Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Unique longitudinal relationships between symptoms of psychopathology in youth: A cross-lagged panel network analysis in the ABCD study.

BACKGROUND: The network theory suggests that psychopathology may reflect causal relationships between individual symptoms. Several studies have examined cross-sectional relationships between individual symptoms in youth. However, these studies cannot address the directionality of the temporal relationships hypothesized by the network theory. Therefore, we estimated the longitudinal relationships between individual internalizing, externalizing, and attention symptoms in youth. METHODS: Data from 4,093 youth participants in the Adolescent Brain Cognitive Development (ABCD) study were used. Symptoms were assessed using the Brief Problem Monitor, which was administered at three time points spaced six months apart. Unique longitudinal relationships between symptoms at T1 and T2 were estimated using cross-lagged panel network modeling. Network replicability was assessed by comparing this network to an identically estimated replication network of symptoms at T2 predicting symptoms at T3. RESULTS: After controlling for all other symptoms and demographic covariates, depressed mood, inattention, and worry at T1 were most predictive of other symptoms at T2. In contrast, threats of violence and destructiveness at T2 were most prospectively predicted by other symptoms at T1. The reciprocal associations between depressed mood and worthlessness were among the strongest bivariate relationships in the network. Comparisons between the original network and the replication network (correlation between edge lists = .61; individual edge replicability = 64%-84%) suggested moderate replicability. CONCLUSIONS: Although causal inferences are precluded by the observational design and methodological considerations, these findings demonstrate the directionality of relationships between individual symptoms in youth and highlight depressed mood, inattention, and worry as potential influencers of other symptoms.

Depression risk factors and affect dynamics: An experience sampling study.

Affect dynamics reflect individual differences in how emotional information is processed, and may provide insights into how depressive episodes develop. To extend prior studies that examined affect dynamics in currently depressed individuals, the present study tested in 68 non-depressed young adults whether three well-established risk factors for major depressive disorder (MDD) - (a) past episodes of MDD, (b) family history of MDD, and (c) reduced neurophysiological responses to reward - predicted mean levels, instability, or inertia (i.e., inflexibility) of positive affect (PA) and/or negative affect (NA). Momentary PA and NA were assessed up to 6 times per day for 14 days (mean number of surveys completed = 45.89). MDD history and family history of MDD were assessed via semi-structured interview, and neurophysiological responses to reward were indexed using the Reward Positivity, an event-related potential related to depression. After adjusting for current depressive symptoms, results indicated that (a) past episodes of MDD predicted higher mean levels of NA, (b) family history of MDD predicted greater PA inertia, and (c) blunted reactivity to reward predicted greater NA inertia. Collectively, these results suggest that elevated mean levels of NA and inflexibility of PA and NA may be potential mechanisms that confer risk for depression.

Test-retest & familial concordance of MDD symptoms.

Psychopathology research has increasingly sought to study the etiology and treatment of individual symptoms, rather than categorical diagnoses. However, it is unclear whether commonly used measures have adequate psychometric properties for assessing individual symptoms. This study examined the test-retest reliability and familial concordance (an indicator of validity) of the symptoms of Major Depressive Disorder (MDD), a disorder consisting of nine core symptoms, most of which are aggregated (e.g., symptom 7 of the DSM criteria for MDD is worthlessness or guilt). Lifetime MDD symptoms were measured in 504 young adults (237 sibling pairs) using the Structured Clinical Interview for DSM-5 (SCID). Fifty-one people completed a second SCID within three weeks of their first SCID. Results indicated that aggregated and unaggregated symptoms demonstrated moderate to substantial test-retest reliability and generally significant, but slight to fair familial concordance (with the highest familial concordance being for markedly diminished interest or pleasure and its unaggregated components - decreased interest and decreased pleasure). Given the increasing focus on the differential validity of individual MDD symptoms, the present study suggests that interview-based assessments of depression can assess most individual symptoms with adequate levels of reliability and validity.