De novo missense variants in SLC32A1 cause a neurodevelopmental disorder with epilepsy due to impaired GABAergic neurotransmission

We describe four patients with a neurodevelopmental disorder and de novo missense variants in SLC32A1, the gene that encodes the vesicular GABA transporter (VGAT). The main phenotype comprises moderate to severe intellectual disability, early onset epilepsy within the first 18 months of life and a choreatic, dystonic or dyskinetic movement disorder. In silico modeling and functional analyses in cultured neurons reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA. The fourth variant, located in the VGAT N-terminus, does not affect quantal size, but increases presynaptic release probability, leading to more severe synaptic depression during high frequency stimulation. Thus, variants in VGAT can impair GABAergic neurotransmission via at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. This work establishes de novo missense variants in SLC32A1 as a novel cause for a neurodevelopmental disorder with epilepsy.

Clinical features of patients with paroxysmal kinesigenic dyskinesia, mutation screening of PRRT2 and the effects of morning draughts of oxcarbazepine

Background The objective of this study was to summarize clinical features and PRRT2 mutations of paediatric paroxysmal kinesigenic dyskinesia (PKD) patients and observe the tolerability and effects of morning draughts of oxcarbazepine. Methods Twenty patients diagnosed with PKD at Children’s Hospital of Fudan University between January 2011 and December 2015 were enrolled. These patients’ medical records were reviewed. Peripheral venous blood was obtained from all enrolled patients, and polymerase chain reaction (PCR) and Sanger sequencing were used to sequence proline-rich transmembrane protein 2 (PRRT2) gene mutations. Clinical features of PKD patients with and without PRRT2 mutations were compared. All enrolled patients were treated with morning draughts of oxcarbazepine (OXC). The starting dose was 5 mg/kg·d, and the dose was increased by 5 mg/kg·d each week until attacks stopped. Effective doses and adverse effects were recorded. Results For all enrolled patients, dyskinesia was triggered by sudden movement. Dyskinetic movement usually involved the limbs and was bilateral; the majority of enrolled patients exhibited both dystonia and choreoathetosis. We identified PRRT2 mutations in 5 patients, including 4 familial patients and 1 sporadic patient. All 20 patients took low doses of OXC (5–20 mg/kg·d) as draughts in the morning, and dyskinesia attacks stopped in 19 patients. Conclusions Paediatric PKD patients have various phenotypes. PRRT2 mutations are common in familial cases. OXC taken as morning draughts can be a treatment option for paediatric PKD patients.

A rare instance of tardive dyskinesia with SSRI use: A case study

IntroductionCase presentation of a middle aged lady Mrs. C.K., who developed tardive dyskinesia (TD) after a trial of an SSRI.Case reportA 49-year-old Australian aboriginal lady, presented with involuntary movement of her face (bucco-linguo masticatory), movements after a 3 months trial of sertraline (maximum dose of 100 mg daily) for her depressive illness. There was no history of trials with anti-psychotics or any other medications, which may have caused the oral dyskinesias. Routine examinations including cognitive testing, EEG and MRI revealed no pathological findings. Her sertraline was ceased and she was commenced on mirtazapine 15 mg at night, which was hiked to 30 mg after 1 week and continued on this dose over the next 3 months. She exhibited good improvement in her depressive symptoms and a significant attenuation of her TD's. Involuntary movement scale rating: she was rated on the abnormal involuntary movement scale (AIMS) and showed gradual improvement in the severity of her orofacial dyskinetic movement. Her scores were–initial presentation (scored 22/36); at 4 weeks (9/36); 8 weeks (6/36) and at 16 weeks (4/36).DiscussionAlthough TD's are seen in approximately 1 to 5% of mental health patients treated with anti-psychotics (and some other medications like Levodopa, Metochlorpromide, etc.), research studies on SSRI's causing TD's are rare and few (Leo et al., 1996; Gerber et al., 1998).ConclusionsTo alert and educate clinicians about a relatively rare adverse-effect of SSRI producing an involuntary movement disorder.Disclosure of interestThe author has not supplied his/her declaration of competing interest.

Movement abnormalities and psychotic-like experiences in childhood: markers of developing schizophrenia?

BackgroundBoth involuntary dyskinetic movements and psychotic-like experiences (PLEs) are reported to be antecedents of schizophrenia that may reflect dysfunctional dopaminergic activity in the striatum. The present study compared dyskinetic movement abnormalities displayed by children with multiple antecedents of schizophrenia (ASz), including speech and/or motor developmental lags or problems, internalising/externalising problems in the clinical range, and PLEs, with those displayed by children with no antecedents (noASz).MethodThe sample included 21 ASz and 31 noASz children, aged 9–12 years old. None had taken psychotropic medication or had relatives with psychosis. The antecedents of schizophrenia were assessed using questionnaires completed by children and caregivers. A trained rater, blind to group status, coded dyskinetic movement abnormalities using a validated tool from videotapes of interviews with the children.ResultsASz children reported, on average, ‘certain experience’ of 2.5 PLEs, while noASz children, by definition, reported none. The ASz children, as compared with noASz children, displayed significantly more dyskinetic movement abnormalities in total, and in the facial and the upper-body regions, after controlling for sex and age. Receiver operator characteristics analyses yielded high area under the curve values for the total score (0.94), facial score (0.91) and upper-body score (0.86), indicating that these scores distinguished between the ASz and noASz children with great accuracy.ConclusionsBrief questionnaires identified children with multiple antecedents of schizophrenia who displayed significantly more involuntary dyskinetic movement abnormalities than children without antecedents. The presence of PLEs and dyskinesias could reflect early disruption of striatal dopamine circuits.