Aichi Developmental Disability Center

Aseptic meningitis occasionally causes neuropathic pain in a dermatomal distribution, but widespread non-dermatomal pain is extremely rare. We report a case of a 62-year-old man with ulcerative colitis who developed neuropathic pain involving the head, trunk, and limbs. Cerebrospinal fluid analysis and brain MRI confirmed aseptic meningitis. Although vitamin B12 deficiency and cervical spondylotic myelopathy were present, they did not explain the symptoms. The pain improved with oral analgesics. This case highlights aseptic meningitis as a possible cause of non-dermatomal neuropathic pain.

Electromyograms (EMGs) of the orbicularis oculi muscle are commonly used to assess the blink reflex, which provides clinically important information. However, mechanomyograms (MMGs) may serve as a promising alternative. This study aimed to evaluate the utility of MMGs in assessing orbicularis oculi responses to stimulation. Electrical stimulation was applied to the facial nerve axons of 25 healthy adult participants, and MMGs were recorded using an accelerometer. The reliability of amplitude-based parameters (Amax and Ap−p) and time-based parameters (Trise, Tzero, Tfall, and Trec) characterizing MMG waveforms was assessed using the intraclass correlation coefficient (ICC), standard error of measurement (SEM), and coefficient of variation (CV). Additionally, the amplitude and temporal characteristics of MMGs evoked by varying stimulus intensities were compared with simultaneously recorded EMGs. All parameters, except Trec, showed high relative reliability (95% confidence interval of ICC of > 0.75) and high absolute reliability (%SEM and CV < 10%). MMG amplitudes (Amax and Ap−p) and EMG amplitudes (Vmax and Vp−p) increased linearly with stimulus intensity. A strong correlation was found between the amplitudes of both signals (Vmax vs. Amax: r = 0.932, p < 0.0001; Vp−p vs. Ap−p: r = 0.937, p < 0.0001). The first positive MMG peak consistently appeared at a fixed interval (5.52 ± 2.10 ms) after the EMG peak, irrespective of stimulus level. These findings suggest that MMG amplitude and latency (stimulus-to-peak time) are reliable indicators of orbicularis oculi muscle activity and can be effectively used alongside EMG in clinical and research settings. Communicated by Bill Yates.

Introduction: Lysophosphatidic acid (LPA) is a bioactive phospholipid that mediates a variety of biological actions through binding to G protein-coupled receptors known as LPA receptors (LPARs). In mammals, six LPAR subtypes (LPAR1-6) have been identified. This study aimed to determine the expression of LPAR4 in the developing mouse brain. Methods: Brains samples were prepared from mice in various stages of development and biochemical and immunohistochemical analyses were conducted using anti-LPAR4. Results: Western blot analysis detected two LPAR4-immunoreactive species at ∼50 kDa and ∼42 kDa from embryonic day 16.5 (E16.5). The ∼50 kDa molecule increased during development, reaching a peak at postnatal day 3 (P3), and then gradually decreased through P22. In contrast, the ∼42 kDa molecule continued to increase up to P22. Immunohistochemical analyses demonstrated strong LPAR4 expression in neural cells in the intermediate zone and cortical plate of the E15.5 cerebral cortex, whereas neural progenitors in the ventricular and subventricular zones exhibited weaker expression. At P15, fiber-like staining resembling the apical dendrites of cortical neurons and hippocampal pyramidal cells was also observed. Conclusion: This study demonstrated dynamic, spatiotemporal changes of LPAR4 expression in the brain from embryonic to postnatal stages. These findings support a potential role for LPAR4 in neural development.

The accurate removal of intronic sequences from pre-mRNA by the spliceosome is essential for correct gene expression, with small nuclear RNAs (snRNAs) such as U4 playing structural and regulatory roles in catalyzing this. De novo variants in the highly constrained critical region including the T-loop region of RNU4-2 have been linked to ReNU syndrome, a neurodevelopmental disorder, but the broader mutational spectrum remains uncharacterized. Here, we show that, in a cohort of unresolved cases with neurodevelopmental disorder, monoallelic and biallelic RNU4-2 variants were identified in 16 affected individuals, expanding the genetic basis beyond the critical region: 12 with de novo T-loop variants and 4 from two families with compound heterozygous variants in non-critical regions (stem II, the k-turn, and the Sm-binding site). Previously reported functional mapping by saturation genome editing confirmed that most of the variant positions in this study are highly functionally constrained. Clinically, individuals with biallelic variants exhibited developmental delay and intellectual disability that were similar to but milder than those with monoallelic variants, notably lacking extracerebral organ involvement. These results suggest that pathogenic RNU4-2 variants act in both dominant and recessive manners, and that non-critical regions may also harbor disease-causing variants. More broadly, this study underscores the diagnostic importance of non-coding RNA genes in neurodevelopmental disorders and demonstrates the need to distinguish pathogenic variants from benign ones, together with their inheritance patterns.

Background and ObjectivesLeigh syndrome is an important manifestation of childhood-onset primary mitochondrial disease. Panel sequencing and whole exome sequencing are cost-effective for diagnosing mitochondrial diseases; however, more than half of mitochondrial disease cases remain genetically undiagnosed. This study aimed to demonstrate that combining whole genome sequencing (WGS) and RNA sequencing (RNA-seq) analyses can identify disease-causing variants that would otherwise be missed.MethodsWe performed WGS and RNA-seq on a patient with Leigh syndrome. Chromosomal phasing using Sanger sequencing of parental and patient blood samples was conducted to confirm compound heterozygous variants. RNA-seq data were analyzed for splicing abnormalities. Overexpression studies of wild-type NDUFA3 in patient-derived fibroblasts were performed to assess restoration of mitochondrial function.ResultsWe discovered compound heterozygous intronic variants (c.86-16_86-15del in intron2 and c.164-362G>A in intron3) of the NDUFA3 gene. RNA-seq data analysis revealed intron retention and exonization in NDUFA3. Exonization was related to a variant involving the mobile element Alu that resulted in complex abnormal splicing events. Overexpression of wild-type NDUFA3 restored mitochondrial dysfunction in patient-derived fibroblasts, confirming NDUFA3 as a Leigh syndrome causative gene.DiscussionThis study highlights the importance of combining WGS and RNA-seq and provides new insights into detecting abnormalities in deep intronic regions, particularly those involving mobile elements, such as Alu. This approach can play a crucial role in identifying genetic variations and elucidating transcriptional control mechanisms that are not readily achieved by conventional methods, especially in the context of mobile element-induced complexities.

DEAF1 functions as both a transcriptional activator and repressor and is implicated in neurodevelopmental disorders (NDDs); however, its role in neuronal development remains poorly understood. In this study, we investigated the role of DEAF1 in cortical development, with a particular focus on neuronal architecture, as well as its contributions to synaptic function and neuronal activity. Invitro analyses revealed that dendritic development, but not axonal development, was inhibited in DEAF1-deficient hippocampal neurons. Using in utero electroporation-based acute knockdown experiments, we further demonstrated that DEAF1 knockdown in post-migratory mouse cortical neurons leads to impaired dendritic arborization and reduced dendritic spine density, without significantly affecting neuronal migration or axonal extension. These findings suggest that DEAF1's primary role in neurodevelopment is associated with the later stages of cortical maturation, specifically in dendritic and synaptic development. Additionally, electrophysiological analyses revealed that DEAF1 knockdown reduces both excitatory and inhibitory synaptic transmission. Furthermore, neuronal excitability was significantly reduced, suggesting a potential dysfunction in voltage-gated sodium and/or potassium channels. Collectively, our findings reveal a critical role for DEAF1 in dendritic and synaptic development, providing new insights into the cellular and functional mechanisms underlying DEAF1-associated NDDs.

Objectives: We examined whether sensory inhibition was altered in patients with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) as deficits in the neural inhibition are considered to be involved in both disorders. Methods: By using auditory change-related brain potentials as the test response, paired pulse suppression (PPS) and prepulse inhibition (PPI) were compared among healthy controls (n = 57), patients with ASD (n = 22), and ADHD (n = 8). The test change-related response was elicited by an abrupt sound pressure increase in a continuous sound. In the PPS experiment, two 15 dB change stimuli were given 600 ms apart to elicit two change-related responses. In the PPI experiment, the test stimulus of a 10 dB increase and prepulse of a 2 dB increase were given with an interval of 50 ms. Evoked potentials were recorded from Cz referenced to the linked mastoids. Results: PPS differed significantly among the three groups, with a significantly lower value for ADHD than controls. PPI was significantly lower for ASD and ADHD than normal controls. Conclusions: Since these two measures are thought to represent changes in circuit excitability due to preceding stimuli via GABAergic transmission, the present results support the idea that dysfunction of the GABAergic system contributes to the etiology of these disorders. The present results showed that the pattern of dysfunction differed between the two disorders and suggest that measurements of inhibitory function may be able to differentiate between the two disorders.

Handgrip strength is a key indicator of overall health in older adults, and its decline is linked to various adverse health outcomes. Despite numerous studies on factors influencing handgrip strength, few attempts have integrated multiple factors into a practical clinical tool. This study aims to develop and validate a nomogram based on a logistic regression model to predict the risk of low handgrip strength in older adults. Using data from the China Health and Retirement Longitudinal Study (CHARLS), 1138 participants were included. Firth-adjusted logistic regression identified predictors of low handgrip strength, with variable selection based on the Bayesian Information Criterion (BIC). Model performance was assessed using calibration curves, ROC curves, and decision curve analysis (DCA). Internal validation was performed with 10-fold cross-validation and bootstrapping, determining the optimal risk threshold. Key predictors identified included age, chronic disease history, marital status, lifestyle, education, BMI, activities of daily living, and glycated hemoglobin. The simplified model exhibited good discriminatory ability (AUC = 0.78) and calibration performance. The optimal threshold (0.40) yielded sensitivity of 72.5% and specificity of 69.8%. Decision curve analysis confirmed significant net benefit within the clinically relevant threshold range. The nomogram provides a practical tool for identifying at-risk individuals and guiding intervention, integrating modifiable and non-modifiable factors for personalized risk assessment and early intervention.

Growth-associated protein 43 (GAP43) is a membrane-associated phosphoprotein predominantly expressed in the nervous systems, and controls axonal growth, branching, and pathfinding. While the association between GAP43 and human neurological disorders have been reported, the underlying mechanisms remain largely unknown. We performed whole exome sequencing on a patient with intellectual disability (ID), neurodevelopmental disorders, short stature, and skeletal abnormalities such as left–right difference in legs and digital deformities, and identified a heterozygous missense variation in the GAP43 gene [NM_001130064.2: c.436G > A/p.(E146K)]. The variant GAP43 protein was unstable in primary cultured cortical neurons and hippocampal neurons in vitro. In utero electroporation of the variant protein also confirmed its instability in vivo, suggesting that the variant led to a condition similar with haploinsufficiency in the patient. Silencing of GAP43 via in utero electroporation of RNAi vectors demonstrated that loss of GAP43 suppressed axon elongation into the contralateral hemisphere and impaired the dendritic arbor formation as shown by decreased dendritic branch points and shortened total dendritic lengths. Collectively, these findings confirmed the critical roles of GAP43 in brain development and the pathological basis of GAP43-associated diseases. Our study will contribute to a better understanding of how dysregulation of GAP43 leads to human diseases.