The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.

Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.

The effect of maternal alcohol and drug abuse on first trimester screening analytes: a retrospective cohort study.

BACKGROUND: The purpose of this study was to determine whether first trimester trisomy screening (FTS) parameters are affected by alcohol and drug use. METHODS: A routine combined FTS including measurements of maternal serum levels of free ß-human chorionic gonadotropin subunit (free ß-hCG) and pregnancy-associated plasma protein A (PAPP-A) were measured at 9-11 weeks of gestation, and fetal nuchal translucency thickness (NTT) at 11-13 weeks of gestation. In total 544 women with singleton pregnancies [71 alcohol and drug abusers, 88 smokers, 168 non-smokers delivering a small for gestational age (SGA) child, and 217 unexposed control women] were assessed. RESULTS: Free ß-hCG levels were higher in alcohol and drug abusing than in unexposed pregnant women [mean 1.5 vs. 1.2 multiples of medians (MoM); P = 0.013]. However, stepwise multiple linear regression analyses suggested that smoking could explain increased free ß-hCG. Additionally, we observed lower PAPP-A levels in the smoking mothers (0.9 vs. 1.2 MoM; P = 0.045) and in those giving birth to an SGA child compared to the controls (1.1 vs.. 1.2 MoM; P < 0.001). Fetal NTT did not differ significantly between any of the groups. CONCLUSIONS: The present study shows increased free ß-hCG levels in alcohol and drug abusers, but maternal smoking may explain the result. Maternal serum PAPP-A levels were lower in smoking than non-smoking mothers, and in mothers delivering an SGA child. However, FTS parameters (PAPP-A, free ß-hCG and NTT) seem not to be applicable for the use as alcohol biomarkers because of their clear overlap between alcohol abusers and healthy controls.

Alcohol and substance use are associated with altered metabolome in the first trimester serum samples of pregnant mothers.

BACKGROUND: Although the effects of alcohol on metabolic processes in the body have been studied widely, there do not appear to be any previous reports clarifying how substance abuse changes metabolic profiles of pregnant women during the first trimester of pregnancy. OBJECTIVE: Our aim was to evaluate the effect of substance abuse, especially alcohol use, on the metabolic profile of pregnant women during the first trimester. STUDY DESIGN: We applied mass spectrometry based non-targeted metabolite profiling of serum collected during routine visit to the hospital between gestational weeks 9 + 0 to 11 + 6 from controls (n = 55), alcohol users (n = 19), drug users (n = 24) and tobacco smokers (n = 40). RESULTS: We observed statistically significantly differences among the study groups in serum levels of glutamate, glutamine, and serotonin (p-values ≤ 0.0001). The serum levels of glutamate were increased in alcohol and drug using mothers when compared to the controls, whereas levels of glutamine were decreased in alcohol and drug using mothers. In addition, serum levels of serotonin were decreased in alcohol using mothers when compared to the controls. CONCLUSION: The present study shows that alcohol and drug use were associated with increased glutamate, and decreased glutamine levels, and alcohol use is associated with decreased serotonin levels. This study serves as a proof-of-concept that the metabolite profile of human first trimester serum samples could be used to detect alcohol exposure during pregnancy.

Maternal drug or alcohol abuse is associated with decreased head size from mid-pregnancy to childhood.

AIM: Maternal alcohol abuse is poorly recognised and causes developmental problems. This study explored the foetal central nervous systems (CNS), head circumference and psychomotor development of children exposed to drugs or alcohol during pregnancy up to 2.5 years of age. METHODS: We recruited 23 pregnant women referred to Kuopio University Hospital, Finland, by their family doctor because of drug or alcohol abuse, and 22 control mothers. Foetal CNS parameters were measured by three-dimensional ultrasonography at the mean gestational age of 20 weeks and the Griffiths Mental Developmental Scales (GMDS), and anthropometric measurements were carried out at the mean ages of one and 2.5 years. RESULTS: The exposed foetuses had decreased biparietal and occipito-frontal distances and head circumferences, but unchanged cerebellar volume at 20 weeks, and decreased head circumferences and length and height at birth, one and 2.5 years of age. They scored lower than the controls on the GMDS general quotient and the hearing, language and locomotor subscales at 2.5 years of age. CONCLUSION: Maternal alcohol or drug exposure was associated with decreased head size from mid-pregnancy to childhood and reduced development at 2.5 years. Foetal head circumference at mid-pregnancy was a useful indicator of substance abuse affecting the CNS.