SCN3A ‐related neurodevelopmental disorder: A spectrum of epilepsy and brain malformation

Objective Pathogenic variants in SCN3A , encoding the voltage‐gated sodium channel subunit Nav1.3, cause severe childhood‐onset epilepsy and malformation of cortical development. Here, we define the spectrum of clinical, genetic, and neuroimaging features of SCN3A ‐related neurodevelopmental disorder. Methods Patients were ascertained via an international collaborative network. We compared sodium channels containing wild‐type vs. variant Nav1.3 subunits co‐expressed with β1 and β2 subunits using whole‐cell voltage clamp electrophysiological recordings in a heterologous mammalian system (HEK‐293 T cells). Results Of 22 patients with pathogenic SCN3A variants, most had treatment‐resistant epilepsy beginning in the first year of life (16/21, 76%; median onset, 2 weeks), with severe or profound developmental delay (15/20; 75%). Many, but not all (15/19; 79%), exhibited malformations of cortical development. Pathogenic variants clustered in transmembrane segments 4–6 of domains II‐IV. Most pathogenic missense variants tested (10/11; 91%) displayed gain of channel function, with increased persistent current and/or a leftward shift in the voltage dependence of activation, and all variants associated with malformation of cortical development exhibited gain of channel function. One variant (p.Ile1468Arg) exhibited mixed effects, with gain and partial loss of function. Two variants demonstrated loss of channel function. Interpretation Our study defines SCN3A‐ related neurodevelopmental disorder along a spectrum of severity, but typically including epilepsy and severe or profound developmental delay/intellectual disability. Malformations of cortical development are a characteristic feature of this unusual channelopathy syndrome, present in over 75% of affected individuals. Gain of function at the channel level in developing neurons is likely an important mechanism of disease pathogenesis

Termination of Pregnancy due to Fetal Abnormalities Performed after 23 Weeks’ Gestation: Analysis of Indications in 144 Cases from a Single Medical Center

&lt;i&gt;Background/Aims:&lt;/i&gt; To assess the indications for late termination (≥23 weeks’ gestation) of pregnancy (LTOP), and to evaluate the rate of cases potentially diagnosable earlier. &lt;i&gt;Methods:&lt;/i&gt; Cases of singleton pregnancy ending in LTOP due to fetal abnormalities in our institute between 1/1998 and 12/2005 were retrospectively reviewed. The women were divided into two groups according to the sequence of events that led to LTOP: Group 1 – the first test indicating an abnormal finding was performed ≤23 weeks’ gestation, but LTOP was performed &gt;23 weeks; Group 2 – the first test indicating an abnormal finding was performed ≥23 weeks of gestation, or the fetal prognosis was not certain at the time of diagnosis and there was a medical recommendation to continue investigation. &lt;i&gt;Results:&lt;/i&gt; There were 144 cases of LTOP (average gestational age 26.2 ± 3.4 weeks). More than 70% of the cases were aborted because of chromosomal/genetic indication in Group 1; many of them could have been detected earlier in pregnancy, while about 80% of the cases were aborted because of structural abnormalities in Group 2 (p &lt; 0.001). The structural anomaly could have been diagnosed earlier in 56 cases (∼74%) if the pregnant woman had undergone an earlier anomaly scan. In another 13 cases (9%), fetal prognosis was not certain and continuing prenatal investigation was required. &lt;i&gt;Conclusions:&lt;/i&gt; The most common indications for LTOP were structural abnormalities (91 cases, 70%) which included the central nervous system (26 cases, 29%), cardiac abnormalities (24 cases, 26%), and multiple malformations (18 cases, 20%). The diagnosis of fetal anomaly could have been made earlier in more than half of the pregnant women undergoing LTOP.</jats:p

Fetal abnormalities leading to third trimester abortion: nine-year experience from a single medical center.

http://dx.doi.org/10.1002/pd.218