Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies
HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.
KEY FINDINGS: HCN4 provides a biomarker for the genetic spectrum of mTORopathies and may present a potential therapeutic target for seizure control in mTOR-related epilepsy.
BACKGROUND: Pathogenic variants in PI3K-AKT-mTOR pathway and GATOR1 complex genes resulting in hyperactivation of mechanistic target of rapamycin (mTOR) complex 1 are a major cause of drug-resistant epilepsy and focal cortical malformations (FCM). Resective neurosurgery is often required to achieve seizure control in patients with mTORopathies due to lack of effectiveness of nonsurgical therapies, including antiseizure medication and mTOR inhibitors. Elevated hyperpolarization-activated cyclic nucleotide-gated potassium channel isoform 4 (HCN4) has been proposed as a key marker in some mTOR-related brain malformations. This study aimed to investigate HCN4 as a biomarker in the brain across the genetic spectrum of mTORopathies in humans.
DETAILS: The study investigated the relative steady-state levels and cellular localization of HCN4 in resected human brain tissue from 18 individuals with mTORopathies (3 individuals with tuberous sclerosis complex (TSC) due to TSC2 variants, 5 individuals with focal cortical dysplasia type IIA (FCD IIA) due to genetic variants in MTOR, AKT3, and PIK3CA, and 10 individuals with FCD IIB due to variants in TSC1, MTOR, RHEB, DEPDC5, or NPRL3). Elevated HCN4 was observed to be highly restricted to abnormal cell types (dysmorphic neurons and balloon cells) in brain tissue from all mTORopathy tissues (p < 0.0001) compared with those in controls, regardless of genetic cause or variant allele frequency. Elevated HCN4 was not observed in controls or individuals with non-mTOR-related focal epilepsy due to pathogenic variants in ATP1A3, SLC35A2, or FGFR1.
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Source: Coleman, M., Pinaes-Garcia, P., Stephenson, S. E., et al. (2024). Ectopic HCN4 Provides a Target Biomarker for the Genetic Spectrum of mTORopathies. Neuro Genetics. 2024; 10(2). Published: March, 2024. DOI: 10.1212/NXG.0000000000200135.
GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia
GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.
KEY FINDINGS: GPi-DBS increases metabolic activity at the stimulation site and sensorimotor network. The clinical benefit and adverse effects are mediated by modulation of specific networks.
BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus interna (GPi) is a highly efficacious treatment for cervical dystonia, but its mechanism of action is not fully understood. Here, we investigate the brain metabolic effects of GPi-DBS in cervical dystonia.
DETAILS: Eleven patients with GPi-DBS underwent brain 18F-fluorodeoxyglucose positron emission tomography imaging during stimulation on and off. Changes in regional brain glucose metabolism were investigated at the active contact location and across the whole brain. Changes in motor symptom severity were quantified using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), executive function using trail making test (TMT) and parkinsonism using Unified Parkinson's Disease Rating Scale (UPDRS). The mean (SD) best therapeutic response to DBS during the treatment was 81 (22)%. The TWSTRS score was 3.2 (3.9) points lower DBS on compared with off (p=0.02). At the stimulation site, stimulation was associated with increased metabolism, which correlated with DBS stimulation amplitude (r=0.70, p=0.03) but not with changes in motor symptom severity (p>0.9). In the whole brain analysis, stimulation increased metabolism in the GPi, subthalamic nucleus, putamen, primary sensorimotor cortex (PFDR0.05). Acute improvement in TWSTRS correlated with metabolic activation in the sensorimotor cortex and overall treatment response in the supplementary motor area. Worsening of TMT-B score was associated with activation of the anterior cingulate cortex and parkinsonism with activation in the putamen.
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Source: Honkanen E. A., Rönkä J., Pekkonen E., et al. (2024). GPi-DBS-Induced Brain Metabolic Activation in Cervical Dystonia. Journal of Neurology, Neurosurgery & Psychiatry. 2024; 95(4): 300-308. Published: April, 2024. DOI: 10.1136/jnnp-2023-331668.
Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant
This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.
KEY FINDINGS: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.
BACKGROUND: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy.
DETAILS: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records. All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene.
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Source: Baskar, D., Polavarapu, K., Preethish-kumar, V., et al. (2024). Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant. Neuro Genetics. 2024; 10(1): Published: February, 2024. DOI: 10.1212/NXG.000000000020012.
Enhancing Functional Recovery Following Postpartum Femoral Neuropathy
The case report describes how an early multimodal rehabilitation program within a multidisciplinary framework allows for sooner neuromotor function improvement and activities of daily living independence.
Summary
Early Neurorehabilitation and Multidisciplinary Obstetric Care
[Posted 5/Mar/2024]
AUDIENCE: Ob/Gyn, Neurology
KEY FINDINGS: The case report describes how an early multimodal rehabilitation program within a multidisciplinary framework allows for sooner neuromotor function improvement and activities of daily living independence.
BACKGROUND: Postpartum femoral neuropathy has a reported incidence of less than 1% and its total recovery time extends up to 6 months to a year. A multidisciplinary approach is vital to rule out permanent disability and to assure a correct diagnosis and earlier rehabilitation.
DETAILS: Authors report a case of a 37-year-old puerperal woman with a history of intrapartum epidural analgesia, who presented post-labor unilateral lower-limb motor weakness and sensory loss, with functional compromise on independent gait. A multidisciplinary team consisting of an anesthesiologist, a physiatrist, a neurologist, and an obstetrician was then established. In the initial physiatry and neurology assessment, the patient reported pain (numerical rating scale 7/10) over the inguinal ligament, lower limb hypoesthesia, and muscle weakness. Femoral neuropathy was suspected. Magnetic resonance imaging ruled out potential complications related to the anesthetic procedure. The patient was then enrolled in a supervised rehabilitation program and, 3 weeks later, electrodiagnostic studies confirmed the initial suspicion. Two months later, the patient had regained lower-limb active range of motion and no pain nor paresthesia was reported.
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Copyright © John Wiley & Sons, Inc. All rights reserved
Source: Goncalves, E. M., Lanzaro, C., Silva, L. C., et al. (2024). Enhancing Functional Recovery Following Postpartum Femoral Neuropathy: Early Neurorehabilitation and Multidisciplinary Obstetric Care. Intl J Gynecol Obstet.. 2024; 164(3): 830-834. Published: March, 2024. DOI: 10.1002/ijgo.15025.
Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment
The review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.
KEY FINDINGS: This review highlights the importance of targeting the frontopolar area and tailoring the treatment according to interindividual variations in brain state and trait and electric field distribution patterns. This converging evidence supports the potential for treatment optimization through context, target, dose, and timing dimensions to improve clinical outcomes of transcranial brain stimulation in people with substance use disorders in future clinical trials.
BACKGROUND: Noninvasive brain stimulation technologies such as transcranial electrical and magnetic stimulation (tES and TMS) are emerging neuromodulation therapies that are being used to target the neural substrates of substance use disorders.
DETAILS: By the end of 2022, 205 trials of tES or TMS in the treatment of substance use disorders had been published, with heterogeneous results, and there is still no consensus on the optimal target brain region. Recent work may help clarify where and how to apply stimulation, owing to expanding databases of neuroimaging studies, new systematic reviews, and improved methods for causal brain mapping. Whereas most previous clinical trials targeted the dorsolateral prefrontal cortex, accumulating data highlight the frontopolar cortex as a promising therapeutic target for transcranial brain stimulation in substance use disorders. This approach is supported by converging multimodal evidence, including lesion-based maps, functional MRI-based maps, tES studies, TMS studies, and dose-response relationships.
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Source: Soleimani, G., Joutsa, J., Moussawi, K., et al. (2024). Converging Evidence for Frontopolar Cortex as a Target for Neuromodulation in Addiction Treatment. American Journal of Psychiatry. 2024; 181(2): 100-114. Published: February, 2024. DOI: 10.1176/appi.ajp.20221022.
A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP
A novel Alu element insertion identified in the 3'UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 3'UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies.
KEY FINDINGS: Authors identified a novel Alu element insertion in the 3'UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 3'UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies.
BACKGROUND: Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but the causal variant at this locus remains unclear. Here, we asked whether a novel structural variant on TMEM106B is the causal variant.
DETAILS: An exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on an Alu element insertion on the 3'UTR of TMEM106B. This study included data from longitudinal aging and neurogenerative disease cohorts at Stanford University, case-control cohorts in the Alzheimer Disease Sequencing Project (ADSP), and expression and proteomics data from Washington University in St. Louis (WUSTL). Four hundred thirty-two individuals from 2 Stanford aging cohorts were whole-genome long-read and short-read sequenced. A total of 16,906 samples from ADSP were short-read sequenced. Genotypes, transcriptomics, and proteomics data were available in 1,979 participants from an aging and dementia cohort at WUSTL. Selection criteria were specific to each cohort. In primary analyses, the linkage disequilibrium between the TMEM106B locus variants in the FTLD-TDP GWAS and the 3'UTR insertion was estimated. We then estimated linkage by ancestry in the ADSP and evaluated the effect of the TMEM106B lead variant on mRNA and protein levels. The primary analysis included 432 participants (52.5% female, age range 45–92 years). We identified a 316 bp Alu insertion overlapping the TMEM106B 3'UTR tightly linked with top GWAS variants rs3173615(C) and rs1990622(A). In ADSP European ancestry participants, this insertion is in equivalent linkage with rs1990622(A) (R2 = 0.962, D' = 0.998) and rs3173615(C) (R2 = 0.960, D' = 0.996). In African ancestry participants, the insertion is in stronger linkage with rs1990622(A) (R2 = 0.992, D' = 0.998) than with rs3173615(C) (R2 = 0.811, D' = 0.994). In public data sets, rs1990622 was consistently associated with TMEM106B protein levels but not with mRNA expression. In the WUSTL data set, rs1990622 is associated with TMEM106B protein levels in plasma and CSF, but not with TMEM106B mRNA expression.
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Source: Chemparathy, A., Guen, Y. L. Zeng, Y., et al. (2024). A 3'UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP. Neuro Genetics. Published: February, 2024. DOI: 10.1212/NXG.0000000000200124.
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