Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene.

Paroxysmal kinesigenic dyskinesia (PKD) is a heterogeneous movement disorder characterized by recurrent dyskinesia attacks triggered by sudden movement. PRRT2 has been identified as the first causative gene of PKD. However, it is only responsible for approximately half of affected individuals, indicating that other loci are most likely involved in the etiology of this disorder. To explore the underlying causative gene of PRRT2-negative PKD, we used a combination strategy including linkage analysis, whole-exome sequencing and copy number variations analysis to detect the genetic variants within a family with PKD. We identified a linkage locus on chromosome 12 (12p13.32-12p12.3) and detected a novel heterozygous mutation c.956 T>G (p.319 L>R) in the potassium voltage-gated channel subfamily A member 1, KCNA1. Whole-exome sequencing in another 58 Chinese patients with PKD who lacked mutations in PRRT2 revealed another novel mutation in the KCNA1 gene [c.765 C>A (p.255 N>K)] within another family. Biochemical analysis revealed that the L319R mutant accelerated protein degradation via the proteasome pathway and disrupted membrane expression of the Kv1.1 channel. Electrophysiological examinations in transfected HEK293 cells showed that both the L319R and N255K mutants resulted in reduced potassium currents and respective altered gating properties, with a dominant negative effect on the Kv1.1 wild-type channel. Our study suggests that these mutations in KCNA1 cause the Kv1.1 channel dysfunction, which leads to familial PKD. The current study further extended the genotypic spectrum of this disorder, indicating that Kv1.1 channel dysfunction maybe one of the underlying defects in PKD.

Development and validation of a machine learning model of radiation-induced hypothyroidism with clinical and dose-volume features.

BACKGROUND AND PURPOSE: Radiation-induced hypothyroidism (RIHT) is a common but underestimated late effect in head and neck cancers. However, no consensus exists regarding risk prediction or dose constraints in RIHT. We aimed to develop a machine learning model for the accurate risk prediction of RIHT based on clinical and dose-volume features and to evaluate its performance internally and externally. MATERIALS AND METHODS: We retrospectively searched two institutions for patients aged >20 years treated with definitive radiotherapy for nasopharyngeal or oropharyngeal cancer, and extracted their clinical information and dose-volume features. One was designated the developmental cohort, the other as the external validation cohort. We compared the performances of machine learning models with those of published normal tissue complication probability (NTCP) models. RESULTS: The developmental and external validation cohorts consisted of 378 and 49 patients, respectively. The estimated cumulative incidence rates of grade ≥1 hypothyroidism were 53.5% and 61.3% in the developmental and external validation cohorts, respectively. Machine learning models outperformed traditional NTCP models by having lower Brier scores at every time point and a lower integrated Brier score, while demonstrating a comparable calibration index and mean area under the curve. Even simplified machine learning models using only thyroid features performed better than did traditional NTCP algorithms. The machine learning models showed consistent performance between folds. The performance in a previously unseen external validation cohort was comparable to that of the cross-validation. CONCLUSIONS: Our model outperformed traditional NTCP models, with additional capabilities of predicting the RIHT risk at individual time points. A simplified model using only thyroid dose-volume features still outperforms traditional NTCP models and can be incorporated into future treatment planning systems for biological optimization.

Research on the Relationship Between Vestibular Migraine With/Without Cognitive Impairment and Brainstem Auditory Evoked Potential.

Background: Vestibular migraine (VM) is the most common cause of spontaneous vertigo with no specific physical and laboratory examinations, and is an under-recognized entity with substantial burden for the individual and the society. In this study, by observing the brainstem auditory evoked potential (BAEP) and cognitive function of VM patients, the possible laboratory diagnostic indicators of VM and the influence of disease on cognitive function were discussed. Method: The study included 78 VM patients, 76 migraine patients, and 79 healthy individuals. The age, gender, and other clinical history of the three groups matched. All participants underwent BAEP examinations, in which patients in the migraine group and outpatients of the VM group were in the interictal period, and inpatients in the VM group were examined during episodes, while all patients tested for the Addenbrooke's cognitive examination-revised (ACE-R) scale were in the interictal period. The differences in BAEP and ACE-R scores between the three groups of members and their relationship with the clinical features of VM patients were analyzed. Result: The peak latency of I, III, and V wave in the BAEP of the VM group was longer than that of the migraine group and the control group (p < 0.05). The peak latency of V wave in the BAEP of the migraine group was longer than that of the control group (p < 0.05). The ACE-R of the VM group scored lower than the migraine group in terms of language fluency and language (p < 0.05), and lower than the control group in terms of total score, language fluency, language, and visuospatial (p < 0.05); and the ACE-R of the migraine group scored lower than the control group in the total score and visuospatial (p < 0.05). Conclusion: Migraine patients have brainstem dysfunction, and VM patients have more severe brainstem dysfunction than migraine patients, suggesting that VM patients have both central nervous system damage and peripheral nerve damage. Migraine patients have cognitive impairment, while cognitive impairment in VM patients is more severe than in migraine patients.