Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.

Munc13 proteins are essential regulators of neurotransmitter release at nerve cell synapses. They mediate the priming step that renders synaptic vesicles fusion-competent, and their genetic elimination causes a complete block of synaptic transmission. Here we have described a patient displaying a disorder characterized by a dyskinetic movement disorder, developmental delay, and autism. Using whole-exome sequencing, we have shown that this condition is associated with a rare, de novo Pro814Leu variant in the major human Munc13 paralog UNC13A (also known as Munc13-1). Electrophysiological studies in murine neuronal cultures and functional analyses in Caenorhabditis elegans revealed that the UNC13A variant causes a distinct dominant gain of function that is characterized by increased fusion propensity of synaptic vesicles, which leads to increased initial synaptic vesicle release probability and abnormal short-term synaptic plasticity. Our study underscores the critical importance of fine-tuned presynaptic control in normal brain function. Further, it adds the neuronal Munc13 proteins and the synaptic vesicle priming process that they control to the known etiological mechanisms of psychiatric and neurological synaptopathies.

Etiology-specific differences in motor function after hemispherectomy.

Prediction of functional motor outcome after hemispherectomy is difficult due to the heterogeneity of motor outcomes observed. We hypothesize that this might be related to differences in plasticity during the onset of the underlying epileptogenic disorder or lesion and try to identify predictors of motor outcome after hemispherectomy. Thirty-five children with different etiologies (developmental, stable acquired or progressive) underwent functional hemispherectomy and motor function assessment before hemispherectomy and 24 months after hemispherectomy. Preoperatively, children with developmental etiologies performed better in terms of distal arm strength and hand function, but not on gross motor function tests. Postoperatively, the three etiology groups performed equally poor in muscle strength and hand function, but gross motor function improved in those with acquired and progressive etiologies. Loss of voluntary hand function and distal arm strength after surgery was associated with etiology, intact insular cortex and intact structural integrity of the ipsilesional corticospinal tract on presurgical MRI scans. In conclusion, postoperative motor function can be predicted more precisely based on etiology and on preoperative MRI. Children with developmental etiology more often lose distal arm strength and hand function and show less improvement in gross motor function, compared to those with acquired pathology.

Effect of biofeedback training on paradoxical pelvic floor movement in children with dysfunctional voiding.

OBJECTIVES: Dynamic perineal ultrasonography to assess the function of the pelvic floor muscles in children with micturition complaints shows that many children with daytime incontinence or recurrent urinary tract infections use their pelvic floor paradoxically. They strain when asked to withhold urine, or they have no voluntary control of the pelvic floor muscles at all. The aim of this study was to record the pelvic floor function and evaluate the physical therapy regimens for children with dysfunctional voiding (DV) and paradoxical pelvic floor function. METHODS: A total of 65 patients with DV, many who also had constipation, were diagnosed with paradoxical movement of the pelvic floor. The patients were asked to contract their pelvic floor muscles during a perineal dynamic ultrasound investigation. Of the 52 patients treated by physical therapists, 32 had a single 1-hour biofeedback session with rectal examination and anal balloon expulsion. In the remaining 20 patients, this was followed by 2 weeks of biofeedback balloon expulsion training at home. Forty control patients were observed. RESULTS: In 13 of the 65 patients, the diagnosis could not be confirmed by the physical therapists. At 6 to 10 months after training, 50 of the 52 other patients had normal voluntary pelvic floor muscle control. Of the 40 control patients, 39 had normal pelvic floor control. CONCLUSIONS: The results of this study have demonstrated that pelvic floor dysfunction occurs frequently in children with DV and can be cured by dedicated physical therapy. The clinical importance of this phenomenon is not yet clear. Prospective studies will teach us more about the true incidence and therapeutic effect of pelvic floor dysfunction on DV.

No deterioration in epilepsy and motor function in children with medically intractable epilepsy ineligible for surgery.

The aim of this study was to examine whether severity of epilepsy, motor functioning, and epilepsy-related restrictions change in children with medically intractable epilepsy who are ineligible for epilepsy surgery. The study was a prospective, longitudinal, 2-year follow-up of 28 children (14 females, 14 males). Their median age was 6 years 1 month (range 7mo-15y 4mo). Seizure types were: complex partial seizures (n=16), secondary generalized seizures (n=7), simple partial seizures (n=2), and mixed seizures (n=3). Severity of seizures, motor impairments, motor development, activities of daily life, and epilepsy-related restrictions were rated at baseline and 6, 12, and 24 months thereafter. Seizure severity did not change significantly, nor did muscle strength, range of motion, or muscle tone. Motor retardation was ubiquitous but did not increase in 20 children without spasticity. Motor function of eight children with spasticity improved (Gross Motor Function Measure: baseline 70.5 [SD 35.5]; 24 months later 81.6 [SD 29.6], p < 0.05) but remained below reference values in four children. In the entire group, functional skills increased and caregiver assistance lessened. Restrictions did not change significantly. We conclude that during a 2-year follow-up period, in children with medically intractable epilepsy who do not have surgical intervention, seizure severity does not deteriorate, motor impairments do not increase, motor development does not deflect negatively, and activities of daily living and restrictions do not worsen.

Health-related quality of life and self-perceived competence of children assessed before and up to two years after epilepsy surgery.

PURPOSE: To measure outcome of epilepsy surgery in terms of health-related quality of life (HrQoL) and self-perceived competence of children and adolescents. METHODS: Prospective longitudinal follow-up study of 21 patients (aged 6.2 to 16.8 years). Frequency and severity of seizures and epilepsy-related restrictions, HrQoL, and self-perceived competence were rated before and 6, 12, and 24 months after epilepsy surgery. Data were analysed nonparametrically and using analysis of variance for repeated measures. RESULTS: Group-wise, seizure parameters had almost normalized 6 months after surgery (p<0.001) and remained so. Two years after surgery, 15 (72%) patients were free of seizures. At the first postsurgical assessment, parents and children evaluated the frequency of activities as improved and that of seizures as diminished (p<0.05). Parents evaluated their children as having positive emotions more frequently (p<0.05). Children started to feel better about seizure variables in the second year after surgery. Two years after surgery, children perceived themselves as being socially more competent and having greater self-worth (p=0.05). In the adolescent group, several aspects of self-perceived competence improved shortly after surgery (p<0.05), whereas 2 years after surgery, athletic competence and romance had improved (p<0.05). CONCLUSIONS: In children and adolescents, epilepsy surgery sets the stage for improvement in HrQoL and in competence to participate in social and societal domains. Most improvement occurs in the first 6 months after surgery.