tremor response following pallidal neuromodulation. We observed excellent resting tremor suppression, but postural and kinetic tremors remained severe, requiring additional thalamic VIM stimulation for management. Discussion: Our findings illustrate the phenotypical differences in PD and differential response to diverse tremor characteristics with distinctive stimulation targets. Additional studies are necessary to understand these differences.

Paraneoplastic cerebellar degeneration associated with anti-protein kinase Cgamma antibodies in a Chinese patient.

Anti-protein kinase Cgamma (anti-PKCγ) antibodies are rare onconeural antibodies associated with paraneoplastic cerebellar degeneration (PCD). To date, only two patients with PCD and anti-PKCγ antibodies have been reported. Here, we report a Chinese patient with PCD and anti-PKCγ antibodies. Screening for tumor revealed lymphoepithelial carcinoma in tonsil. The patient's symptoms improved gradually after radiotherapy for the lymphoepithelial carcinoma and intravenous immunoglobulin immunotherapy.

Non-motor Symptoms in Chinese Patients With Isolated Generalized Dystonia: A Case-Control Study.

Background: Previous studies have indicated that non-motor symptoms are primary problems in focal dystonia, but limited data are available about non-motor problems and their correlation with motor severity in generalized dystonia (GD). Methods: In the present study, we performed a case-control study and enrolled isolated inherited or idiopathic GD patients and age- and sex-matched healthy controls (HC). Clinical characteristics, motor symptoms, non-motor problems, including psychiatric co-morbidity, sleep problems, fatigue, and quality of life (QoL) were assessed in both groups using various rating scales and assessments. Results: Thirty-three patients with GD and 33 controls were enrolled. Significant higher scores on depression and anxiety (p < 0.001) were shown in GD compared with HC, whereas the frequency of obsessive-compulsive disorders approached that of HC (p = 0.238). Patients with GD also had significantly higher Pittsburg Sleep Quality Index (PSQI) and fatigue scores than HC, whereas no difference was observed in excessive daytime somnolence. In GD, QoL was more impaired, with statistically lower scores in both physical and mental components. Psychiatric rating scales did not correlate to motor severity or disease duration but might influence quality of sleep. Subgroup analysis suggests non-motor manifestations differ with different etiologies in GD. Conclusion: This study suggests that non-motor symptoms in GD, such as psychiatric problems, are likely to be primary determinants not correlated to motor severity, which may also affect quality of sleep and fatigue.

Biopsy histopathology in the diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

AIM: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an inherited rare disease affecting young adults. We present the clinical, imaging, and neuropathological results of our case series, emphasizing biopsy histology combined with clinical information will increase the accuracy of early diagnosis. METHODS: In total, 4 females and 2 male ALSP patients with onset at ages 24-45 years were enrolled. Clinical manifestations, neuroimaging, and histopathology as well as gene mutation were analyzed and compared with literature. RESULTS: Clinical manifestations include cognitive decline with/without psycho-behavior problems and movement disorders including paralysis, hemiplegia, parkinsonism, and pyramidal tract injury, as well as dysarthria, dysphagia, and sensory disturbances. MRI showed multiple periventricular and subcortical white matter lesions, involving the corpus callosum, with no enhancement, but with persistent hyperintensity on diffuse-weighted imaging. Histology showed widespread white matter damage and pale stain, especially destroyed axons with spheroids and funicular axons which were stained with neurofilament and ubiquitin. Foamy and pigmented macrophages were another typical change. CSF1R mutation was found in 4 of them. All of the patients were misdiagnosed and treated for a long time for multiple sclerosis, cerebral infarction, normal pressure hydrocephalus, etc. CONCLUSION: ALSP will cause rapidly progressing dementia with/without movement disorders in young adults. The definite diagnosis should be based on a comprehensive analysis of clinical manifestations, and neuroimaging, histology, and genetic results. Early biopsy will add to the accuracy of the diagnosis.

Identification of Novel KMT2B Variants in Chinese Dystonia Patients via Whole-Exome Sequencing.

Background: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Recently mutations in lysine-specific histone methyltransferase 2B (KMT2B) gene have been reported to be associated with early-onset progressive dystonia. Methods: We performed whole-exome sequencings (WES) in a cohort of early-onset dystonia patients from China. Bioinformatics analysis and cosegregation testings were conducted to select candidate causal variants. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. Results: Three novel KMT2B variants were identified, including p.Q1359* in patient 1, p.R1487AfsTer7 in patient 2, and p.R152W in patient 3. Among these variants, the nonsense variant p.Q1359* and the frameshift variant p.R1487AfsTer7 showed high pathogenicity and were rated as pathogenic according to the ACMG guideline. Regarding the phenotypes of these two patients with pathogenic variants, patient 2 showed the similar presentation as reported whereas patient 1 seemly harbored the atypical presentations, including later onset age, atypical sites of onset and milder degree of dystonia. Conclusions: We further report three dystonia patients with novel variants in KMT2B and expand the spectrums of genotype and phenotype of KMT2B.

ANO3 Mutations in Chinese Dystonia: A Genetic Screening Study Using Next-Generation Sequencing.

Background: Dystonia-24 (DYT24) is a monogenic autosomal dominant dystonia caused by mutations in the gene ANO3, which has shown phenotypic and genotypic heterogeneity according to previous reports. Objective: To screen and identify ANO3 mutations in a cohort of patients with dystonia in China and to expand the spectrum of DYT24. Methods: This study screened ANO3 mutations in 187 Chinese dystonia patients using next-generation sequencing (NGS). In silico investigations were conducted in detected ANO3 variants and co-segregation analysis was carried out if applicable. The effects of identified variants were classified according to the standards and guidelines of the American College of Medical Genetics and Genomics (ACMG). Results: Four different variants were identified in four unrelated dystonia patients, including three missense variants [c.1789G>C (p.V600L), c.182A>C (p.E61A), c.787A>G (p.M263V)] and one splice site change (c.1714-3T>C). The novel missense mutation c.1798G>C (p.V600L), identified in a teenaged girl with generalized dystonia, showed high pathogenicity and was classified as "likely pathogenic" according to ACMG guidelines. Of note, she responded well to deep brain stimulation. Conclusion: Our study helps expand the mutational and clinical spectrum of DYT24 due to ANO3 mutations by further reporting four variants. Rare ANO3 variants appear to represent an uncommon cause of dystonia in China.

Targeted gene capture sequencing in diagnosis of dystonia patients.

BACKGROUND: Dystonia is a movement disorder with high clinical and genetic heterogeneity. Molecular diagnosis is important for an accurate diagnosis of dystonia. Targeted gene capture sequencing has been an effective method for screening multiple candidate genes simultaneously. This method, however, has been rarely reported to be used with dystonia patients. OBJECTIVES AND METHODS: To assess the effectiveness of the targeted gene capture sequencing in dystonia, we performed custom target gene capture followed by next-generation sequencing in dystonia patients from China. Sanger sequencing was utilized to substantiate the findings. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: A total of 65 patients (34 female and 31 male) were recruited in this study. The mean age at onset was 22.7 ±â€¯13.3 years ranging from 2 to 59 years. According to ACMG standards and guidelines, of 65 patients, 12 were identified with pathogenic variants (12/65, 18.5%) in gene TOR1A, PANK2 or ATP1A3, and another four were identified with likely-pathogenic variants (4/65, 6.2%) in gene PRRT2, GCH1 or THAP1. In total, 24.6% of patients in this cohort were detected to have a genetic cause of dystonia. Another four patients (4/65, 6.2%) were identified with variants which were considered to be VUS (Variants of Uncertain Significance) in gene SGCE, TH, ANO3 and ATP1A3 respectively. The most common detected gene was TOR1A, known to be causative for DYT1 (8/65, 12.3%). CONCLUSIONS: The study demonstrates that targeted gene capture sequencing is an effective tool for identifying the genetic cause of heterogeneous dystonia patients.

Pallidal Deep Brain Stimulation in Patients With Chorea-Acanthocytosis.

INTRODUCTION: Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disorder caused by the mutation of gene VPS13A. Deep brain stimulation of ChAc has made substantial progress in the recent decades. However, the reports were scattered across centers and performed by different neurosurgeons. Here, we report a case series consisting of six patients diagnosed with ChAc, receiving bilateral high-frequency stimulation of globus pallidus internus (GPi) in a single center. METHODS: We report six consecutive patients diagnosed with ChAc and present a review of the literature. All patients received neurological evaluations using the Unified Huntington's Disease Rating Scale (UHDRS) motor score before surgery and during clinical follow-ups. One patient was observed over six months, while five patients were seen over 12 months. RESULTS: All patients underwent high-frequency stimulation ranging from 130 Hz to 175 Hz. In the follow-up period, a general trend was found toward higher amplitude and broader pulse widths, with a mean current range of 2.08 mA to 3.06 mA and a mean pulse width range of 75 µsec to 98 µsec. On preoperative evaluation, the mean UHDRS motor score was 35.7 ± 16.3 and the chorea subscore was 11.3 ± 4.7. At the three-month postoperative follow-up, both UHDRS motor score (13.5 ± 5.8) and chorea subscore (3.0 ± 1.2) reached valley values. Thereafter, the UHDRS motor score and chorea subscore showed a gradual rise, reaching 19.2 ± 5.9 and 4.8 ± 1.7, respectively, at the 12-month follow-up. In addition, adverse events were also seen. Patient 1 developed dysarthria six months after surgery, whereas Patient 6 had a generalized tonic-clonic seizure attack one day after surgery CONCLUSION: High frequency stimulation of the GPi is an effective and safe modality for the treatment of ChAc, with both rapid symptomatic improvements and steady chronic outcomes.

Subthalamic Nuclei Stimulation in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN).

INTRODUCTION: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive genetic disease that leads to extrapyramidal symptoms, such as dystonia, ataxia, dysarthria, and involuntary movements. Treatment of PKAN with deep brain stimulation (DBS) has been reported, but mainly focuses on targeting the globus pallidus internus (GPi). Subthalamic nuclei (STN) may also be a potential target for treatment of PKAN. METHODS: In this study, we reviewed three patients with PKAN (two with typical PKAN and one with atypical PKAN) treated by bilateral STN stimulation and present a review of the literature. All patients received neurological evaluation using the Burke-Fahn-Marsden Dystonia Rating Scale-movement (BFMDRS) scoring system before and after surgery. Patients were then subject to regular clinical follow-ups (ranging from 22 to 44 months). RESULTS: The mean stimulation amplitude, pulse width and frequency was 2.65 ± 0.45 V, 91.7 ± 21.9 µs, and 146.7 ± 12.5 Hz, respectively. BFMDRS scores were improved in all patients after surgery, ranging from 41.6 to 73.1%. Improvements of appendicular symptoms ranged from 46.2 to 94.1%, and improvements of axial symptoms ranged from 27.3 to 33.3%. No side effects were reported in patients 1 and 2; whereas patient 3 exhibited a mild decline in verbal fluency one year after surgery. CONCLUSION: STN stimulation could serve as a candidate DBS target in the treatment of PKAN, especially for patients with prominent appendicular symptoms.

Brain-derived neurotrophic factor Val66Met polymorphism is not associated with primary dystonia in a Chinese population.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a modulator of synaptic and neural plasticity. Considering the association between dystonia and abnormal sensorimotor cortex plasticity, BDNF may be a candidate gene that confers susceptibility to dystonia. However, the association between Val66Met polymorphism of BDNF gene and primary dystonia is controversial. METHODS: A case-control study was performed to evaluate the association between Val66Met polymorphism in the BDNF gene and primary dystonia in a cohort of 252 Chinese patients and in 214 age- and gender-matched healthy control subjects. RESULTS: No association was identified between Val66Met polymorphism and primary dystonia or cervical dystonia (P=0.309 and P=0.803 respectively). In a subsequent subgroup analysis, there was also no difference in the distribution for age of onset. CONCLUSION: Our findings do not support that BDNF Val66Met polymorphism contributes to the risk of primary dystonia.

Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas.

CONTEXT: The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. OBJECTIVE: Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch repair (MMR) genes in the tumors, and to evaluate the possibility to distinguish benign and malignant insulinoma or to predict the clinical outcome of patients with these alterations. DESIGN AND PATIENTS: We detected MSI and inactivation of MLH1 gene in 55 sporadic insulinomas by PCR, immunohistochemical staining, allelic typing, analysis of promoter methylation, and exon mutations. Their correlations with clinicopathological characteristics were analyzed with univariate and multivariate statistic analysis. RESULTS: A high rate of MSI (MSI-H) was found in 33% of sporadic insulinomas. Reduced expression of mutL homolog 1 (MLH1) protein was observed in 36% of insulinomas and correlated with MSI-H (P = 0.008). Promoter methylation and loss of heterozygosity of MLH1 gene was found in 31 and 49% of insulinomas, respectively. Reduced expression of MLH1 and MSI-H were significantly associated with both tumor malignancy (P = 0.033 and P = 4.8 x 10(-6), respectively) and incurable disease (P = 0.006 and P = 0.001, respectively). CONCLUSION: High frequency of MSI occurred in sporadic insulinomas. The silencing of MLH1 gene may partially contribute to the MSI-H in the tumors. Assessing MSI-H and expressions of MLH1 could be used to distinguish benign and malignant insulinomas and to predict the outcome of patients.