Ingrid E. Scheffer

Description:The evolution from nocturnal paroxysmal dystonia (NPD) to sleep-related hypermotor epilepsy (SHE) is a complex and fascinating journey, marked by numerous twists and discoveries.1 This topic was recently reviewed by Fotedar and Luders,2 who erroneously concluded that SHE is not an identifiable focal epilepsy syndrome as they believed that it is based on weak evidence. We wish to address errors in their analysis and offer a more balanced understanding of this important form of epilepsy.

Description:KIF1A-associated neurological disorder (KAND) is a genetic condition characterised by motor, cognitive and ophthalmologic features. The speech and language phenotype have not been systematically analysed. Here, we assess speech and language using observer- and clinician-reported outcomes, and performance outcome measures. 44 individuals (25 female) with KAND (median age 7 years, range 1-60 years) participated. Median age at diagnosis was 4 years (range 0.5-58 years). KIF1A variants were missense (41/44 individuals, 93%), intragenic deletion (2/44, 5%) and splice site (1/44, 2%). Age at first words was delayed (>12 months) in 38/44 (86%) individuals. At assessment, 28/44 (64%) combined words into sentences and all of the 20 individuals assessed had dysarthria. Apraxic speech features and phonological impairments occurred in children aged under 8 years. 36/37 (97%) participants had language impairment, with expressive language skills stronger than receptive (p = 0.02) and written (p = 0.03) language on the Vineland Adaptive Behaviour Scales. 7/32 (22%) caregivers reported speech and language regression. Mild to severe intellectual disability occurred in 31/33 (94%) individuals. 22/44 (50%) participants had used augmentative and alternative communication, such as key word sign or speech generating devices. Individuals had average social motivation skills in contrast to moderately impaired social cognition, communication and awareness on the Social Responsiveness Scale (p < 0.05). 16/44 (36%) had epilepsy and 40/44 (91%) had visual impairment, namely nystagmus (16/44, 36%), optic nerve atrophy and strabismus (both 12/44, 27%). Individuals with KAND frequently have speech and language disorders necessitating early and targeted speech and language interventions.

Description:Objectives Accurate and user-friendly methods to measure beta-hydroxybutyrate (BHB) concentration are needed to guide the optimal use of ketogenic diet therapy (KDT). We aimed to determine the correlation between serum, capillary, and salivary BHB concentration, and to validate an electrochemical salivary BHB point-of-care test (POCT) in children commencing KDT for drug-resistant epilepsy. Methods This was a single center, prospective cohort study. Children <18 years with drug-resistant epilepsy electively admitted to Shenzhen Children's Hospital to initiate KDT between January 1, 2020 and June 30, 2021, were included. Over the 7-day admission, we collected paired saliva and capillary blood samples twice a day and serum blood samples on the first and last days of admission from each participant. Salivary BHB was measured using liquid chromatography mass spectrometry (LCMS) and the POCT. Primary outcome was the correlation between serum and salivary BHB concentration measured using LCMS. Secondary outcomes were the correlation between both the capillary blood and salivary BHB concentration, measured by LCMS, and the POCT device. Results Seventy-one serum and 334 capillary blood paired with salivary samples were collected from 42 children (median age 4.5 years, interquartile range 1 to 8 years, 45% female). Salivary BHB measured using LCMS strongly correlated with serum BHB (Spearman's ρ = 0.910) and capillary blood BHB concentrations (Spearman's ρ = 0.865). Salivary BHB concentration was 6% and 7% of serum and capillary blood BHB concentration, respectively. The POCT demonstrated excellent test–retest reliability when compared with LCMS (ICC(A,k) = 0.983, 95% confidence interval: 0.980–0.986). Salivary BHB concentration measured by the POCT showed good accuracy in predicting the capillary blood BHB concentration within the therapeutic range of 2–5 mM. Significance Salivary BHB concentration strongly correlates with both serum and capillary blood BHB concentration. The POCT accurately measures salivary BHB concentration and provides a simple, user-friendly method to guide the use of KDT for children with drug-resistant epilepsy.

Description:DNA methylation signatures (“episignatures”) can be used as biomarkers of genetic aberrations, clinical phenotypes, and environmental exposures in rare diseases. Episignatures are utilized in molecular diagnostics and can clarify variants of uncertain significance. A growing number of disease genes, including epilepsy genes, exhibit robust and reproducible episignatures. However, whether SCN1A, the most prominent epilepsy gene, has one or more episignatures has not yet been determined. We generated genome-wide DNA methylation data and performed episignature analysis on 64 individuals with Dravet syndrome due to pathogenic loss-of-function (LOF) variants in SCN1A and seven individuals with early infantile SCN1A developmental and epileptic encephalopathy due to pathogenic gain-of-function (GOF) variants in SCN1A, relative to a large reference database of controls and rare disease episignature-positive cohorts. We analyzed all samples with LOF variants together and performed separate analyses for missense, nonsense, and GOF variant cohorts. A reproducible blood-derived episignature was not evident in any of the cohorts using current analytical approaches and reference data.

Description:Objectives Accurate and user-friendly methods to measure beta-hydroxybutyrate (BHB) concentration are needed to guide the optimal use of ketogenic diet therapy (KDT). We aimed to determine the correlation between serum, capillary, and salivary BHB concentration, and to validate an electrochemical salivary BHB point-of-care test (POCT) in children commencing KDT for drug-resistant epilepsy. Methods This was a single center, prospective cohort study. Children <18 years with drug-resistant epilepsy electively admitted to Shenzhen Children's Hospital to initiate KDT between January 1, 2020 and June 30, 2021, were included. Over the 7-day admission, we collected paired saliva and capillary blood samples twice a day and serum blood samples on the first and last days of admission from each participant. Salivary BHB was measured using liquid chromatography mass spectrometry (LCMS) and the POCT. Primary outcome was the correlation between serum and salivary BHB concentration measured using LCMS. Secondary outcomes were the correlation between both the capillary blood and salivary BHB concentration, measured by LCMS, and the POCT device. Results Seventy-one serum and 334 capillary blood paired with salivary samples were collected from 42 children (median age 4.5 years, interquartile range 1 to 8 years, 45% female). Salivary BHB measured using LCMS strongly correlated with serum BHB (Spearman's ρ = 0.910) and capillary blood BHB concentrations (Spearman's ρ = 0.865). Salivary BHB concentration was 6% and 7% of serum and capillary blood BHB concentration, respectively. The POCT demonstrated excellent test–retest reliability when compared with LCMS (ICC(A,k) = 0.983, 95% confidence interval: 0.980–0.986). Salivary BHB concentration measured by the POCT showed good accuracy in predicting the capillary blood BHB concentration within the therapeutic range of 2–5 mM. Significance Salivary BHB concentration strongly correlates with both serum and capillary blood BHB concentration. The POCT accurately measures salivary BHB concentration and provides a simple, user-friendly method to guide the use of KDT for children with drug-resistant epilepsy.