Clinical utility of a genetic diagnosis in individuals with cerebral palsy and related motor disorders.

OBJECTIVE: Evaluation of the clinical utility of a genetic diagnosis in CP remains limited. We aimed to characterize the clinical utility of a genetic diagnosis by exome sequencing (ES) in patients with CP and related motor disorders. METHODS: We enrolled participants with CP and "CP masquerading" conditions in an institutional ES initiative. In those with genetic diagnoses who had clinical visits to discuss results, we retrospectively reviewed medical charts, evaluating recommendations based on the genetic diagnosis pertaining to medication intervention, surveillance initiation, variant-specific testing, and patient education. RESULTS: We included 30 individuals with a molecular diagnosis and clinical follow-up. Nearly all (28 out of 30) had clinical impact resulting from the genetic diagnosis. Medication interventions included recommendation of mitochondrial multivitamin supplementation (6.67%, n = 2), ketogenic diet (3.33%, n = 1), and fasting avoidance (3.33%, n = 1). Surveillance-related actions included recommendations for investigating systemic complications (40%, n = 12); referral to new specialists to screen for systemic manifestations (33%, n = 10); continued follow-up with established specialists to focus on specific manifestations (16.67%, n = 5); referral to clinical genetics (16.67%, n = 5) to oversee surveillance recommendations. Variant-specific actions included carrier testing (10%, n = 3) and testing of potentially affected relatives (3.33%, n = 1). Patient education-specific actions included referral to experts in the genetic disorder (30%, n = 9); and counseling about possible changes in prognosis, including recognition of disease progression and early mortality (36.67%, n = 11). INTERPRETATION: This study highlights the clinical utility of a genetic diagnosis for CP and "CP masquerading" conditions, evident by medication interventions, surveillance impact, family member testing, and patient education, including possible prognostic changes.

Morphometric analysis on T1-weighted MRI complements visual MRI review in focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasia (FCD) is a common pathology in focal drug resistant epilepsy (DRE). Voxel based morphometric MRI analysis has been proposed as an adjunct to visual detection of FCD, which remains challenging given the subtle radiographic appearance of FCD. This study evaluates the diagnostic value of morphometric analysis program (MAP) in focal DRE with pathology-confirmed FCD. METHODS: Automated morphometric analysis program analysis generated z-score maps derived from T1 images, referenced to healthy adult or pediatric controls for each of 39 cases with pathology-confirmed FCD. MAP identified abnormal extension of gray matter into white matter (MAP-E) and blurring of the gray-white matter junction (MAP-J), independently of clinical data and other imaging modalities. MRI was visually reviewed by neuroradiologists as part of usual clinical care, and independently re-reviewed retrospectively by a neuroradiologist with >10-years' experience in epilepsy MRI. Sensitivity and specificity were calculated for MRI, MAP, scalp-EEG, PET and SISCOM compared to resection area (RA). RESULTS: In this cohort of 39 histologically proven FCD cases, the sensitivity and specificity of MAP-J [64% (95% CI 48%-77%) and 96% (95% CI 93%-0.98%)] and MAP-E [74% (95% CI 59%-86%) and 94% (95% CI 91%-97%)] were higher than qualitative MRI review, SISCOM, and FDG-PET. Initial MRI review detected FCD in 17, expert review identified 26. Among cases not detected by initial MRI review, MAP-J correctly identified FCD in 12 additional cases and MAP-E in 13 cases. Among cases not detected by expert MRI review, MAP-J correctly identified 6 and MAP-E 8 cases. Excellent surgical outcome was achieved in 76% of patients. SIGNIFICANCE: MAP showed favorable sensitivity compared to visual inspection and other non-invasive imaging modalities. MAP complements non-invasive imaging evaluation for detection of FCD in focal DRE patients.

Caffeine stimulates locomotor activity in the mammalian spinal cord via adenosine A1 receptor-dopamine D1 receptor interaction and PKA-dependent mechanisms.

Caffeine is a potent psychostimulant that can have significant and widely variable effects on the activity of multiple neuronal pathways. The most pronounced caffeine-induced behavioral effect seen in rodents is to increase locomotor activity which has been linked to a dose-dependent inhibition of A1 and A(2A) receptors. The effects of caffeine at the level of the lumbar spinal central pattern generator (CPG) network for hindlimb locomotion are lacking. We assessed the effects of caffeine to the locomotor function of the spinal CPG network via extracellular ventral root recordings using the isolated neonatal mouse spinal cord preparation. Addition of caffeine and of an A1 receptor antagonist significantly decreased the cycle period accelerating the ongoing locomotor rhythm, while decreasing burst duration reversibly in most preparations suggesting the role of A1 receptors as the primary target of caffeine. Caffeine and an A1 receptor antagonist failed to stimulate ongoing locomotor activity in the absence of dopamine or in the presence of a D1 receptor antagonist supporting A1/D1 receptor-dependent mechanism of action. The use of caffeine or an A1 receptor blocker failed to stimulate an ongoing locomotor rhythm in the presence of a blocker of the cAMP-dependent protein kinase (PKA) supporting the need of this intracellular pathway for the modulatory effects of caffeine to occur. These results support a stimulant effect of caffeine on the lumbar spinal network controlling hindlimb locomotion through the inhibition of A1 receptors and subsequent activation of D1 receptors via a PKA-dependent intracellular mechanism.